Ibrutinib/Rituximab Improves PFS in Waldenström's Macroglobulinemia

SUNDAY · JUNE 3, 2018 A HIGHLIGHTS Ibrutinib/Rituximab Improves PFS in Immunotherapy MEETING COVERAGE Now Standard BCMA-Directed CAR T Cells in Relapsed/Refractory Waldenström’s Macroglobulinemia for Some Patients Multiple Myeloma 3A he combination of ibruti- David A. Karnofsky Memorial Dr. Meletios A. Dimopoulos With CRC Lecture Highlights 3A nib and rituximab signifi - Patient-Reported Outcomes, cantly improved progres- Mobile Technology, and sion-free survival (PFS) ith recent approvals Response Burden 4A Tand response rates compared to of pembrolizumab Seeking a ‘Better Mousetrap’ placebo plus rituximab in pa- and nivolumab for for HER2-Positive Tumors 6A tients with Waldenström’s mac- the treatment of roglobulinemia (WM), accord- Wrefractory defi cient mismatch NCI Director Highlights Progress, Challenges in Cancer Research 6A ing to a prospective randomized repair (dMMR) metastatic Carfi lzomib Dosing for Relapsed/ trial (Abstract 8003) presented colorectal cancer (CRC), im- Refractory Multiple Myeloma 7A during an Oral Abstract Session munotherapy has made its way Expanding the Uses of on June 1. into the fi eld of gastrointesti- Cell-Free DNA Assays 7A “Waldenström’s macroglobu- nal oncology. Many questions In Briefs 8A linemia is an unusual disease,” remain, however, including Much Work Remains to Determine said Meletios A. Dimopoulos, optimal approaches to dMMR Optimal Immunotherapy MD, of the National and Kapo- cancers and reasons for a lack of Combinations 19A distrian University of Athens, used to treat WM. Dr. Dimo- tients) or placebo (75 patients), effi cacy seen in profi cient MMR FDA Commissioner Discusses Greece. It is characterized by poulos presented results from a both in combination with ritux- (pMMR) CRC. Experts discussed How Agency Plans to Speed serum monoclonal immuno- planned interim analysis of the imab infusions of 375 mg/m2/ these issues and the manage- Access to Cancer Advances 21A globulin M (IgM) levels and iNNOVATE trial that added the week at weeks 1 to 4 and 17 to ment of immunotherapy tox- PHYSICIAN-AUTHORED by infi ltration of bone mar- Bruton’s tyrosine kinase inhibi- 20. In both groups, 45% of pa- icities during the Education Expert Editorials row and of organs by IgM- tor ibrutinib to rituximab. tients were treatment naive. Pa- Session, “Where We Stand With Recognizing Patients With Anxiety producing lymphoplasmacytic The study included 150 patients who had received a prior Immunotherapy in Colorectal or Depression Symptoms 14A cells. Rituximab, which has tients with confi rmed symp- rituximab-based therapy were Cancer,” held June 2. PROs Bring Value 1B shown activity in patients with tomatic WM. They were ran- required to have had a response “dMMR tumors have much Global Health Equity 14B treatment-naive and relapsed or domly assigned to receive either to that treatment. better outcomes than pMMR Assessing the Older Adult refractory disease, is commonly daily ibrutinib (420 mg; 75 pa- See PFS in WM, Page 3A tumor types,” said Michael J. With Cancer 21B Overman, MD, of The Universi- Medical Marijuana 1C ty of Texas MD Anderson Can- PROs in Oncology Practices 12C cer Center, who chaired the session and spoke about optimal Smoking Cessation in LOXO-292 Phase I Results Show Promise Current Practice 15C approaches to dMMR CRC. The Clinical Corners exception to this is in stage IV in the Treatment of RET-Altered Cancers CRC, where the situation is re- Early-Stage Breast Cancer: Duration of Adjuvant versed and dMMR tumors have Chemotherapy 14B earranged during trans- tive tumors (38 NSCLC, nine poorer outcomes than pMMR Complete Resection for fection (RET) is an on- thyroid, two pancreatic), 29 tumors. Approximately 15% Second-Line Ovarian cogene activated by RET (35%) had RET-mutant MTC, of all CRCs have dMMR, but Cancer Treatment 21B fusions or RET muta- and four patients (5%) had this decreases as stage increas- Anthracycline in Rtions. RET fusions are associ- other types of cancer. Twelve es.1 Only about 4% of stage IV Breast Cancer 26C ated with 2% of non–small cell patients (15%) had brain me- CRCs demonstrate dMMR. ASCO NEWS lung cancers (NSCLCs), 10%- tastases. “This was a heavily MMR is a mechanism used by New Guidelines Provide 20% of papillary and other pretreated population, with cells to repair damaged DNA, Additional Options for Reducing thyroid cancers, and smaller two-thirds of patients having particularly during DNA repli- Breast Cancer Recurrence 9A proportions of other cancers. previously received a multiki- cation. Defi ciency in this sys- Bone-Modifying Agents in In addition, RET mutations are nase inhibitor, many of whom tem leads to an accumulation of Multiple Myeloma 4B commonly found in medullary were treated with more than See Immunotherapy and CRC, Page 18A 2018 GU Cancers thyroid cancers (MTCs). one agent,” Dr. Drilon noted. Symposium Recap 6B LOXO-292 is a highly se- Patients received LOXO-292 Guideline on Global lective RET inhibitor that has at doses ranging from 20 mg Palliative Care 16B shown effi cacy in preclini- once daily to 240 mg twice a Why I Attend: cal models. Alexander Drilon, day; the MTD has not been Dr. Leslie Samuel 18B MD, of Memorial Sloan Ketter- reached. LOXO-292 was well Tip of In the Journals: mRCC in ing Cancer Center, presented tolerated. The most frequently Low-Resource Settings 30B data from the phase I open- Dr. Alexander Drilon reported (≥ 10% overall) treat- the Day Looking Back: label study of the RET inhibi- were allowed. The primary ment-emergent adverse events Download ASCO Daily First Antibody-Drug Conjugate 8C tor LOXO-292 (LIBRETTO001; endpoint of the study was the (AEs) were fatigue (20%), di- News Podcasts Palliative Care Abstract 102). Eligible patients determination of the maxi- arrhea (16%), constipation in the Philippines 9C were age 12 or older with ad- mum tolerated dose (MTD). (15%), dry mouth (12%), nau- The ASCO Daily News SPECIAL AWARDS vanced or metastatic solid Secondary endpoints includ- sea (12%), and dyspnea (11%). podcast series features Science of Oncology Award: tumors refractory to or intol- ed safety, pharmacokinetics, Most AEs were grade 1. Two oncology thought leaders Dr. Douglas R. Lowy 1B erant of standard treatment. overall response rate (ORR; grade 3 treatment-related AEs discussing the latest Gianni Bonadonna Breast LOXO-292 was administered RECIST 1.1), and duration of occurred: tumor lysis syndrome research and therapies in Cancer Award: in 28-day cycles, with the dose response. (the only dose-limiting toxic- their areas of expertise. The Dr. Gabriel Hortobagyi 1C escalation following a 3 + 3 de- As of April 2, 82 patients ity) and increased alanine ami- series is available on iTunes, Young Investigator Award: sign. Dose escalation among (40 women, 42 men) had been notransferase. Google Play, and Libsyn. Dr. Bishoy M. Faltas 30C patients and additional enroll- treated. Forty-nine patients The ORR was 77% (95% CI ment at doses considered safe (59%) had RET fusion–posi- See LOXO-292 Phase I, Page 8A STRIVING TO OUTSMART CANCER. TOGETHER.

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PFS in WM BCMA-Directed CAR T Cells Yield Deep, Durable Continued from page 1A

Responses in Relapsed/Refractory Multiple Myeloma After a median follow-up of 26.5 months, the ibrutinib/rituximab com- he bb2121 chimeric antigen re- T-cell persistence than the CD28 costim- penia (79%), thrombocytopenia (51%), bination resulted in a signifi cantly pro- ceptor (CAR) T-cell therapy engi- ulatory domain used in other CAR T-cell and anemia (44%) predominated as the longed PFS. In that group, the median neered to target B-cell maturation therapies, as well as a CD3 zeta T-cell ac- most common treatment-emergent ad- PFS was not yet reached compared with antigen (BCMA) holds great prom- tivation domain. verse events of grade 3 or higher and 20.3 months with placebo (HR 0.20, Tise for the treatment of multiple myelo- CRB-401 represents the phase I dose- were largely associated with the condi- 95% CI [0.11, 0.38]; p < 0.0001). At ma (MM). In 22 evaluable patients who escalation and dose-expansion study tioning chemotherapy, according to Dr. 30 months, the PFS rate was 82% with received 150-450 × 106 bb2121 CAR T evaluating the preliminary effi cacy and Raje. ibrutinib and 28% with placebo. Inves- cells in a phase I study, the objective re- safety of bb2121 in patients with re- CRS, now recognized as one of the tigator-assessed PFS was similar to the sponse rate reached 95.5%, and 50.0% of lapsed/refractory MM. As of March 29, most prevalent and dangerous adverse IRC assessment. individuals achieved complete response 2018, 43 patients had received bb2121 effects following infusion of CAR T-cell This advantage was seen across all rele- (Abstract 8007). (dose, 50-800 × 106 CAR T cells) after un- therapy, has proven manageable in CRB- vant subgroups. These included patients As Noopur S. Raje, MD, of Massachu- dergoing lymphodepletion with fl udara- 401. No grade 4 or grade 5 CRS events with treatment-naive disease (HR 0.34, setts General Hospital Cancer Center, bine and cyclophosphamide. occurred, and the two cases of grade 3 95% CI [0.12, 0.95]) as well as patients underscored during her presentation of Prior assessment of the dose-escalation CRS resolved within 24 hours. who relapsed. In patients who relapsed, these data, the fi ndings are particularly portion of CRB-401 garnered bb2121 a Dr. Raje indicated that the CRB-401 the 30-month PFS rate was 80% with impressive considering that this was an breakthrough therapy designation from fi ndings have prompted a global pivotal ibrutinib and 22% with placebo. extremely heavily pretreated popula- the U.S. Food and Drug Administra- phase II trial of bb2121 called KarMMa Data on MYD88L265P and CXCR4WHIM tion. The 22 individuals noted above tion in November 2017. With the dose- that is currently open for enrollment in mutations were available in 136 pa- had received a median of eight prior expansion data now available, the fi nd- North America and Europe. Moreover, tients. The PFS advantage with ibru- regimens (range, 3-23) for MM, and 32% ings show that patients need a minimum additional trials in earlier lines of my- tinib was seen in patients who had were refractory to bortezomib, lenalido- bb2121 dose of 150 × 106 CAR T cells eloma are planned. MYD88L265P but wild-type CXCR4 (HR mide, carfi lzomib, pomalidomide, and to achieve optimal outcomes. The ob- 0.165, 95% CI [0.06, 0.49]); those who daratumumab. jective response rate steadily increased Dr. Parameswaran Hari had both MYD88L265P and CXCR4WHIM from 33.3% with 50 × 106 CAR T cells, mutations (HR 0.237, 95% CI [0.09, Dr. Noopur S. Raje to 57.1% with 150 × 106 CAR T cells, to 0.66]); and in those with both wild- 95.5% with more than 150 × 106 CAR T type variants, although this did not cells. Similarly, median progression-free reach statistical signifi cance (HR 0.214, survival extended to 11.8 months for 95% CI [0.04, 1.1]). patients who received at least 150 × 106 The overall response rate was 92% CAR T cells, as compared to 2.7 months with ibrutinib plus rituximab compared for patients who received lower doses. to 47% with placebo and rituximab (p Dr. Raje highlighted the impressive < 0.0001); the major response rates for depth of response to bb2121. Of 16 pa- the two groups were 72% and 32%, re- tients with morphologic complete respectively (p < 0.0001). There was a mission who were evaluated for the pres- Discussant Parameswaran Hari, MD, of more rapid decline in IgM levels with ence of minimal residual disease (MRD), the Medical College of Wisconsin, laud- ibrutinib, and 73% of all patients treated all of them—100%—showed no trace of ed the rapidity and depth of response ob- with ibrutinib saw an improvement in MM in the bone marrow at one or more served with bb2121 in MM. However, he hemoglobin compared with 41% of pa- bb2121 is the most mature CAR T-cell time points. Median progression-free could not help but be disappointed by tients receiving a placebo (p < 0.0001). approach undergoing development in survival for these individuals was 17.7 the median PFS of 17.7 months among Dr. Dimopoulos noted that this is an im- MM. The therapy leverages a lentiviral months. patients with MRD-negative disease, portant outcome with regard to patient vector system to modify autologous T The safety profi le of bb2121 appears which refl ects eventual relapse. “Unfor- quality of life. cells to home in on BCMA, a member relatively well-tolerated up to doses as tunately, this is not yet a cure,” Dr. Hari The median time to next treatment of the TNF superfamily and the latest high as 800 × 106 CAR T cells. The most commented. was not reached in the ibrutinib group promising target in MM. bb2121 in- common treatment-emergent adverse Dr. Hari suggested, as did Dr. Raje, that compared with 18 months in the pla- cludes the 4-1BB costimulatory domain events overall included neutropenia applying bb2121 in an earlier line of cebo plus rituximab group (HR 0.096; p that triggers T-cell activation after anti- (81%), cytokine release syndrome (CRS; therapy might prove more effective for < 0.0001). Overall survival data were not gen binding, which is associated with 63%), thrombocytopenia (61%), infec- conferring long-lasting MM remission. yet mature. less acute toxicity and more durable CAR tion (61%), and anemia (56%). Neutro- –Kara Nyberg, PhD Grade 3 or higher treatment-emergent adverse events occurred in 60% of patients treated with ibrutinib/rituximab and in 61% of those treated with placebo/rituximab. Serious adverse events ASCO Honors Radiation Oncologist Dr. Ralph occurred in 43% and 33% of patients, respectively; there were three fatal ad- Weichselbaum With David A. Karnofsky Memorial Award verse events with placebo/rituximab and none with ibrutinib/rituximab. IgM alph R. Weichselbaum, MD, ac- Ludwig Distinguished Service Professor fl are of any grade occurred in 8% of the Dr. Ralph R. Weichselbaum cepted the 2018 David A. Karnof- of Radiation and Cellular Oncology at ibrutinib group and in 47% of the pla- sky Memorial Award and Lecture the University of Chicago Medicine and cebo group. June 2 for his contributions to the co-director of the Ludwig Center at the “This is a combination with remark- Rfi eld of radiation oncology. Dr. Weichsel- University of Chicago. In his award lec- able activity as far as PFS is concerned,” baum was honored for his work defi n- ture, “Oligometastasis From Conception Dr. Dimopoulos said. “[It is] well- ing the state of oligometastases and for to Treatment,” he outlined the frame- tolerated, becoming a new standard of developing new areas for innovation in work of the signifi cant hypotheses and care for this disease.” translational research. subsequent fi ndings that have driven his Craig C. Hofmeister, MD, MPH, of Daniel F. Hayes, MD, FACP, FASCO, Im- research interests over the course of his The Ohio State University, was the dis- mediate Past President of ASCO, present- career. cussant for the abstract. He said that the ed the award that is bestowed on those One important area of Dr. Weichsel- high response rate in patients with the whose clinical research has “changed the baum’s research was defi ning, along MYD88L265P mutation make it particu- way we practice oncology.” In accepting with his colleague Samuel Hellman, MD, larly appealing in that setting. He also the award, Dr. Weichselbaum said he was FASCO, the clinical state of oligometas- these metastases to a single or a lim- pointed out that atrial fi brillation and “extremely honored,” particularly given tasis, which they hypothesized refers ited number of organs.…An attractive infections should be closely monitored the “academic and clinical accomplish- to a distinct clinical entity. For certain consequence of the presence of a clini- when using this combination. ments of [the] previous recipients.” tumors, they said, “the anatomy and cally signifi cant oligometastatic state is –Dave Levitan Dr. Weichselbaum is the Daniel K. physiology may limit or concentrate See Karnofsky Memorial Award, Page 22A A 4 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Patient-Reported Outcomes, Mobile Technology, and Response Burden

he value of patient-reported up arm were eligible to cross over to the using wearable technology, and explore Dr. Fabrice Denis outcomes (PROs) on increasing web-based arm. the ability of the emoji to assess PROs. physician awareness of patients’ After 2 years of follow-up, 70 deaths Recruited adult patients had a range of functioning and well-being can occurred and the median OS was 22.5 different cancers with a life expectancy Tbe useful, but it can have drawbacks de- months in the web-based follow-up arm of at least 6 months. All patients had an pending on the methods used to assess (60 patients) and 14.9 months in the iPhone version 5.0 or higher and received the PROs, according to several presenta- standard follow-up arm (61 patients), an Apple Watch. Dr. Thompson and col- tions at the “Health Services Research, without adjustment for cross-over leagues created the study app by using Clinical Informatics, and Quality of from the control arm (HR 0.594, 95% Care” Oral Abstract Session, held June 1. CI [0.368, 0.959]; p = 0.03). Censoring Dr. Carrie A. Thompson cross-over resulted in a hazard ratio of Web-Based Monitoring 0.496 (95% CI [0.305, 0.806]; p = 0.004). In the fi rst of three presentations on Other studies have evaluated intensive PROs (Abstract 6500), Fabrice Denis, follow-up, Dr. Denis said, “but our ran- MD, PhD, of the Jean Bernard Cancer domized study is the fi rst assessing the Institute, France, said using a web-based survival rates as a primary outcome.” Fu- monitoring system to follow patients ture plans include initiating large (more with lung cancer resulted in an overall cancer with our algorithm,” Dr. Denis than 1,000 patients), multicenter, inter- survival (OS) that was signifi cantly high- said. “Those fi rst results suggested a national studies in other cancers; a simi- er than that with routine follow-up by 1-year survival that was 27% greater in lar program will be available soon for CT scans alone. patients with our web-mediated follow- cancer screening among patients who An overwhelming majority of lung up than in patients with a standard smoke. cancer relapses are symptomatic—some- follow-up.” where between 75% and 90%, he said, The confi rmatory phase III, random- Emojis and the Apple Watch but patients may have symptoms weeks ized, multicenter study enrolled 133 pa- In a second study (Abstract 6501), Car- before a follow-up visit with their treat- tients with lung cancer (either small cell rie A. Thompson, MD, of the Mayo Clin- Apple’s ResearchKit, which is an opening physician. Moovcare is an algorithm [SCLC] or non–small cell) who had inter- ic, reported on the ability of an emoji source framework for building medical based on the chaos theory model that net access (12 were deemed ineligible af- available on the Apple Watch to assess research, that the patients downloaded reports on 12 symptoms every week, ter randomization); of the remaining 121 patient-reported quality of life (QOL). to their iPhones and watches. with notifi cations sent to nurses and/or patients, median age was 65, 41% were The aims of the study were 3-fold: to “All patients were asked to wear the oncologists. receiving maintenance or tyrosine ki- develop technology to measure physical Apple Watch for a minimum of 8 hours “In a nonrandomized study, we as- nase inhibitors, and 17% had SCLC. At 9 activity and PROs using the Apple Watch per day for 12 weeks, from which we sessed the survival of 98 patients after months, OS improvement was observed and iPhone, determine feasibility and collected physical activity data,” Dr. their treatment for a stage III/IV lung and patients in the standard follow- patient acceptability of collecting PROs See Patient-Reported Outcomes, Page 20A 3 DISTINCT INDICATIONS APPROVED FOR YOUR PATIENTS1

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herapies that target the protein cancers, and other solid tumors (endo- breast, HER2-high and -intermediate Dr. Dennis J. Slamon HER2 have changed the landscape metrial, salivary gland, and colorectal). gastroesophageal (GE), and other HER2- of cancer treatment, improv- Initially, seven patients were enrolled high cancers. High HER2 expression was ing survival in advanced HER2- in each cohort, and an interim response defi ned as immunohistochemistry 3+ or Tpositive breast and gastric cancers. But analysis was performed for each cohort. 2+/fl uorescent in situ hybridization pos- researchers at multiple centers are striv- If no response was seen in a cohort, it itive. Patients enrolled had progressive ing to further improve outcomes in these was closed to accrual. If response was disease after standard of care, including HER2-expressing cancers. During the seen in at least one patient in a cohort, HER2-targeted agents. “Developmental Therapeutics—Clinical 11 more patients were enrolled in that At the time of this interim analysis, Pharmacology and Experimental Thera- cohort, for a total of 18 patients. 42 patients had been treated in parts 1 peutics” Oral Abstract Session on June Patients received ado-trastuzumab em- and 2, with a median age of 63 (range, 1, speakers discussed novel strategies tansine at 3.6 mg/kg every 3 weeks until 27-79) and a median number of previous for addressing HER2-driven tumors, in- progression or unacceptable toxicity. The systemic regimens of fi ve (range, 0-17). cluding two new, promising agents and primary endpoint was overall response Cancer diagnoses included breast (20 additional indications for a recently ap- rate (ORR), a combination of complete patients; 48%), GE (13 patients; 31%), proved agent. response (CR) and partial response (PR) colorectal (5 patients; 12%), and other Bob T. Li, MD, MPH, of Memorial as measured by RECIST v1.1. Secondary 3 thrombocytopenia. There were no tumors (4 patients; 9%). Sloan Kettering Cancer Center, discussed endpoints included progression-free sur- treatment-related deaths. No dose-limiting toxicities were ob- results with the recently approved vival (PFS), duration of response (DOR), Discussant Dennis J. Slamon, MD, served at any of the dose levels evaluat- agent—ado-trastuzumab emtansine—in and adverse events (AEs). PhD, of the David Geffen School of Med- ed. Treatment-related AEs were all grade a multi-histology basket trial including In total, 62 patients were treated, with icine at the University of California, Los 1 or 2, except for reversible grade 3 hy- patients with HER2-amplifi ed or HER2- a median age of 63 (range, 34-90). The Angeles, congratulated the authors for pophosphatemia, arthralgia, and fatigue mutated cancers (Abstract 2502). median number of lines of previous sys- demonstrating that “molecular altera- in one patient receiving the 10 mg/kg temic therapy was two (range, 1-7), and tion trumps histology” and that multi- weekly dose. There were no treatment- Dr. Bob T. Li the ORR was 28% (16/57; 95% CI [17, ple tumor types with HER2 amplifi cation related serious AEs or discontinuations, 42]). Median PFS was 3 months (95% CI respond to ado-trastuzumab emtansine. no left ventricular ejection fraction de- [4, 7]), and median DOR was 8 months Results with two new agents targeting creases of 10% or greater during treat- (range, 2 - >25). HER2 were also presented at the session. ment, and no new detectable anti-drug The researchers also looked at results Funda Meric-Bernstam, MD, of The Uni- antibodies. for individual HER2-amplifi ed cohorts. versity of Texas MD Anderson Cancer For lung cancers, the ORR was 43% Center, presented an interim analy- (3/7; 95% CI [10, 82]), median PFS was sis of single-agent activity of ZW25, a 7 months (95% CI [3, 13]), and medi- HER2-targeted bispecifi c antibody, in an DOR was 5 months (range, 5-17+). patients with heavily pretreated HER2- For endometrial cancers, ORR was 25% expressing cancers (Abstract 2500). She (5/20; 95% CI [9, 49]), median PFS was explained that ZW25 is biparatopic, 3 months (95% CI [2, 9]), and median which simultaneously binds to two DOR was not reached (range, 2 - >25). HER2 epitopes, resulting in novel mech- This single-center phase II trial found For salivary gland cancers, ORR was anisms of action, including increased that “ado-trastuzumab emtansine 100% (6/6; 95% CI [54, 100]), median tumor cell binding and improved recep- showed clinical effi cacy against HER2- PFS was 9 months (95% CI [4, 12]), and tor internalization and downregulation amplifi ed lung, endometrial, salivary median DOR was not reached (range, relative to trastuzumab. Dr. Funda Meric-Bernstam gland, and other cancers,” Dr. Li said. 2 - >10). In this two-part phase I study, ZW25 The trial met its primary endpoint, he Overall, the researchers found that was well tolerated at all dose levels in- Decreases in target lesions were seen added, “and further development is war- the degree of HER2 amplifi cation cor- vestigated and showed promising an- in most patients with measurable dis- ranted in these HER2-amplifi ed cancers.” related with response, but not all HER2- titumor activity in multiple cancers, ease. Of 18 patients with breast cancer, The trial enrolled patients with ad- amplifi ed cancers responded, Dr. Li Dr. Meric-Bernstam said. Part 1, a dose- six (33%) had a PR and three (17%) had vanced solid tumors with HER2 ampli- noted. The ORRs for HER2-amplifi ed escalation study, evaluated 5, 10, and 15 stable disease (SD). In nine patients with fi cation as identifi ed by next-generation colorectal cancers and for bladder and mg/kg of ZW25 weekly and 20 mg/kg bi- GE cancer, four (44%) had a PR and one sequencing (NGS) and patients with urinary tract cancers were both 0%, and weekly to identify a recommended dose (12%) had SD. In six patients with other HER2-mutated lung cancer. Patients these cohorts were not expanded. for further study. cancers, two (33%) had a PR and two were divided into four cohorts: HER2- Regarding safety, most AEs in the Part 2 of the study is ongoing, evalu- (33%) had SD. mutant lung cancers, HER2-amplifi ed study were grades 1 or 2, with one grade ating safety and effi cacy in separate ex- Dr. Meric-Bernstam said the single- lung cancers, bladder and urinary tract 3 febrile neutropenia and one grade pansion cohorts, including HER2-high See HER2-Positive Tumors, Page 8A

NCI Director Highlights Progress, Challenges in Cancer Research

ast week, the National Cancer In- get passed by Congress this year provid- that many are just starting to appreciate, stitute (NCI) of the National Insti- ed a $275 million increase for the NCI but that “clearly can be devastating for tutes of Health (NIH) released its budget, as well as full continued funding cancer survivors.” 2018 Annual Report to the Nation for the Cancer Moonshot, he said. Dr. Sharpless identifi ed four areas he Lon the Status of Cancer. During the June With improving survival, successful wants the NCI to focus on during his 2 Opening Session, NCI Director Nor- treatment approaches, and continued term: continued support of basic sci- man E. Sharpless, MD, was on hand to support for research, there is good reason ence; development of a modern, diverse highlight for Annual Meeting attendees for the oncology community to be opti- workforce; effective harnessing of big the top-line good news from the report: mistic. “The potential for breakthroughs data; and innovation and progress in Overall cancer death rates continue to has never, I believe, been greater than it clinical trial design. decrease for men, women, and children is now,” he said. Regarding the fi rst of those foci, sup- in all major racial and ethnic groups. At the same time, signifi cant chal- port for basic science, Dr. Sharpless an- But Dr. Sharpless brought other good lenges remain, including certain cancer nounced that this year he has earmarked news as well: “the strong and bipartisan types, such as glioblastoma, that remain an additional $127 million for research support we’ve been receiving from Con- resistant to treatment efforts, and the project grants for investigator-initiated gress for cancer research,” with budget toxicities that accompany some treat- science. This announcement received a increases for the NCI and the NIH for the ments—including, he noted, fi nancial robust round of applause. fourth year in a row. The omnibus bud- toxicity, a complication of treatment Dr. Norman E. Sharpless –Tim Donald, ELS am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 7 A Once-Weekly Dosing With Carfi lzomib Promising for Relapsed/Refractory Multiple Myeloma

atients with relapsed or refractory was 7.1% in the once-weekly group vs. Dr. María-Victoria Mateos multiple myeloma treated with 1.7% in the twice-weekly group. Among once-weekly carfi lzomib had a patients treated with the once-weekly higher response rate than patients regimen, 27.1% had a very good partial Ptreated with the twice-weekly regimen response vs. 11.8% of patients treated in the ARROW study, introducing the twice weekly. potential for more convenient dosing Median duration of treatment in the for patients. once-weekly group was 38 weeks with María-Victoria Mateos, MD, PhD, of carfi lzomib and 37.1 weeks with dexa- the University Hospital of Salamanca, methasone; in the twice-weekly group, Spain, presented results of the phase III the median duration of treatment was trial during the “Hematologic Malig- 29.1 weeks with both carfi lzomib and nancies—Plasma Cell Dyscrasia” Oral dexamethasone. Abstract Session on June 1 (Abstract Dr. Mateos said that the safety fi nd- 8000). According to the trial results, the ings “were consistent with the known once-weekly regimen signifi cantly im- safety profi le of carfi lzomib” and that proved progression-free survival by 3.6 “no new risks were identifi ed.” The per- months, reducing the risk of progres- centage of grade 3 or higher adverse sion or death by 30.7% compared with events was 67.6% in the once-weekly the twice-weekly treatment regimen. carfi lzomib with dexamethasone for pa- Patients in the twice-weekly arm were group vs. 61.7% in the twice-weekly “In comparison with the twice- tients with relapsed or refractory mul- treated with carfi lzomib (10-minute in- arm; the percentage of treatment-related weekly schedule, once-weekly carfi lzo- tiple myeloma. fusion) on days 1, 2, 8, 9, 15, and 16, grade 5 adverse events was 2.1% in the mib showed a favorable benefi t-risk pro- The two-arm ARROW study, an inter- with 20 mg/m2 on days 1 and 2 during once-weekly group vs. 0.9% in the twice- fi le with a more convenient dosing regi- national trial conducted at about 100 the fi rst cycle and then 27 mg/m2 for weekly group. men,” Dr. Mateos said during the session. sites, included 478 patients who had each subsequent treatment. All patients Discussant Noopur S. Raje, MD, of The phase I/II CHAMPION-1 study1 received two to three prior therapies received 40 mg dexamethasone on days Massachusetts General Hospital, said the had earlier assessed once-weekly carfi l- and had prior exposure to a proteasome 1, 8, and 15 of all cycles; they all also re- ARROW trial results present important zomib plus dexamethasone in an effort inhibitor and an immunomodulatory ceived 40 mg of dexamethasone on day considerations for future study, includ- to fi nd a more convenient treatment drug. Patients were randomly assigned 22 for cycles one through nine only. ing whether there is a more convenient regimen for patients, Dr. Mateos said. 1:1 to receive either once- or twice- Median progression-free survival, the way of administering carfi lzomib and The study established the maximum weekly carfi lzomib plus dexamethasone primary endpoint, was 11.2 months in whether carfi lzomib has a dose response. tolerated dose of carfi lzomib at 70 mg/ in 28-day cycles until disease progres- the once-weekly arm vs. 7.6 months in She pondered, “Will this be the new m2. Based on the promising results of sion or unacceptable toxicity. the twice-weekly arm (HR 0.693, 95% standard of giving carfi lzomib going for- CHAMPION-1, researchers initiated the The once-weekly group received carfi l- CI [0.544, 0.883], p = 0.0029). The over- ward?” ARROW study to compare the once- zomib (30-minute infusion) on days 1, all response rate, a secondary endpoint, –Kathy Holliman, MEd weekly regimen of 70 mg/m2 of carfi l- 8, and 15 of all cycles, with a 20 mg/m2 was 62.9% in the once-weekly group zomib with dexamethasone to a dose on day 1 of the fi rst cycle and 70 vs. 40.8% in the twice-weekly group (p Reference: twice-weekly regimen of 27 mg/m2 of mg/m2 for each subsequent treatment. < 0.0001). Complete response or better 1. Berenson JR, et al. Blood. 2016;127:3360-8.

Expanding the Uses of Cell-Free DNA Assays: From Guiding Treatment Decisions to Applications in Early Disease Detection

nalyzing cell-free DNA (cfDNA) rently, cfDNA assays are being used in cfDNA assays focus on treating patients Dr. Maximilian Diehn circulating in plasma or serum the clinic for genotyping patients with with early-stage cancer, including de- can help oncologists deter- advanced cancer who cannot have or tecting disease, monitoring local treat- mine the genotype of tumors refuse to have biopsies to monitor treatment response such as radiotherapy, de- Anoninvasively to guide treatment deci- ment response and detect resistance tecting minimal residual disease (MRD), sions and may eventually allow them variants. and surveillance, explained Dr. Diehn. to monitor treatment response, predict However, cfDNA assays have techni- Assays for detecting MRD could have recurrence, and screen for cancer. cfDNA cal limitations; it can be diffi cult to de- particular clinical utility for monitor- is released into the blood following the tect ctDNA. The polymerase chain reac- ing adjuvant therapy and determining death of normal and cancer cells, and tion (PCR)–based assays, which detect a whether to avoid or escalate adjuvant in patients with cancer the circulating single mutation or panel of mutations therapy, he said. There are currently no tumor DNA (ctDNA) has been shown to and are typically used clinically to guide MRD assays for solid tumors. bear the same tumor-related mutations treatment decisions, have a sensitivity of To that end, Dr. Diehn and colleagues and other genetic alterations found in 0.05% to 0.1% in a 10-mL blood draw. developed an assay called CAPP-Seq tissue from tumor biopsies. Yet these assays can fail to pick up po- (Cancer Personalized Profi ling by Deep The Education Session “Liquid Bi- tentially clinically important alterations. Sequencing)—a next-generation se- opsies: Current Uses and Future Direc- Next-generation methods such as quencing capture-based assay that looks tients with stage I-III localized lung can- tions,” held June 2, covered cfDNA ad- whole-genome or whole-exome se- at approximately 300 common cancer cer prior to curative treatment and fol- vantages and limitations compared with quencing, which have the advantage genes and detects all the major classes of lowing the fi rst treatment. They found analyzing tumor tissue and new technol- of being able to look broadly, currently mutations. CAPP-Seq can be performed that the patients who had detectable ogies in development. have a sensitivity of only about 1.0% be- as either a naive detection method or a ctDNA following treatment went on to “One of the exciting things in this cause the cost of the technology is still tumor-informed detection method, in have disease recurrence, whereas among fi eld is that you can imagine using these prohibitively expensive, which prevents which a tumor biopsy has already been patients with no detected ctDNA, only assays anywhere along a patient’s care adequately high sequence coverage for performed and the same mutations that one patient had recurrence, and the pres- trajectory,” from localized disease to me- better detection, Dr. Diehn explained. were found in the tumor tissue can be ence of ctDNA correlated with disease- tastasis and recurrence, said Maximilian probed in the cfDNA sample. specifi c survival. The levels of ctDNA Diehn, MD, PhD, of the Stanford Cancer Emerging Clinical Applications In one study, Dr. Diehn and colleagues in this cohort were very low, between Institute, who opened the session. Cur- Many of the emerging applications for collected plasma prospectively from pa- See Cell-Free DNA Assays, Page 21A A 8 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

LOXO-292 Phase I 68]). Disease regres- Dr. Christine Marie Lovly Continued from page 1A sion occurred in most patients, indepen- [61, 89]) in 39 evaluable patients with dent of starting dose Systemic Therapy Costs and Use in RET fusion–positive cancers, 77% (95% or RET mutation. No Patients With mCC CI [58, 90]) in 30 evaluable patients responses were seen Abstract LBA3579 with NSCLC, and 78% (95% CI [40, 97]) in the three evalu- Use and cost of systemic therapy for in patients with other RET fusion–posi- able patients without metastatic colorectal cancer is signifi cantly tive cancers. Importantly, responses in a known activating higher for patients in western Washington RET fusion–positive cancers occurred RET alteration. state in the United States compared to regardless of tumor type, RET fusion “The activity of those in British Columbia, Canada, with no partner, starting dose, or prior therapy. LOXO-292 was du- signifi cant differences in overall survival. Confi rmed intracranial responses were rable, with over 90% Researchers analyzed data from 1,622 observed in the three patients with of patients still on patients in British Columbia and 575 in intracranial disease (Fig. 1). In the 22 treatment as of the Washington. Patients in British Columbia evaluable patients with RET-mutant data cutoff, including all responding pansion cohorts are currently enrolling were more likely to be older (median age, MTC, the ORR was 45% (95% CI [24, patients,” Dr. Drilon said. The study ex- additional patients with RET fusion– 60 vs. 66) and male (57% vs. 48%, p ≤ positive solid tumors, MTC, and other 0.01) than those in Washington. The most Fig. 1. MRI Images of Intracranial Response to LOXO-292 Therapy in a cancers with RET activation. common fi rst-line regimen in British Colum- Patient With CLIP1-RET Fusion-Positive NSCLC. Discussant Christine Marie Lovly, MD, bia was FOLFIRI plus bevacizumab (32%), PhD, of Vanderbilt University, congratu- whereas FOLFOX was the most common CLIP1-RET fusion-positive NSCLC1 lated the investigators on the fi ndings of fi rst-line regimen in Washington (39%). previously received two multikinase inhibitors and chemotherapy the trial. As multikinase inhibitors are The mean monthly cost of fi rst-line not specifi c to RET, they can come with therapy per patient was $12,345 in the off-target effects when treating patients United States vs. $6,195 in Canada (p ≤ with RET rearrangements. “Multikinase 0.01) for all regimens assessed. Mean life- inhibitors have modest activity, with a time monthly costs were also signifi cantly response rate of about 30%, and came higher in Washington ($7,883 vs. $4,830, p with the cost of signifi cant toxicity,” Dr. ≤ 0.01). Overall median survival of patients Lovly said. receiving therapy was similar (21.4 months She found the LOXO-292 AE profi le in Washington vs. 22.1 months in British encouraging, with RET selectivity lead- Columbia), with similar overall median ing to better tolerability. Determining survival among those who did not receive the optimal sequence of treatment, therapy (5.4 months in Washington vs. 6.3 the durability of the central nervous months in British Columbia). system response, effects across differ- Baseline (pre-treatment) Week 4 (post-treatment) ent RET mutations, and mechanisms of Sex May Affect Toxicity of Adjuvant Abbreviation: NSCLC, non–small cell lung cancer acquired resistance are areas for further Chemotherapy in Patients With 1 Initiated treatment at 120 mg BID; dose escalated at C5D1 to 160 mg BID; on study in month 4. study. Colorectal Cancer Brain metastases only observed in RET fusion-positive cancers; April 2, 2018, data cut-off date. –Muriel Cunningham Abstract 3603 Researchers compared major adverse events (nausea, vomiting, stomatitis, diarrhea, leucopenia, neutropenia, anemia, 12.9 months in HER2-low breast cancer. thrombocytopenia, and neuropathy) among HER2-Positive Tumors Dr. Hiroji Iwata Continued from page 6A In HER2-positive gastric cancer, con- 28,636 patients (54% men) in the ACCENT fi rmed ORR was 43.2% (19 of 44 pa- database treated with adjuvant chemother- agent evaluation of ZW25 is ongoing, tients). Median DOR was 7.0 months, apy after curative resection of colorectal and investigators are also evaluating and median PFS was 5.6 months. In oth- cancer. Their results show that women had combinations with other agents in ear- er cancers, confi rmed ORR was 38.7% a signifi cantly higher risk of several grade lier lines of therapy, as well as expand- (12 of 31 patients), median DOR was 3/4 toxicities in three of the chemotherapy ing their dataset with cancers expressing 12.9 months, and median PFS was 12.1 regimens evaluated: single-agent fl uoropy- lower levels of HER2. months. rimidine (5-fl uorouracil [5-FU]), FOLFIRI, and Hiroji Iwata, MD, of Aichi Cancer The drug’s safety profi le was generally FOLFOX. Center, Japan, presented long-term effi - manageable, Dr. Iwata said, although The greatest differences between the cacy and safety data from a phase I study interstitial lung disease (ILD) and pneu- sexes were seen in those treated with of trastuzumab deruxtecan (DS-8201a), a monitis were important identifi ed risks. 5-FU, in which nearly twice as many wom- HER2-targeted antibody-drug conjugate Almost all patients (98.8%) experienced en as men experienced nausea/vomiting (ADC), in patients with HER2-expressing treatment-emergent AEs (TEAEs), and (8.1% vs. 4.3%). A greater percentage of solid tumors (Abstract 2501). half of patients (50.2%) experienced women also experienced stomatitis (7.2% Dr. Iwata explained that in preclinical grade 3 or greater TEAEs. Any-grade vs. 4.4%); diarrhea (20.0% vs. 16.0%); leu- studies, DS-8201a, which targets HER2 positive gastric cancer, and 51 patients drug-related TEAEs occurred in 97.5% of copenia (5.6% vs. 3.1%); and neutropenia cell surface receptors, demonstrated ac- with other cancers. Consistent tumor patients, while those grade 3 or greater (16.0% vs. 11.0%). Under the FOLFOX regi- tivity across a broad range of tumors with shrinkage was seen across all tumor occurred in 41.9%. men, women were nearly twice as likely varying degrees of HER2 cell surface ex- types, whether patients were treated AEs were generally low grade, with the to experience nausea and vomiting (13.0% pression. Investigators hypothesize that with 5.4 or 6.4 mg/kg every 3 weeks. most frequent being gastrointestinal or vs. 6.8%), diarrhea (21.0% vs. 15.0%), and this ADC has a “bystander effect”—the Overall, 86.3% of patients experienced hematologic. As noted, ILD/pneumo- neutropenia (27.0% vs. 18.0%). Signifi cant ability to kill neighboring tumor cells re- tumor shrinkage, and 91.5% of these pa- nitis events were observed, including differences in the FOLFIRI regimen included gardless of their receptor expression. tients showed shrinkage at the time of fi ve fatal cases. There were a total of 10 nausea/vomiting (13.0% vs. 9.6%), diarrhea In this ongoing trial, DS-8201a has fi rst imaging assessment at 6 weeks. The (4.1%) TEAEs leading to death. (21.0% vs. 16.0%), leucopenia (11.0% vs. shown promising antitumor activity in confi rmed ORR in the overall popula- In his discussion, Dr. Slamon asked 7.4%), and neutropenia (40.0% vs. 26.0%). patients with heavily pretreated HER2- tion was 49.3%. two questions: “Do we need a better Although differences in perception positive breast and gastric cancers, Dr. Looking at individual cohorts, in mousetrap for HER2-positive cancers?” could account for the differences in Iwata said. Antitumor activity was also HER2-positive breast cancer, the con- and if so, can we build one? He said gastrointestinal effects, the researchers observed in nonarchetypical HER2- fi rmed ORR was 54.5% (54 of 99 pa- that, if the answer to the fi rst question is noted that they do not explain the sig- expressing tumor types other than breast tients), and in HER2-low breast cancer yes, the drug(s) should enhance effi cacy nificant differences in neutropenia. They and gastric cancers. it was 50.0% (17 of 34 patients). The signals and maintain or improve safety recommended additional investigation At the time of this interim analysis, median DOR was not reached in HER2- profi les. In conclusion, he proposed that and suggested that clinicians may need to the phase I study included 111 patients positive breast cancer and was 11.0 not only can we build a “better mouse- consider sex-specific strategies for drug with HER2-positive breast cancer, a sepa- months in HER2-low breast cancer. trap,” but ongoing research is under way dosing and supportive care. rate cohort of 34 patients with HER2-low Median PFS was also not reached in to do just that. –Debra Gordon breast cancer, 44 patients with HER2- HER2-positive breast cancer and was –Tim Donald, ELS am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 9 A

erature review New Guidelines Provide Additional Options and results from the APH- INITY trial, the for Reducing Breast Cancer Recurrence Expert Panel decided that he use of adjuvant chemotherapy cycles of adjuvant capecitabine after States, there was a fairly substantial ben- oncologists to reduce the recurrence of breast completion of standard preoperative efi t for a high-risk group. So, we felt this can safely add cancer has been linked to signifi - anthracycline and taxane-based combi- was an important option for doctors to 1 year of adju- cant improvements in mortality nation chemotherapy in patients with discuss with patients,” Sharon H. Gior- vant pertuzum- Tand morbidity, including disease-free stage I-III HER2-negative breast cancer dano, MD, MPH, FASCO, of The Univer- ab to this treat- Dr. Sharon H. Giordano survival (DFS) and overall survival (OS), with invasive residual disease at surgery. sity of Texas MD Anderson Cancer Cen- ment regimen, in women with early-stage disease. How- This decision was made based on fi nd- ter and Expert Panel co-chair, said. as it appears to extend invasive DFS. ever, the optimal regimen must be per- ings from CREATE-X, which showed that The second new recommendation Lastly, the Expert Panel considered sonalized, as clinicians weigh the poten- the addition of capecitabine resulted in pertains to the use of adjuvant pertu- whether neratinib should be used as ex- tial life-extending benefi ts of adjuvant signifi cant improvements in DFS and OS. zumab in addition to trastuzumab-based tended therapy for patients with early- treatment against adverse sequelae like “Even though [CREATE-X] was con- combination chemotherapy in patients stage, HER2-positive breast cancer fol- neuropathy, cardiotoxicity, and dimin- ducted in Asia and used a higher dose with high-risk, early-stage, HER2- lowing combination chemotherapy and shed quality of life. than we typically use in the United positive breast cancer. Based on the lit- See New Guidelines, Page 16A In 2016, ASCO published a clinical practice guideline on the selection of optimal adjuvant chemotherapy regimens for early-stage breast cancer and adjuvant targeted therapy for HER2- positive breast cancer, which were adapted from Cancer Care Ontario. But with the recent completion of several large-scale phase III clinical trials, an Ex- pert Panel was convened to review and update the 2016 guidelines according to the latest data. Consequently, ASCO has now published a revised set of guidelines, “Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: American Soci- ety of Clinical Oncology Clinical Prac- tice Guideline Focused Update.”

A Trio of Findings The updated guidelines include a series of potentially practice-changing recommendations designed to improve outcomes in women with early-stage breast malignancies. Three recent phase III randomized controlled trials (i.e., CREATE- X, APHINITY, and ExteNET) on the adjuvant use of capecitabine, pertuzumab, and neratinib, respectively, helped form the basis of the revisions. Changes were implemented following a systematic literature review and discussion by a subset of the original multidisciplinary Expert Panel involved in the development of the 2016 guidelines. “The revisions were made because these three pivotal trials showed important Connecting Research and Practice benefi ts for a subpopulation of patients with breast cancer,” Neelima Denduluri, Recent achievements in medicine have resulted in progress beyond what many could have imagined MD, of The US just decades ago. New science and technology have empowered physicians to make better, faster Oncology Net- work, Virginia treatment decisions. Our understanding of the human genome and targeted drug research is producing Cancer Special- major improvements in treatments for cancer, heart disease, and many other chronic illnesses. ists, and Expert Panel co-chair, Connecting medicine’s thought leaders and practitioners to advances in science and practice is the said. “For exam- unifying goal of the New England Journal of Medicine, NEJM Journal Watch, NEJM Knowledge+, ple, pertuzumab NEJM Catalyst, and NEJM Resident 360, the premier products of NEJM Group. may now be discussed as an additional ther- NEJM Group brings together the people and expertise behind these products to drive innovation and apeutic agent Dr. Neelima Denduluri ensure rigorous quality in our ongoing mission to further advance knowledge, learning, and practice. for those with high-risk HER2-positive disease. Simi- NEJM Group. Working together to advance research and improve care. nejmgroup.org larly, neratinib can be considered after the completion of trastuzumab. And for the fi rst time, we have something in the guidelines for women with residual dis- Visit NEJM Group at booth #20097. ease after standard chemotherapy, allowing us to incorporate an agent that may improve outcomes after surgery.” The fi rst new recommendation concerns the inclusion of up to six to eight Indications IBRANCE® (palbociclib) is indicated for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC) in combination with: • an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women, or • fulvestrant in women with disease progression following endocrine therapy

IBRANCE is the #1 PRESCRIBED FDA-approved oral combination treatment for HR+/HER2- MBC1

Important Safety Information Neutropenia was the most frequently reported adverse reaction women not to breastfeed during IBRANCE treatment and for in PALOMA-2 (80%) and PALOMA-3 (83%). In PALOMA-2, Grade 3 weeks after the last dose because of the potential for serious 3 (56%) or 4 (10%) decreased neutrophil counts were reported in adverse reactions in nursing infants. patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade The most common adverse reactions (≥10%) of any grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in PALOMA-2 for IBRANCE plus letrozole vs placebo reported in patients receiving IBRANCE plus fulvestrant. Febrile plus letrozole were neutropenia (80% vs 6%), infections neutropenia has been reported in 1.8% of patients exposed to (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), IBRANCE across PALOMA-2 and PALOMA-3. One death due to nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis neutropenic sepsis was observed in PALOMA-3. Inform patients (30% vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), to promptly report any fever. rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia Monitor complete blood count prior to starting IBRANCE, (16% vs 1%), vomiting (16% vs 17%), decreased appetite at the beginning of each cycle, on Day 15 of first 2 cycles and (15% vs 9%), dry skin (12% vs 6%), pyrexia (12% vs 9%), as clinically indicated. Dose interruption, dose reduction, or delay and dysgeusia (10% vs 5%). in starting treatment cycles is recommended for patients who The most frequently reported Grade ≥3 adverse reactions (≥5%) develop Grade 3 or 4 neutropenia. in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole Based on the mechanism of action, IBRANCE can cause fetal were neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections harm. Advise females of reproductive potential to use effective (7% vs 3%), and anemia (5% vs 2%). contraception during IBRANCE treatment and for at least Lab abnormalities of any grade occurring in PALOMA-2 for 3 weeks after the last dose. IBRANCE may impair fertility in IBRANCE plus letrozole vs placebo plus letrozole were decreased males and has the potential to cause genotoxicity. Advise male WBC (97% vs 25%), decreased neutrophils (95% vs 20%), patients with female partners of reproductive potential to use anemia (78% vs 42%), decreased platelets (63% vs 14%), effective contraception during IBRANCE treatment and for increased aspartate aminotransferase (52% vs 34%), and 3 months after the last dose. Advise females to inform their increased alanine aminotransferase (43% vs 30%). healthcare provider of a known or suspected pregnancy. Advise IBRANCE is backed by guidelines and unmatched experience in its class

Based upon high-level evidence, there is uniform National Comprehensive Cancer Network® (NCCN®) consensus that both palbociclib (IBRANCE) combination regimens are appropriate interventions.2

Palbociclib (IBRANCE) + Palbociclib (IBRANCE) + NCCN aromatase inhibitor fulvestrant CATEGORY may be considered as a treatment for postmenopausal women or premenopausal option for ﬁrst-line therapy for women receiving ovarian suppression with postmenopausal women with an LHRH agonist with HR+/HER2- MBC that HR+/HER2- MBC2* has progressed on or after prior adjuvant or 1 metastatic endocrine therapy2*

CDK4/6=cyclin-dependent kinases 4 and 6; LHRH=luteinizing hormone-releasing hormone. * If there is disease progression while on CDK4/6 inhibitor therapy, there are no data to support an additional line of therapy with another CDK4/6-containing regimen.2

3+ years 11,500+ prescribers 75,000+ patients since initial FDA approval have chosen IBRANCE1† prescribed IBRANCE1†

†Data projected as of January 2018.1

Visit IBRANCEhcp.com to learn more.

The most common adverse reactions (≥10%) of any grade concomitant use of strong CYP3A inducers. The dose reported in PALOMA-3 for IBRANCE plus fulvestrant vs placebo of sensitive CYP3A substrates with a narrow therapeutic plus fulvestrant were neutropenia (83% vs 4%), leukopenia index may need to be reduced as IBRANCE may increase (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea their exposure. (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), For patients with severe hepatic impairment (Child-Pugh diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting class C), the recommended dose of IBRANCE is 75 mg. (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased The pharmacokinetics of IBRANCE have not been studied appetite (16% vs 8%), and pyrexia (13% vs 5%). in patients requiring hemodialysis. ≥ ≥ The most frequently reported Grade 3 adverse reactions ( 5%) Please see Brief Summary on the following pages. in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (66% vs 1%) and leukopenia (31% vs 2%). References: 1. Data on file. Pfizer Inc, New York, NY. 2. Referenced with permission Lab abnormalities of any grade occurring in PALOMA-3 for from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.4.2017. © National Comprehensive Cancer Network, Inc. 2018. All IBRANCE plus fulvestrant vs placebo plus fulvestrant were rights reserved. Accessed February 8, 2018. To view the most recent and complete decreased WBC (99% vs 26%), decreased neutrophils version of the guideline, go online to NCCN.org. NCCN makes no warranties of any (96% vs 14%), anemia (78% vs 40%), decreased platelets kind whatsoever regarding their content, use or application and disclaims any (62% vs 10%), increased aspartate aminotransferase (43% vs 48%), responsibility for their application or use in any way. and increased alanine aminotransferase (36% vs 34%). Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid Brief Summary of Prescribing Information Monitor complete blood counts prior to starting IBRANCE therapy and at the beginning of each ® F\FOHDVZHOODVRQ'D\RIWKH¿UVWF\FOHVDQGDVFOLQLFDOO\LQGLFDWHG'RVHLQWHUUXSWLRQGRVH IBRANCE (palbociclib) capsules, for oral use reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 Initial U.S. Approval: 2015 or 4 neutropenia. INDICATIONS AND USAGE Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across Studies 1 and 2. IBRANCE is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth One death due to neutropenic sepsis was observed in Study 2. Physicians should inform patients to factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with: promptly report any episodes of fever. • an aromatase inhibitor as initial endocrine based therapy in postmenopausal women; or (PEU\R)HWDO7R[LFLW\%DVHGRQ¿QGLQJVIURPDQLPDOVWXGLHVDQGLWVPHFKDQLVPRIDFWLRQ,%5$1&( • fulvestrant in women with disease progression following endocrine therapy. can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, DOSAGE AND ADMINISTRATION administration of palbociclib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal WR[LFLW\DWPDWHUQDOH[SRVXUHVWKDWZHUHWLPHVWKHKXPDQFOLQLFDOH[SRVXUHEDVHGRQDUHDXQGHUWKH Recommended Dose and Schedule. The recommended dose of IBRANCE is a 125 mg capsule taken curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete potential to use effective contraception during treatment with IBRANCE and for at least 3 weeks after cycle of 28 days. IBRANCE should be taken with food. the last dose. Administer the recommended dose of an aromatase inhibitor when given with IBRANCE. Please refer ADVERSE REACTIONS to the Full Prescribing Information for the aromatase inhibitor being used. &OLQLFDO6WXGLHV([SHULHQFHBecause clinical trials are conducted under varying conditions, the When given with IBRANCE, the recommended dose of fulvestrant is 500 mg administered on Days 1, DGYHUVHUHDFWLRQUDWHVREVHUYHGFDQQRWEHGLUHFWO\FRPSDUHGWRUDWHVLQRWKHUWULDOVDQGPD\QRWUHÀHFW 15, 29, and once monthly thereafter. Please refer to the Full Prescribing Information of fulvestrant. the rates observed in clinical practice. Patients should be encouraged to take their dose of IBRANCE at approximately the same time 6WXG\,%5$1&(SOXV/HWUR]ROH3DWLHQWVZLWK(5SRVLWLYH+(5QHJDWLYHDGYDQFHGRU each day. PHWDVWDWLFEUHDVWFDQFHUIRULQLWLDOHQGRFULQHEDVHGWKHUDS\ If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus placebo plus letrozole dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, ZDVHYDOXDWHGLQ6WXG\ 3$/20$ 7KHGDWDGHVFULEHGEHORZUHÀHFWH[SRVXUHWR,%5$1&(LQ crush or open them prior to swallowing). Capsules should not be ingested if they are broken, cracked, RXWRISDWLHQWVZLWK(5SRVLWLYH+(5QHJDWLYHDGYDQFHGEUHDVWFDQFHUZKRUHFHLYHGDW or otherwise not intact. least 1 dose of IBRANCE plus letrozole in Study 1. The median duration of treatment for IBRANCE Pre/perimenopausal women treated with the combination IBRANCE plus fulvestrant therapy should plus letrozole was 19.8 months while the median duration of treatment for placebo plus letrozole arm be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical was 13.8 months. practice standards. 'RVHUHGXFWLRQVGXHWRDQDGYHUVHUHDFWLRQRIDQ\JUDGHRFFXUUHGLQRISDWLHQWVUHFHLYLQJ 'RVH0RGL¿FDWLRQ,IGRVHUHGXFWLRQLVUHTXLUHGWKH¿UVWUHFRPPHQGHGGRVHUHGXFWLRQLVWR IBRANCE plus letrozole. No dose reduction was allowed for letrozole in Study 1. 100 mg/day and the second dose reduction is to 75 mg/day. If further dose reduction below Permanent discontinuation associated with an adverse reaction occurred in 43 of 444 (9.7%) patients 75 mg/day is required, discontinue the treatment. receiving IBRANCE plus letrozole and in 13 of 222 (5.9%) patients receiving placebo plus letrozole. 'RVH0RGL¿FDWLRQDQG0DQDJHPHQW±+HPDWRORJLF7R[LFLWLHVa Adverse reactions leading to permanent discontinuation for patients receiving IBRANCE plus letrozole included neutropenia (1.1%) and alanine aminotransferase increase (0.7%). Monitor complete blood counts prior to the start of IBRANCE therapy and at the beginning of each F\FOHDVZHOODVRQ'D\RIWKH¿UVWF\FOHVDQGDVFOLQLFDOO\LQGLFDWHG 7KHPRVWFRPPRQDGYHUVHUHDFWLRQV RIDQ\JUDGHUHSRUWHGLQSDWLHQWVLQWKH,%5$1&(SOXV letrozole arm by descending frequency were neutropenia, infections, leukopenia, fatigue, nausea, )RUSDWLHQWVZKRH[SHULHQFHDPD[LPXPRI*UDGHRUQHXWURSHQLDLQWKH¿UVWF\FOHVPRQLWRU alopecia, stomatitis, diarrhea, anemia, rash, asthenia, thrombocytopenia, vomiting, decreased appetite, complete blood counts for subsequent cycles every 3 months, prior to the beginning of a cycle and as dry skin, pyrexia, and dysgeusia. clinically indicated. 7KHPRVWIUHTXHQWO\UHSRUWHG*UDGHDGYHUVHUHDFWLRQV LQSDWLHQWVUHFHLYLQJ,%5$1&(SOXV CTCAE Grade 'RVH0RGL¿FDWLRQV letrozole by descending frequency were neutropenia, leukopenia, infections, and anemia. Grade 1 or 2 No dose adjustment is required. $GYHUVH5HDFWLRQV 10%) in Study 1

Day 1 of cycle: ,%5$1&(/HWUR]ROH 1 3ODFHER/HWUR]ROH 1 Withhold IBRANCE, repeat complete blood count All Grades Grade 3 All Grades Grade 3 monitoring within 1 week. When recovered to Grade 2, $GYHUVH5HDFWLRQ *UDGH *UDGH start the next cycle at the same dose. % % % % % % 'D\RI¿UVWF\FOHV Infections and infestations If Grade 3 on Day 15, continue IBRANCE at current Infectionsa b 14230 Grade 3 dose to complete cycle and repeat complete blood count Blood and lymphatic system disorders on Day 22. Neutropenia 80 10 11 ,I*UDGHRQ'D\VHH*UDGHGRVHPRGL¿FDWLRQ guidelines below. Leukopenia 39 24 1 2 0 0 Anemia 24 5 <1 9 2 0 Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 Thrombocytopenia 1<11 0 0 neutropenia on Day 1 of subsequent cycles. Metabolism and nutrition disorders Decreased appetite 15 1 0 9 0 0 Grade 3 neutropeniab with At any time: Nervous system disorders :LWKKROG,%5$1&(XQWLOUHFRYHU\WR*UDGH fever 38.5 ºC and/or infection Resume at the next lower dose. Dysgeusia 10 0 0 5 0 0 Gastrointestinal disorders At any time: Stomatitisc 30 1 0 14 0 0 Grade 4 :LWKKROG,%5$1&(XQWLOUHFRYHU\WR*UDGH Nausea 35 <1 0 20 Resume at the next lower dose. Diarrhea 101910 Grading according to CTCAE 4.0. Vomiting 101710 CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal. Skin and subcutaneous tissue disorders a Table applies to all hematologic adverse reactions except lymphopenia (unless associated with Alopecia 33d N/A N/A e N/A N/A clinical events, e.g., opportunistic infections). Rashf 18 1 0 12 1 0 b Absolute neutrophil count (ANC): Grade 1: ANC < LLN - 1500/mm3; Grade 2: ANC 1000 - <1500/mm3; Grade 3: ANC 500 - <1000/mm3; Grade 4: ANC <500/mm3. Dry skin 12 0 0 00 General disorders and administration site conditions 'RVH0RGL¿FDWLRQDQG0DQDJHPHQW±1RQ+HPDWRORJLF7R[LFLWLHV Fatigue 37 2 0 28 1 0 Asthenia 17 2 0 12 0 0 CTCAE Grade 'RVH0RGL¿FDWLRQV Pyrexia 12 0 0 9 0 0 Grade 1 or 2 No dose adjustment is required. Grading according to CTCAE 3.0. N=number of patients; N/A=not applicable Withhold until symptoms resolve to: a Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Grade 3 non-hematologic toxicity • Grade 1; Infections and infestations. (if persisting despite optimal medical • G r a d e 2 (if not considered a safety risk b Most common infections (>1%) include: nasopharyngitis, upper respiratory tract infection, urinary treatment) for the patient) WUDFWLQIHFWLRQRUDOKHUSHVVLQXVLWLVUKLQLWLVEURQFKLWLVLQÀXHQ]DSQHXPRQLDJDVWURHQWHULWLV Resume at the next lower dose. conjunctivitis, herpes zoster, pharyngitis, cellulitis, cystitis, lower respiratory tract infection, tooth infection, gingivitis, skin infection, gastroenteritis viral, respiratory tract infection, respiratory tract Grading according to CTCAE 4.0. infection viral, and folliculitis. c Refer to the Full Prescribing Information for coadministered endocrine therapy dose adjustment Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal guidelines in the event of toxicity and other relevant safety information or contraindications. LQÀDPPDWLRQRUDOSDLQRUDOGLVFRPIRUWRURSKDU\QJHDOSDLQDQGVWRPDWLWLV d Grade 1 events – 30%; Grade 2 events – 3%. 'RVH0RGL¿FDWLRQVIRU8VH:LWK6WURQJ&<3$,QKLELWRUV Avoid concomitant use of strong e Grade 1 events – 15%; Grade 2 events – 1%. CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A f Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the IBRANCE dose papular, dermatitis, dermatitis acneiform, and toxic skin eruption. to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3 to 5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving 'RVH0RGL¿FDWLRQVIRU+HSDWLF,PSDLUPHQWNo dose adjustment is required for patients with Ibrance plus letrozole in Study 1 included alanine aminotransferase increased (9.9%), aspartate mild or moderate hepatic impairment (Child-Pugh classes A and B). For patients with severe hepatic DPLQRWUDQVIHUDVHLQFUHDVHG HSLVWD[LV ODFULPDWLRQLQFUHDVHG GU\H\H impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg once daily for 21 YLVLRQEOXUUHG DQGIHEULOHQHXWURSHQLD consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. Laboratory Abnormalities in Study 1 '26,1*)2506$1'675(1*7+6 125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, ,%5$1&(/HWUR]ROH 1 3ODFHERSOXV/HWUR]ROH 1 SULQWHGZLWKZKLWHLQN³3¿]HU´RQWKHFDS³3%&´RQWKHERG\ Laboratory Abnormality All Grades Grade 3 *UDGH All Grades Grade 3 *UDGH 100 mg capsules: opaque hard gelatin capsules, size 1, with caramel cap and light orange % % % % % % ERG\SULQWHGZLWKZKLWHLQN³3¿]HU´RQWKHFDS³3%&´RQWKHERG\ WBC decreased 97 35 1 25 1 0 75 mg capsules: opaque hard gelatin capsules, size 2, with light orange cap and body, Neutrophils decreased 95 12 20 1 1 SULQWHGZLWKZKLWHLQN³3¿]HU´RQWKHFDS³3%&´RQWKHERG\ Anemia 78 04220 &2175$,1',&$7,216 None Platelets decreased 11 140 0 :$51,1*6$1'35(&$87,216 Aspartate aminotransferase increased 52 3 0 34 1 0 1HXWURSHQLD Neutropenia was the most frequently reported adverse reaction in Study 1 (PALOMA-2) with an incidence of 80% and Study 2 (PALOMA-3) with an incidence of 83%. A Alanine aminotransferase 43 2 <1 30 0 0 *UDGHGHFUHDVHLQQHXWURSKLOFRXQWVZDVUHSRUWHGLQRISDWLHQWVUHFHLYLQJ,%5$1&(SOXV increased OHWUR]ROHLQ6WXG\DQGRISDWLHQWVUHFHLYLQJ,%5$1&(SOXVIXOYHVWUDQWLQ6WXG\,Q6WXG\ N=number of patients; WBC=white blood cells. DQGWKHPHGLDQWLPHWR¿UVWHSLVRGHRIDQ\JUDGHQHXWURSHQLDZDVGD\VDQGWKHPHGLDQGXUDWLRQ RI*UDGHQHXWURSHQLDZDVGD\V 6WXG\,%5$1&(SOXV)XOYHVWUDQW3DWLHQWVZLWK+5SRVLWLYH+(5QHJDWLYHDGYDQFHG The estimated background risk of major birth defects and miscarriage for the indicated population is RUPHWDVWDWLFEUHDVWFDQFHUZKRKDYHKDGGLVHDVHSURJUHVVLRQRQRUDIWHUSULRUDGMXYDQWRU unknown. In the U.S. general population, the estimated background risk of major birth defects and PHWDVWDWLFHQGRFULQHWKHUDS\ miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The safety of IBRANCE (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was In a fertility and early embryonic development study in female rats, palbociclib was administered HYDOXDWHGLQ6WXG\ 3$/20$ 7KHGDWDGHVFULEHGEHORZUHÀHFWH[SRVXUHWR,%5$1&(LQRXW orally for 15 days before mating through to Day 7 of pregnancy, which did not cause embryo toxicity of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at at doses up to 300 mg/kg/day with maternal systemic exposures approximately 4 times the human least 1 dose of IBRANCE plus fulvestrant in Study 2. The median duration of treatment for IBRANCE exposure (AUC) at the recommended dose. plus fulvestrant was 10.8 months while the median duration of treatment for placebo plus fulvestrant In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses up to arm was 4.8 months. 300 mg/kg/day and 20 mg/kg/day palbociclib, respectively, during the period of organogenesis. The 'RVHUHGXFWLRQVGXHWRDQDGYHUVHUHDFWLRQRIDQ\JUDGHRFFXUUHGLQRISDWLHQWVUHFHLYLQJ maternally toxic dose of 300 mg/kg/day was fetotoxic in rats, resulting in reduced fetal body weights. IBRANCE plus fulvestrant. No dose reduction was allowed for fulvestrant in Study 2. $WGRVHVPJNJGD\LQUDWVWKHUHZDVDQLQFUHDVHGLQFLGHQFHRIDVNHOHWDOYDULDWLRQ LQFUHDVHG incidence of a rib present at the seventh cervical vertebra). At the maternally toxic dose of 3HUPDQHQWGLVFRQWLQXDWLRQDVVRFLDWHGZLWKDQDGYHUVHUHDFWLRQRFFXUUHGLQRI SDWLHQWV 20 mg/kg/day in rabbits, there was an increased incidence of skeletal variations, including small UHFHLYLQJ,%5$1&(SOXVIXOYHVWUDQWDQGLQRI SDWLHQWVUHFHLYLQJSODFHERSOXVIXOYHVWUDQW phalanges in the forelimb. At 300 mg/kg/day in rats and 20 mg/kg/day in rabbits, the maternal Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus fulvestrant systemic exposures were approximately 4 and 9 times the human exposure (AUC) at the LQFOXGHGIDWLJXH LQIHFWLRQV DQGWKURPERF\WRSHQLD recommended dose, respectively. 7KHPRVWFRPPRQDGYHUVHUHDFWLRQV RIDQ\JUDGHUHSRUWHGLQSDWLHQWVLQWKH,%5$1&(SOXV &'.GRXEOHNQRFNRXWPLFHKDYHEHHQUHSRUWHGWRGLHLQODWHVWDJHVRIIHWDOGHYHORSPHQW fulvestrant arm by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea, (gestation Day 14.5 until birth) due to severe anemia. However, knockout mouse data may not be anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and pyrexia. predictive of effects in humans due to differences in degree of target inhibition. 7KHPRVWIUHTXHQWO\UHSRUWHG*UDGHDGYHUVHUHDFWLRQV LQSDWLHQWVUHFHLYLQJ,%5$1&(SOXV Lactation. There is no information regarding the presence of palbociclib in human milk, nor its fulvestrant in descending frequency were neutropenia and leukopenia. effects on milk production or the breastfed infant. Because of the potential for serious adverse reactions in breastfed infants from IBRANCE, advise a lactating woman not to breastfeed during $GYHUVH5HDFWLRQV LQ6WXG\ treatment with IBRANCE and for 3 weeks after the last dose. ,%5$1&()XOYHVWUDQW 1 3ODFHER)XOYHVWUDQW 1 )HPDOHVDQG0DOHVRI5HSURGXFWLYH3RWHQWLDO Based on animal studies, IBRANCE can cause All Grades Grade 3 *UDGH All Grades Grade 3 *UDGH fetal harm when administered to a pregnant woman. Females of reproductive potential should $GYHUVH5HDFWLRQ % % % % % % have a pregnancy test prior to starting treatment with IBRANCE. IBRANCE can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective Infections and infestations contraception during treatment with IBRANCE and for at least 3 weeks after the last dose. Because Infectionsa 47b 31313 0of the potential for genotoxicity, advise male patients with female partners of reproductive potential Blood and lymphatic system disorders to use effective contraception during treatment with IBRANCE and for 3 months after the last dose. Neutropenia 83 55 11 4 1 0 Based on animal studies, IBRANCE may impair fertility in males of reproductive potential. Leukopenia 53 30 1 5 1 1 Pediatric Use.7KHVDIHW\DQGHI¿FDF\RI,%5$1&(LQSHGLDWULFSDWLHQWVKDYHQRWEHHQVWXGLHG Anemia 30 3 0 13 2 0 Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes Thrombocytopenia 23 2 1 0 0 0 in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), kidney (tubule vacuolation, FKURQLFSURJUHVVLYHQHSKURSDWK\ DQGDGLSRVHWLVVXH DWURSK\ ZHUHLGHQWL¿HGLQDZHHN Metabolism and nutrition disorders repeat-dose toxicology study in rats that were immature at the beginning of the studies and were Decreased appetite 10810PRVWSUHYDOHQWLQPDOHVDWRUDOSDOERFLFOLEGRVHVPJNJGD\ DSSUR[LPDWHO\WLPHVWKH Gastrointestinal disorders DGXOWKXPDQH[SRVXUH>$8&@DWWKHUHFRPPHQGHGGRVH 6RPHRIWKHVH¿QGLQJV JO\FRVXULD hyperglycemia, pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present with Nausea 34 0 0 28 1 0 lower incidence and severity in a 15 week repeat-dose toxicology study in immature rats. Altered Stomatitisc 28 1 0 13 0 0 glucose metabolism or associated changes in the pancreas, eye, kidney and adipose tissue were not Diarrhea 24 0 0 19 1 0 LGHQWL¿HGLQDZHHNUHSHDWGRVHWR[LFRORJ\VWXG\LQUDWVWKDWZHUHPDWXUHDWWKHEHJLQQLQJRIWKH Vomiting 19 1 0 15 1 0 study and in dogs in repeat-dose toxicology studies up to 39 weeks duration. Skin and subcutaneous tissue disorders Toxicities in teeth independent of altered glucose metabolism were observed in rats. Administration d e of 100 mg/kg palbociclib for 27 weeks (approximately 15 times the adult human exposure [AUC] Alopecia 18 N/A N/A N/A N/A at the recommended dose) resulted in abnormalities in growing incisor teeth (discolored, ameloblast Rashf 17 1 0 00GHJHQHUDWLRQQHFURVLVPRQRQXFOHDUFHOOLQ¿OWUDWH 2WKHUWR[LFLWLHVRISRWHQWLDOFRQFHUQWRSHGLDWULF General disorders and administration site conditions patients have not been evaluated in juvenile animals. Fatigue 41 2 0 29 1 0 Geriatric Use. Of 444 patients who received IBRANCE in Study 1, 181 patients (41%) were Pyrexia 13 <1 0 5 0 0 \HDUVRIDJHDQGSDWLHQWV ZHUH\HDUVRIDJH2ISDWLHQWVZKRUHFHLYHG ,%5$1&(LQ6WXG\SDWLHQWV ZHUH\HDUVRIDJHDQGSDWLHQWV ZHUH\HDUV Grading according to CTCAE 4.0. of age. No overall differences in safety or effectiveness of IBRANCE were observed between these a Infections includes all reported preferred terms (PTs) that are part of the System Organ Class patients and younger patients. Infections and infestations. b Most common infections (>1%) include: nasopharyngitis, upper respiratory tract infection, urinary +HSDWLF,PSDLUPHQW No dose adjustment is required in patients with mild or moderate hepatic WUDFWLQIHFWLRQEURQFKLWLVUKLQLWLVLQÀXHQ]DFRQMXQFWLYLWLVVLQXVLWLVSQHXPRQLDF\VWLWLVRUDO impairment (Child-Pugh classes A and B). For patients with severe hepatic impairment (Child-Pugh herpes, respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes class C), the recommended dose of IBRANCE is 75 mg once daily for 21 consecutive days followed simplex, and paronychia. by 7 days off treatment to comprise a complete cycle of 28 days. Based on a pharmacokinetic trial c Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal in subjects with varying degrees of hepatic function, the palbociclib unbound exposure (unbound LQÀDPPDWLRQRUDOSDLQRURSKDU\QJHDOGLVFRPIRUWRURSKDU\QJHDOSDLQVWRPDWLWLV AUCINF) decreased by 17% in subjects with mild hepatic impairment (Child-Pugh class A), and d Grade 1 events – 17%; Grade 2 events – 1%. increased by 34% and 77% in subjects with moderate (Child-Pugh class B) and severe (Child-Pugh e*UDGHHYHQWV± class C) hepatic impairment, respectively, relative to subjects with normal hepatic function. Peak f Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, palbociclib unbound exposure (unbound Cmax) increased by 7%, 38% and 72% for mild, moderate dermatitis acneiform, toxic skin eruption. and severe hepatic impairment, respectively, relative to subjects with normal hepatic function. Review the Full Prescribing Information for the aromatase inhibitor or fulvestrant for dose Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving IBRANCE plus fulvestrant in Study 2 included asthenia (7.5%), aspartate aminotransferase increased PRGL¿FDWLRQVUHODWHGWRKHSDWLFLPSDLUPHQW G\VJHXVLD HSLVWD[LV ODFULPDWLRQLQFUHDVHG GU\VNLQ DODQLQH 5HQDO,PSDLUPHQW No dose adjustment is required in patients with mild, moderate, or severe renal aminotransferase increased (5.8%), vision blurred (5.8%), dry eye (3.8%), and febrile neutropenia (0.9%). impairment (CrCl >15 mL/min). Based on a pharmacokinetic trial in subjects with varying degrees of renal function, the total palbociclib exposure (AUCINF) increased by 39%, 42%, and 31% with /DERUDWRU\$EQRUPDOLWLHVLQ6WXG\ PLOG P/PLQ&U&O P/PLQ PRGHUDWH P/PLQ&U&O P/PLQ DQGVHYHUH ,%5$1&()XOYHVWUDQW 1 3ODFHER)XOYHVWUDQW 1 (CrCl <30 mL/min) renal impairment, respectively, relative to subjects with normal renal function. Laboratory Abnormality Peak palbociclib exposure (Cmax) increased by 17%, 12%, and 15% for mild, moderate, and severe All Grades Grade 3 *UDGH All Grades Grade 3 *UDGH renal impairment, respectively, relative to subjects with normal renal function. The pharmacokinetics % % % % % % of palbociclib have not been studied in patients requiring hemodialysis. WBC decreased 99 45 1 01 OVERDOSAGE Neutrophils decreased 11 14 0 1 Anemia 78 3 0 40 2 0 There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of general supportive measures. Platelets decreased 21 100 0 PATIENT COUNSELING INFORMATION Aspartate aminotransferase increased 43 4 0 48 4 0 Advise the patient to read the FDA-approved patient labeling (Patient Information). Alanine aminotransferase Myelosuppression/Infection increased 20 340 0 • Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness or any increased tendency to bleed DRUG INTERACTIONS and/or to bruise. Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. Drug Interactions In vivo, palbociclib is a time-dependent inhibitor of CYP3A. • Grapefruit may interact with IBRANCE. Patients should not consume grapefruit products while on treatment with IBRANCE. (IIHFWRI&<3$,QKLELWRUV Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%. Avoid concomitant use • Inform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers. of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ • Advise patients to inform their health care providers of all concomitant medications, including ULWRQDYLUQHID]RGRQHQHO¿QDYLUSRVDFRQD]ROHULWRQDYLUVDTXLQDYLUWHODSUHYLUWHOLWKURP\FLQDQG prescription medicines, over-the-counter drugs, vitamins, and herbal products. voriconazole). Avoid grapefruit or grapefruit juice during IBRANCE treatment. If coadministration Dosing and Administration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of IBRANCE. • Advise patients to take IBRANCE with food. (IIHFWRI&<3$,QGXFHUV Coadministration of a strong CYP3A inducer (rifampin) decreased the • If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed plasma exposure of palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not inducers (e.g., phenytoin, rifampin, carbamazepine, enzalutamide, and St John’s Wort). chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact. 'UXJV7KDW0D\+DYH7KHLU3ODVPD&RQFHQWUDWLRQV$OWHUHGE\3DOERFLFOLE Coadministration RIPLGD]RODPZLWKPXOWLSOHGRVHVRI,%5$1&(LQFUHDVHGWKHPLGD]RODPSODVPDH[SRVXUHE\ Pregnancy, Lactation, and Fertility in healthy subjects, compared with administration of midazolam alone. The dose of the sensitive Embryo-Fetal Toxicity CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, • Advise females of reproductive potential of the potential risk to a fetus and to use effective ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be contraception during treatment with IBRANCE therapy and for at least 3 weeks after the last reduced as IBRANCE may increase their exposure. dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. • Advise male patients with female partners of reproductive potential to use effective contraception USE IN SPECIFIC POPULATIONS during treatment with IBRANCE and for at least 3 months after the last dose. Pregnancy.%DVHGRQ¿QGLQJVIURPDQLPDOVWXGLHVDQGLWVPHFKDQLVPRIDFWLRQ,%5$1&(FDQ Lactation cause fetal harm when administered to a pregnant woman. There are no available data in pregnant • Advise women not to breastfeed during treatment with IBRANCE and for 3 weeks after the women to inform the drug-associated risk. In animal reproduction studies, administration of last dose. palbociclib to pregnant rats and rabbits during organogenesis resulted in embryofetal toxicity at PDWHUQDOH[SRVXUHVWKDWZHUHWLPHVWKHKXPDQFOLQLFDOH[SRVXUHEDVHGRQ$8&$GYLVHSUHJQDQW 5[RQO\ women of the potential risk to a fetus. This brief summary is based on IBRANCE® (palbociclib) Prescribing Information LAB-0723-4.0, Rev. 02/2018.

PP-IBR-USA-1887-01 3¿]HU,QF $OOULJKWVUHVHUYHG )HEUXDU\ A 14 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn Patients With Moderate to Severe Anxiety or Depression Symptoms: Recognizing, Assessing, Referring, and Monitoring

benefi ts, health insurance, education the normal range of patients’ responses EXPERT beyond high school, a partner or close to cancer. If depression is suspected, hav- confi dant, and U.S. citizenship. ing the patient complete the Physicians ARTICLE EDITORIAL Still, individuals reporting none to Health Questionnaire-9 (PHQ-9) is the few anxiety and/depressive symptoms quickest 5- to 10-minute step to aid in HIGHLIGHTS Barbara L. Andersen, PhD, and benefi t from modest psychological or be- confi rming or disconfi rming one’s clini- ■ Anxiety is the most common Marlena M. Ryba, PhD havioral resources (Fig. 1). Patients need cal hypothesis. Many patients with mod- mental health problem for cancer accessibility to information on topics erate to severe symptoms will have ma- survivors, and many patients go tress from a cancer diagnosis and such as cancer as an illness (preferably jor depressive disorder as a preexisting undiagnosed. anticipation of treatment is ubiq- disease specifi c); easy to understand de- chronic illness, and the stresses of cancer ■ The consequences of anxiety or uitous among patients. However, scriptions of diagnostic and treatment can trigger another episode.4 mood disorder diagnosis “misses” for roughly 50% of patients it is processes/procedures with sensations/ are considerable. The disorders Soverwhelming, promoting a cascade of symptom descriptions; medical team Comorbidity of Anxiety and Depression produce signifi cant life impair- negative sequelae—psychological, behav- contact information; and information Life stressors and neurobiological pro- ment and lead to lower treatment ioral, and biological. High stress can even regarding supportive care persons or cesses and psychological vulnerabilities tolerance and adherence. generate anxiety or depressive disorders. programs in the hospital/clinic and the contribute to both anxious and depressive ■ In fact, psychiatric disorders are more community for which professional refer- emotions and behaviors. The disorders Proper referral to empirically sup- prevalent among patients with cancer ral is not needed. For example, the Can- share symptoms including avoidance of ported treatments is necessary, than among those with any other chronic cer Support Community (CancerSupport people and activities, diffi culties concen- and continued monitoring will in- illness. Although studies vary, prevalence Community.org) provides free psychoso- trating, psychomotor restlessness, fatigue, crease the likelihood that patients estimates are near 40% for any mood cial services in 44 affi liates in the United and sleep problems. More than half of will receive services and be more disorder, 10% for anxiety disorders, and States and many more abroad. patients diagnosed with major depressive successful in meeting cancer’s 20% for any adjustment disorder.1,2 By disorder (MDD) are found to have an anx- challenges. comparison, the World Health Organiza- Identifi cation: Who They Are iety disorder, usually GAD and/or panic. tion (WHO) World Mental Health reports Patients with anxiety disorders Conversely, patients with an anxiety dis- impairment and may interfere with a 12-month prevalence estimates for the Anxiety disorders have several variants, order have high rates of MDD. Patients person’s decision-making, undermine United States as 9.7% for mood disorders but the most common is generalized anx- with comorbidity have greater symptom the emotional and physical strength and 19.0% for anxiety disorders.3 In this iety disorder (GAD; Box 1). The pathog- severity and a lower response to treatment required to undergo cancer treatment, editorial, we focus on the individuals in nomonic GAD symptom (i.e., multiple than those with either disorder alone.5,6 yield more symptoms (e.g., pain), and greatest need—patients with cancer who excessive worries) may be evidenced by a lower treatment tolerance or adherence. have moderate to severe symptoms of patient mentioning multiple concerns or When Patients Are Not Diagnosed They pose a substantial fi nancial burden anxiety and/or depression. fears rather than worry, per se. Whereas The consequences of anxiety or mood on the economy and personal fi nances. cancer worries are common, GAD worry disorder diagnosis “misses” are consider- Without treatment, symptoms increase Identifi cation: Who They Are Not or fear is disproportionate to actual risk able. The disorders produce general life See Severe Anxiety or Depression, Page 16A Many patients (50% + 10%) have no (e.g., excessive fear of recurrence when to few symptoms of anxiety or mood the probability is low). The patient with 1 disorders. These individuals have natu- GAD also has worries about a range of Diagnostic Criteria for Generalized Anxiety Disorder* rally available resources that facilitate other, noncancer topics with the focus A. Excessive anxiety and worry (apprehensive expectation), occurring more days for at positive emotional coping (e.g., ac- changing over time, be it probable or im- least 6 months, about a number of events or activities (e.g., work, school). ceptance, learning to live with cancer), probable, emergent or distant, low inten- B. The individual fi nds it diffi cult to control the worry. cognitively (e.g., thinking of a plan of sity or high. C. The anxiety and worry are associated with three (or more) of the following six symptoms action), and behaviorally (e.g., seeking (with at least some symptoms having been present for more days than not for the past support from others, concentrating on Patients with mood disorders 6 months): helpful actions). They often have mul- A major barrier to identifying mood 1. Restlessness, feeling keyed up or on edge; tiple resources that reduce the likelihood disorders in patients is lack of familiarity 2. Being easily fatigued; of added cancer stress, such as adequate with diagnostic criteria for major depres- 3. Diffi culty concentrating or mind going blank; income, food and housing security, ad- sive disorder (Box 2). Even when depres- 4. Irritability; equate employment and/or retirement sion is suspected, there may be inaccurate 5. Muscle tension; and clinical judgments of severity (“He has 6. Sleep disturbance (diffi culty falling or staying asleep, or restless, unsatisfying sleep). Fig. 1. lung cancer, of course he is depressed.”) D. The anxiety, worry, or physical symptoms cause clinically signifi cant distress or impair- or not in need of treatment because of ment in social, occupational, or other important functioning. other concurrent problems (“She has a *Abbreviated Patient drinking problem.”). Regardless, depres- High-Intensity Education Treatment sion is not an acceptable symptom of liv- + Patient Education ing with cancer. 2 That said, distinguishing depression Diagnostic Criteria for Major Depressive Disorder can be diffi cult. The vegetative symptoms Five (or more) of the following symptoms weight gain (e.g., > 5% of body weight in a (e.g., poor appetite, sleep problems, and have been present during the same 2-week month), or decrease or increase in appetite; Support Services ■ Low-Intensity + Patient Education weight loss/gain) may overlap with can- period and represent a change from previous Insomnia or hypersomnia; Treatment cer symptoms or treatment side effects. functioning; at least one of the symptoms is ■ Psychomotor agitation or retardation + Patient Education Instead, a focus on psychological and either #1 or #2. Symptoms must occur at (observable by others, not merely subjec- behavioral indicators may be more in- a high frequency, i.e., most of the day(s), tive feelings of restlessness or being slowed formative. Low moods can come and go, nearly every day. The symptoms cause down); but it is persistent depressed or irritable clinically signifi cant distress or impairment ■ Fatigue or loss of energy; This is a representation of the prevalence and moods coupled with decreased interest in social, occupational, or other important ■ Feelings of worthlessness or excessive or severity of symptoms of anxiety and depressive symptoms in adults with cancer and the or pleasure with most activities on most functioning. inappropriate guilt (not merely self-reproach corresponding need for services. All patients days (anhedonia) that signals major de- or guilt about being sick); need educational information to reduce stress pressive disorder. Some patients may not ■ Depressed mood reported most of the day, ■ Diminished ability to think or concentrate, or and enhance positive coping. General sup- view themselves as depressed but report nearly every day (e.g., feels sad, empty, indecisiveness (either by subjective account portive services are needed for 15% to 20% of fatigue with energy or activity levels so hopeless) or observed by others (e.g., or as observed by others); and, patients with low- to low-moderate symptom severity. In contrast, 50% (+/- 10%) of patients low that they stop engaging in activities appears tearful); ■ Recurrent thoughts of death (not just fear of have anxiety and/or depressive symptoms in or maintaining relationships previously ■ Markedly diminished interest or pleasure in dying), recurrent suicidal ideation without the moderate to severe or severe range. For the enjoyed. Feelings of guilt, worthlessness, all, or almost all, activities; a specifi c plan, or a suicide attempt or a latter groups, empirically supported treatments hopelessness, or negative feelings about ■ Signifi cant weight loss when not dieting or specifi c plan for committing suicide. of low or high intensity are needed. oneself are red fl ags, as they are not in VISIT US AT BOOTH #18157

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Severe Anxiety or Depression ■ History: Any prior psychiatric diag- have him/her specify the content, mode About the Authors Continued from page 14A noses, with or without treatment, or of treatment (group, individual, phone- history of/or current substance use or based), and typical treatment duration, as Dr. Andersen is a in severity, recovery becomes diffi cult, abuse; ASCO recommends. Distinguished Uni- and remission intervals become shorter. ■ Additional chronic illnesses, such as Discussion with the patient and, if versity Professor in These patients have more frequent phy- diabetes or severe arthritis; possible, scheduling the fi rst appoint- the Department of Psychology at ■ sician visits, spend more time with phy- Marital status: Single, not married, ment will increase the likelihood that The Ohio State sicians, have more hospitalizations, and separated, or divorced; the patient will follow through. Provid- University. have higher health care costs. Generally, ■ Employment status: Unemployed or ing specifi city (date, time, place, and individuals with depression have higher underemployed; person) helps circumvent avoidance. mortality, with both stress and depres- ■ Education level: High school or tech- Dr. Ryba is an as- sion predictive of cancer progression and nical school graduate or lower; and Empirically support treatments sistant professor premature death.7 ■ Financial resources: Low income, no/ An accompanying podcast discusses in the Department insuffi cient insurance coverage, or cognitive behavioral treatments for of Psychology at Identifying Patients in Need ongoing fi nancial obligations. GAD and MDD disorders of both low Coastal Carolina The Commission on Cancer (CoC) and high intensity. The podcast is avail- University. mandate for distress screening has pre- Of these, prior history of psychiatric di- able on iTunes, Google Play, and Libsyn. sented oncology with multiple challenges agnosis is the most infl uential. For older Search for “ASCO Daily News.” of implementation (e.g., Which screening patients, further assessment of those scor- empirically supported treatments is nec- measure is to be used? How does referral ing in the low-moderate symptom range After Referral, Helping Patients essary, and continued monitoring will come about?). ASCO recommends that (PHQ-9 scores of 8-14, GAD-7 scores of Stay in Treatment increase the likelihood that patients will every person be evaluated for anxiety and 10-14) could be considered when addi- Sometimes we can be our own worst receive services and be more success- depressive symptoms when diagnosed tional risk factors (e.g., social isolation, enemy. Cautiousness and a tendency to ful in meeting cancer’s challenges. This and regularly thereafter.8 ASCO screening bereavement, and fi nancial diffi culty) are avoid threatening stimuli are cardinal pathway is an achievable goal which of- measures were chosen for their psycho- present.12 features of anxiety pathology, making fers huge returns for patients and oncol- metric validity, reliability, specifi city for it common for persons to not follow ogy care systems. anxiety and depression, and successful After Patients Are Identifi ed: Next Steps through on referral or treatment rec- use in primary care. Distress tools were Committing effort to follow screening ommendations. Persons with depres- References: excluded, as the term “distress” is non- with patient discussion sive symptoms can lack motivation and 1. Mitchell AJ, et al. Lancet Oncol. specifi c and the tools are neither suited to It is estimated that 7.6 million cancer do the same. These characteristics and 2012;12:160-74. discovery of criterion symptoms nor de- survivors in the United States have not behaviors are disorder-based, and do 2. Stark D, et al. J Clin Oncol. 2002;20:3137- termination of the severity. discussed their psychosocial function- not refl ect personal failings or lack of 48. As GAD is the most common anxiety ing with health care providers.13 Even responsibility. 3. Kessler RC, et al. Epidemiol Psichiatr Soc. disorder, the GAD-7 assessment was rec- though they are aware of their emotional With this in mind, oncology follow-up 2009:18;23-33. ommended (Box 2, page 14A). The PHQ- problems, they want their medical team is critical. At the next oncology visit, de- 4. Kendler KS, et al. Am J Psychiatry. 9 includes the items for MDD symptoms, to ask and offer help, and they have gen- termine the patient’s follow-through. If 2001;158:582-6. including one for suicide ideation. Survey erally positive views of psychosocial ser- it has been poor, reiterate the rationale 5. DiMatteo MR, et al. Arch Intern Med. data suggest approximately 14% of Ameri- vices.14 Patients are not surprised when and description of the provider’s offering, 2000;160:2101-7. cans report suicide ideation as having oc- learning a screening measure suggests discuss and address barriers, and provide 6. Greer JA, et al. J Psychosom Res. curred at some point during their lifetime.9 they are having signifi cant diffi culty support and encouragement to try again 2008;65:549-52. As might be expected, suicidal thoughts with anxiety, depression, or both. with rescheduling or redirecting to anoth- 7. Satin JR, et al. Cancer. 2009;115:5349-61. are more frequent for the individual with er option. If there is compliance though 8. Andersen BL, et al. J Clin Oncol. a chronic illness.10 If ideation is endorsed, Identifying and evaluating dissatisfaction, seek out the reasons and 2014;32:1605-19. a second step evaluation would include referral resources address as is possible, with referral to an- 9. Schreiber J, et al. UpToDate. Suicidal assessment of the presence or absence of Persons and/or programs within the other provider considered. Request refer- ideation and behavior in adults. uptodate. characteristics shown empirically and tem- clinic/facility and the community who ral sources to provide monthly updates com/contents/suicidal-ideation-and- porally related to the acute onset of sui- can aid in diagnosis, problem identifi ca- for the fi rst 2 months as this is the period behavior-in-adults. Updated February 19, cidal behavior, with the most prominent tion, and provide empirically supported during which symptoms should remit, 2018. Accessed April 30, 2018. being threats to kill or hurt oneself, look- treatment need to be identifi ed. In so do- and if not, there is need for a treatment 10. Webb RT, et al. Arch Gen Psychiatry. ing for ways to kill oneself, and talking or ing, evaluate the mental health provider/ adjustment. Continue to monitor the pa- 2012;69:256-64 writing about death, dying, or suicide.11 service candidates, including education tient’s follow-through. 11. Hales RE, et al. The American Psychiatric In addition to the GAD-7/PHQ-9, sim- and licensure, training in the diagnosis Publishing Textbook of Suicide Assess- ple questions asked of the patient and and treatment of psychopathology, and Conclusion ment and Management. Washington, DC: recorded in the medical record would in- cost structure for services provided, with Cancer has modifi able psychological American Psychiatric Publishing, 2006. form screening and referral. The follow- experience in treating patients with can- and behavioral patient elements capable 12. Cole MG, et al. Am J Psychiatry. ing characteristics portend that symp- cer and familiarity with ASCO guidelines of reducing risk, morbidity, and mortal- 2003;160:1147-56. toms may be of longer duration, pose desirable. Ask the provider which empiri- ity. Identifying patients with moderate 13. Forsythe LP, et al. J Clin Oncol. diffi culty to treatment, or limit treat- cally supported psychological and/or be- to high anxiety and depressive symp- 2013;31:1961-9. ment response: havioral interventions are offered, and toms is the fi rst step. Proper referral to 14. Owen JE, et al. Cancer. 2007;109:2580-9.

New Guidelines address a gap in practice. It was previ- wasn’t on the level of ‘everyone needs to treatments and best chances of being Continued from page 9A ously unclear which intervention best re- get this.’ We wanted to present these rec- cured, but we also don’t want to expose duces the high risk of disease recurrence ommendations as options, something to people to treatments unnecessarily if trastuzumab-based adjuvant therapy. in patients who underwent preoperative discuss—especially for patients who are they might not have a substantial ben- Findings from the ExteNET trial showed chemotherapy and had residual disease high-risk. But these recommendations efi t,” Dr. Giordano said. “We wanted the that women who were randomly as- at surgery. The other two recommen- aren’t necessarily for everyone.” recommendations to be individualized signed to receive neratinib for 1 year af- dations suggest escalating current ap- In determining whether to include the so physicians and patients can make deter completing adjuvant trastuzumab proaches to therapy in hopes of provid- recommendations, the Expert Panel had cisions based on factors like risk of re- had better invasive DFS than women ing incremental benefi ts. to consider real-world effects of the ad- currence and disease stage.” who received placebo. However, all three recommendations juvant treatment regimens on patients. Although the new guidelines are not “We know that many patients do in- are clear in suggesting these regimens “With any treatment decisions, the likely—nor intended—to be adopted for credibly well with standard chemothera- are ones that oncologists may want toxicity of the chemotherapy and/or all patients, their likelihood of improv- py and trastuzumab alone, but these two to consider, not necessarily ones they biologic therapy and a patient’s baseline ing clinical outcomes is strong. agents—trastuzumab and neratinib—pro- should or must provide. As Dr. Giordano risk of the cancer coming back need to “I think there’s a potential for these vide another therapeutic avenue for pa- noted, that subtle distinction is inten- be balanced with the potential benefi ts recommendations to impact many peo- tients at highest risk,” Dr. Denduluri said. tional—and critical. of these agents,” Dr. Denduluri said. ple because they address two specifi c “Although the clinical trials were But because the results from the trials subtypes of breast cancer—the HER2- Practical for Practices? positive, they had smaller benefi ts than were smaller than expected, achieving positive and also patients at highest risk The fi rst recommendation regarding people were hoping for,” she said. “So, this balance may be challenging. for recurrence,” Dr. Denduluri said. the use of adjuvant capecitabine helps it was reasonable to include them, but it “We want to give patients the best –Emily A. Kuhl, PhD DISCOVER WHAT’S NEW VISIT US AT BOOTH #6097

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Immunotherapy and CRC Dr. Michael A. Morse “Standard-of-care therapy for second- considered standard in some patients Continued from page 1A line [and after] for dMMR CRC is with dMMR CRC, considerations re- nivolumab or pembrolizumab,” Dr. garding toxicity have become more mutations, thus CRCs that are defi cient Overman said. “I think we do need more relevant. “It is important for us to in MMR have substantially increased understanding of resistance mecha- recognize these toxicities and learn tumor mutation burden. Because the nisms,” he added, since not all patients how to deal with them,” said Marc S. types of errors recognized and repaired with dMMR CRC respond to these im- Ernstoff, MD, of Roswell Park Com- by MMR occur at areas of DNA repeats munotherapy approaches. prehensive Cancer Center. He noted known as microsatellites, dMMR CRC that a recent survey of oncologists is also termed microsatellite-instability Profi cient MMR Tumors found that only approximately half high (MSI-H). “We know that there is no benefi t for of respondents said they were some- Because of the known differences in anti–PD-1 antibody therapy in pMMR what or very comfortable managing outcomes, as well as in effective thera- tumors,” said Michael A. Morse, MD, immune-related adverse events (irAEs). pies, guidelines have now shifted with MHS, FACP, of the Duke University Can- irAEs can be caused by several mecha- regard to testing for MMR status. “Any cer Institute. “It’s night and day.” He nisms, including the development of patient with a colon or rectal cancer spoke about why pMMR tumors do not autoimmunity, expression of immune should be tested for defi cient MMR,” Dr. respond and provided some potential checkpoints, and infl ammatory cyto- Overman said. This is true regardless of approaches to change this situation. kine releases. Often, the toxicity can be family history or other baseline charac- “It does seem to be that having more delayed and it can affect nearly every teristics. T cells in the tumor may be important,” organ. Testing can be done using immuno- Dr. Morse said. Having neoantigens or histochemistry staining, polymerase something else for the T cells to respond chain reaction (PCR), or next-generation to may improve the response to immu- sequencing. Dr. Overman said that they tecan, and who do not have satisfactory notherapy. It is possible that WNT sig- all function reasonably well, although alternate treatment options. naling could play a role in this, as it has there are some downsides to each ap- Soon afterward, in July 2017, the FDA been found to be inversely correlated proach. PCR testing has a sensitivity and also approved nivolumab for the treat- with T-cell infi ltration. Targeting WNT specifi city of 97% and 95%, respectively, ment of dMMR CRC after the same prior signaling is diffi cult, though, because it although it is known to be less accu- treatment. This was based on results of is mainly a protein-protein interaction, rate in noncolon cancers. IHC staining the CheckMate-142 study, in which 74 Dr. Morse said. has a sensitivity of 92% and a specifi c- patients with dMMR CRC were treated Still, some therapeutic approaches ity of 99%, but it cannot detect loss-of- with single-agent nivolumab; that study have been proposed. For example, in function mutations. Next-generation showed a response rate of 31%, and one ongoing clinical trial, the porcupine sequencing is effective but there are 69% demonstrated disease control for inhibitor CGX1321 is being tested along multiple approaches using different mic- 12 weeks or longer.1 At 12 months, the with pembrolizumab in patients with rosatellite targets, with varying sensitiv- progression-free survival (PFS) rate was advanced gastrointestinal tumors. ity and specifi city. 50%, and the overall survival (OS) rate There is also potential with approach- “I think it is key that everyone under- was 73%. es that modulate the cytokine envi- stands the universal testing approach is The same study also examined the ronment since this can also induce an now listed in guidelines,” Dr. Overman combination of nivolumab and ipi- immune response. This could be accom- said. “Everyone should be tested.” limumab in 119 patients with dMMR plished by inducing infl ammation in the CRC.1 The combination appeared ef- tumor. A phase Ib study of talimogene Dr. Michael J. Overman fective, with an overall response rate of laherparepvec along with atezolizum- 55%, a 12-month PFS rate of 71%, and a ab is ongoing in patients with triple- Dr. Marc S. Ernstoff 12-month OS rate of 85%. negative breast cancer or colorectal can- Dr. Overman noted that the responses cer with liver metastases. Pruritus, rash, and diarrhea are among appear to be extremely durable. Long- Dr. Morse said it could also be pos- the most common irAEs. The timing can term follow-up of several cohorts has sible to focus on natural killer (NK) vary: skin reactions tend to occur early, revealed a fl attening of both PFS and OS cells rather than on T cells as a way to and gastrointestinal, endocrine, and he- curves, suggesting the effect is a lasting improve pMMR responses to immuno- patic toxicities are usually seen within one. This is true of nivolumab and pem- therapy. Early results from a fi rst-in- the fi rst 12 weeks of therapy. brolizumab monotherapy, as well as the human trial of monalizumab, which “About 10% to 20% of patients will combination of an anti–PD-1 agent with suppresses inhibitory signaling by tu- have lasting, unresolved toxicities re- an anti–CTLA-4 agent; the 12-month mors on NK cells, plus durvalumab in quiring ongoing management,” Dr. Ern- PFS rate in a cohort of patients receiving metastatic pMMR CRC will be present- stoff said. the combination was 77%, compared ed on Sunday (Abstract 3540). There Some of the main principles of irAE with 48% in a group receiving nivolum- were three partial responses out of 37 management include ruling out other ab monotherapy. patients, while none would be expected causes such as infection or comorbid With pembrolizumab monotherapy, with only the checkpoint inhibitor in diseases and consulting early on with Dr. Overman noted that in 18 patients this patient population.2 organ-specifi c specialists when appropri- who stopped therapy at 2 years per the Looking toward the future, Dr. Morse ate. Also, several established treatment study protocol (11 with a response and said cancer vaccine approaches may be algorithms have now been published seven with residual disease), the medi- necessary. “It is likely that there will be that provide guidance for manage- an time off therapy was 8 months and patients who do not have adequate T-cell ment. It is important to be aware of life- none have yet recurred. The 12-month responses,” he said. “If we could acti- threatening AEs such as myocarditis, Checkpoint Inhibitors PFS rates seen with both nivolumab and vate them with cancer vaccines, then we myositis, pneumonitis, and bowel per- It has long been known that dMMR pembrolizumab are among the highest would have the substrate for checkpoint foration. CRC has a unique immune tumor mi- seen across the variety of tumor types in molecules to work on at the tumor site.” “Immune checkpoint inhibition of croenvironment consisting of tumor- which these agents have been tested and He stressed that the dramatic differ- the PD-1/PD-L1 axis is, in general, well- infi ltrating lymphocytes and a Crohn- approved. ences between dMMR and pMMR out- tolerated and has an excellent safety like lymphoid reaction.1 The immune Several phase III trials are now ongo- comes and responses suggest a new ap- profi le compared to conventional che- activity is likely responsible for the fa- ing in this fi eld. In one, atezolizumab is proach may be needed. “At some point motherapy,” Dr. Ernstoff said. “Familiar- vorable outcomes observed in resected being tested alone and in combination we’re going to have to diverge; they are ize yourself and your community with dMMR CRC and led to the initial trials with chemotherapy (mFOLFOX6) and biologically different,” Dr. Morse said. the toxicity profi le.” of immune checkpoint inhibitors in this bevacizumab in more than 300 patients “It may be that we have to forge our own –Dave Levitan setting. with MSI-high metastatic CRC. Enroll- path and study microsatellite-stable as a In May 2017, the U.S. Food and Drug ment has completed for another study completely separate entity without con- References: Administration (FDA) approved pembro- in the metastatic setting. A total of 270 sidering what goes on in MSI-high.” 1. Overman MJ, et al. Am Soc Clin Oncol Educ lizumab for treatment of patients with patients will be randomly assigned to Book. 2018;38:239-47. dMMR CRC after prior treatment with either mFOLFOX6 and bevacizumab or Managing Toxicity 2. Segal NH, et al. J Clin Oncol. 2018;36 fl uoropyrimidine, oxaliplatin, and irino- pembrolizumab monotherapy. Since checkpoint inhibitors are now (suppl; abstr 3540). am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 19 A Much Work Remains to Determine Optimal Immunotherapy Combinations

he fi eld of cancer immunotherapy combining something with an anti–PD-1 Panelists from the Education Session “Rational has greatly advanced during the agent in melanoma will be signifi cantly Combinations With an Immuno-Oncology Backbone.” last 7 years. Agents approved for better,” Dr. Eggermont noted. the treatment of advanced melano- A small increase in overall survival has Tma by the U.S. Food and Drug Adminis- been observed when the anti–PD-1 agent tration include the anti–CTLA-4 antibody nivolumab was combined with ipilim- ipilimumab (2011), the anti–PD-1 anti- umab compared with nivolumab alone. bodies nivolumab (2014) and pembro- More recently, anti–PD-1 agents com- lizumab (2014), ipilimumab combined bined with indoleamine 2,3-dioxygenase with nivolumab (2015), and the oncolyt- (IDO) inhibitors showed promising re- ic virus vaccine talimogene laherparepvec sults. An interim analysis of a study of (T-VEC; 2015). In addition, the combina- the IDO inhibitor epacadostat and pem- tion of the kinase inhibitors dabrafenib brolizumab showed an overall response and trametinib was approved in 2014 for rate of 58%. This led to a phase III pro- BRAF-mutant melanoma. Disease remis- gram that was stopped in April because sion has been achieved in many more pa- of negative results. Combining the on- tients thanks to these agents. The avail- colytic vaccine T-VEC with pembroli- able evidence and continuing research zumab in patients with melanoma led to for effi cacious combinations of therapies an overall response rate of 57%. for melanoma treatment was the topic “Is this suffi cient to be better than of the Education Session “Rational Com- anti–PD-1 alone? I doubt it,” Dr. Egger- sity of gut bacteria and had prolonged which radiation acts as an in situ vaccine binations With an Immuno-Oncology mont said. More research is needed to progression-free survival. The results leading to increased control of distant Backbone,” held June 1. obtain better insight into the optimal were recapitulated using fecal samples disease sites. The second type of inter- Alexander M. Eggermont, MD, PhD, of mechanisms and timing of combining from the patients in mechanistic stud- action is immunogenic modulation, in Cancer Institut Gustave Roussy, France, therapies. ies in germ-free mice. A collaborative which changes occur in the tumor mi- provided an overview of treatment with effort is currently underway to conduct croenvironment and any residual cancer multiple immunotherapies. Combin- Biomarkers to Monitor Disease Response a clinical trial to further investigate the cells leading to immune-mediated clear- ing therapies does not always lead to a Jennifer A. Wargo, MD, MMedSc, of modifi cation of the gut microbiome to ance of remaining local disease. successful outcome. For example, the The University of Texas MD Anderson elicit better response to therapy via fecal Evidence to date indicates that a high- combination of dacarbazine with ipi- Cancer Center, discussed ways to opti- transplant and other methodologies. er radiation dose may lead to a better limumab in patients with advanced mize treatment regimens based on dis- “Combination therapy holds tremen- endogenous vaccine effect, but an in- melanoma was less successful than ipi- ease response to therapy. Reverse trans- dous promise, but there are a lot of com- fl exion point may exist. To date, most limumab monotherapy. The immune- lation follows patients longitudinally plexities with regard to ideal combina- clinical trials of combined radiation related adverse event profi le of 3 mg/ using blood and tumor samples. This tions, dosing schedules, and optimal and immunotherapy have been early- kg ipilimumab is well-characterized and methodology was used to determine biomarkers of response. As we move for- phase studies. When combined with includes colitis, hepatitis, hypophysitis, potential biomarkers in a cohort of 53 ward, I think we need to embrace novel interleukin-2, the data indicate better re- and rare cases of myocarditis and neu- patients with melanoma who received biomarkers and targets,” Dr. Wargo con- sponse with ablative doses of radiation ritis syndromes. Combination therapy treatment with ipilimumab. cluded. therapy. The response rates of radiation may result in unforeseen events, further Seven patients experienced a disease combined with immune checkpoint in- complicating the development of opti- response; 46 patients experienced dis- Radiation and Immunotherapy hibitors in clinical studies have not been mal treatment. ease progression and subsequently re- Marka R. Crittenden, MD, PhD, of the as high as those seen in the preclinical ceived anti–PD-1 therapy. Of those 46 Earle A. Chiles Research Institute, Provi- setting. patients, 13 demonstrated disease re- dence Cancer Center, provided an up- Recent reports indicate that responses sponse and 33 had disease progression. date on the preclinical data of radiation to immune checkpoint inhibition com- Baseline biopsies and biopsies during with immunotherapy combinations and bined with radiation therapy are depen- treatment were obtained from all pa- available clinical trial information. Sev- dent on preexisting immunity. Although tients with molecular and immune pro- eral synergistic mechanisms exist that there is a solid basis for combining radia- fi ling conducted at each time point. The relate to radiation and the subsequent tion with immuno-oncology agents to immune signatures in the pretreatment immune response. These include tumor boost abscopal responses, the details are biopsy did not predict response to ther- antigen release and increased priming, still being researched. Preclinical studies apy, but the immune signatures in the tumor adjuvant release, the deletion of will help guide the timing, appropriate biopsies obtained during treatment were anergic and regulatory T cells, as well immunotherapy combinations, and the highly predictive. as T-cell activation, antigen processing amount of optimal fractionation. In ad- “If we stress the system and look for an machinery, death receptor upregulation, dition, immuno-oncology agents other adaptive response during treatment, we induction of cytokines and chemokines, than immune checkpoint inhibition may get a better answer, suggesting that and increased immune-cell traffi cking. should be investigated in clinical trials. early on-treatment biomarkers may have Dr. Crittenden discussed two types of “Radiation struggles a lot more when more utility, at least in the short-term, synergistic interactions between radia- a patient does not have a competent until we can identify better pretreatment tion therapy and the immune response. immune system, suggesting that part of biomarkers,” Dr. Wargo said. The fi rst is the abscopal response, in why radiation works is that the immune Several lines of evidence suggest that system helps clear the last residual cells,” Dr. Alexander M. Eggermont the gut microbiome affects the response Dr. Crittenden said. to immunotherapy. The microbiome is Patients receiving anti–PD-1 therapy Anti–PD-1 and anti–PD-L1 antibodies comprised of 100 trillion microbes, mak- have demonstrated enhanced local con- have a more favorable toxicity profi le ing up 3% of the human body mass. The trol of radiated tumors. PD-1 axis acti- compared with anti–CTLA-4 antibod- gastrointestinal tract harbors the great- vation occurs following radiation as a ies. Various combinations of ipilimumab est number of microbes. Dr. Wargo and result of PD-L1 upregulation. with other immune-modulating, antian- her team wanted to investigate the role “If you have patients receiving PD-1 giogenic, chemotherapeutic, or targeted of the gut microbiome in patients who inhibition, even if they are not respond- agents have been investigated or are un- received immune checkpoint blockade ing systemically, they often show very der evaluation, but nivolumab and pem- for melanoma. good responses to the radiated tumor. brolizumab have taken center stage in Oral and gut microbiome samples and Now we are starting to look at immu- the development of combination thera- biopsies were obtained from 233 patients notherapy in the upfront neoadjuvant pies. at baseline and after therapy. The sam- setting in combination with radiation “Monotherapy with anti–PD-1 agents ples underwent microbiome sequencing to see if we can start reducing our doses has been phenomenally successful in and immune profi ling, revealing that and perhaps spare toxicity,” Dr. Critten- melanoma and is actually an overachiev- patients who responded to anti–PD-1 den concluded. er. Thus, it will be diffi cult to show that therapy had a much greater diver- Dr. Jennifer A. Wargo –Muriel Cunningham A 20 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Patient-Reported Outcomes (physical and mental health); physical said. Patients wore the watches an aver- Dr. Manali I. Patel Continued from page 4A function, fatigue, sleep disturbance, age of 9.8 hours a day, meaning captur- social/role function; and anxiety. Ad- ing the activity data on the device was Thompson said. “Patients were random- ditionally, patients were asked four sin- feasible. ly assigned into three groups for mode gle-item linear analog self-assessment Response rates over the 12-week study of survey collection. These groups were questions: physical well-being, emotion- varied: Group 1 had an average response stratiﬁ ed by cancer state—active treat- al well-being, fatigue, and quality of life. rate of 76%, Group 2 had an average of ment, survivorship, and observation The median age of the 294 patients 77%, and Group 3, who completed their alone—as these groups were likely to was 53 (range, 20-79) and the median weekly surveys on the iPhone app but have different PRO and activity levels.” time since cancer diagnosis was 14.4 the emoji component on the watch, Group 1 answered weekly surveys on pa- months. There were 99 patients in Group had a 60% response rate. In all groups, per only, Groups 2 and 3 answered weekly 1 (paper only), 98 patients in Group 2, the response rates decreased over time. surveys on their iPhones, with Group 2 and 97 patients in Group 3. The majority In Group 3, the response rate decreased receiving daily emoji questions on their of patients were receiving active therapy, to about 40% by week 12; the other two iPhone and Group 3 receiving daily emoji predominantly white, and predominant- groups had a response rate of more than questions on the Apple Watch. ly female. 60% at week 12. associations between PROs and activ- The weekly surveys included Patient- “In general, this was a computer-savvy Activity levels were analyzed using ity levels were analyzed with Spearman Reported Outcomes Measurement Infor- group, but only 27% had used a smart- square root of average daily values in or- correlations (SC) for univariate analysis, mation short forms: global health scale watch prior to the study,” Dr. Thompson der to minimize the effect of outliers. The stepwise linear regression models for multivariate associations, and mixed models for longitudinal associations; in all, the researchers collected more than 21.4 million discrete data points. “We found having more steps per day was associated with less fatigue, better physical function, better global physical well-being, better social function, and Submit Your less sleep disturbance,” Dr. Thompson said. “Having more minutes of exercise per day was associated with better global mental well-being and less sleep Cancer Research to disturbance.” The researchers developed two emoji scales (one ordinal, one mood), each of which met the criteria for a valid ordinal scale. There was a high association between the emoji scale and fatigue (SC -0.80; p < 0.0001), between the emoji scale and physical function (SC 0.70; p < 0.0001), on the emotional scale (SC Publish with ASCO journals to have your work read by nearly 45,000 0.68; p < 0.0001), and overall QOL (SC 0.75; p < 0.0001). Patients who selected members and thousands of institutions in more than 150 countries: the “happy face” emoji in the mood analysis had better overall ratings than • Journal of Clinical Oncology® other groups, whereas the “thinking • Journal of Oncology Practice® face” group had the lowest QOL, physical health, and mental health, and the • Journal of Global Oncology® highest anxiety scores. Dr. Thompson’s group will continue • JCO™ Clinical Cancer Informatics following patients every 3 months for 24 months for events, including relapse, re- • JCO™ Precision Oncology treatment, hospitalization, and death to determine associations between activity level and PROs with clinical outcomes. Submit Your Manuscript Today “In addition, we are performing further analysis to understand the dis- ascopubs.org crepancies in response rates between groups,” she said.

Lay Health Worker–Led Symptom Assessment In the third study (Abstract 6502), Manali I. Patel, MD, MPH, MS, of Stanford University, said rising cancer costs “are demanding novel ways to deliver effective care.” Numerous barriers to symptom management have been previously identiﬁ ed, including professional workforce shortages. Dr. Patel’s group implemented a proactive symptom assessment conducted by a lay health worker supervised by a nurse practitioner. Patients were enrolled if they were newly diagnosed with stage III or IV cancer, required medical oncology, planned to receive all of their care at the oncology practice where the assessment was implemented, and were enrolled in Care- More Medicare Advantage. The primary See Patient-Reported Outcomes, Page 22A am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 21 A

already be familiar with the data, and FDA Commissioner Discusses How Agency the analysis and review teams will be in a better position to conduct more effi cient and thorough data review,” Dr. Plans to Speed Access to Cancer Advances Gottlieb said. The second pilot program includes e are at a turning point in have created a single therapeutic ap- a new application assessment aid. This Dr. Scott Gottlieb the history of cancer,” said proach based on the solid understanding tool is a voluntary submission form that Scott Gottlieb, MD, commis- of the underlying biology of microsatel- applicants can use to facilitate the FDA’s sioner of the U.S. Food and lite stability,” Dr. Gottlieb said. assessment of the drug application. Un- “WDrug Administration (FDA), addressing Dr. Gottlieb also announced the der this templated approach to review- the crowded room of ASCO attendees launch of two new FDA pilot programs. ing applications, the FDA will annotate during the Opening Session on June 2. The fi rst is aimed at focusing submissions the sponsor’s drug fi le with its own as- During his presentation, Dr. Gottlieb more squarely on the most relevant data sessment. The annotated application highlighted some of the new efforts that for assessing safety and effi cacy. will be presented at the Oncology Drug the FDA is pursuing across the entire drug “The goal is to improve the overall Advisory Committee meeting as a single, development and regulatory process and quality of drug applications and make combined background document that how the FDA hopes to create policies sure that resource and review times are contains the applicant’s position and the that are as sophisticated as some of the being focused on evaluating data that FDA’s analysis of that position. treatments currently in development. are most meaningful to clinicians and “A world is being created in many For example, in 2017, the FDA ap- patients,” Dr. Gottlieb said. places where individual health and well- proved 16 new drugs and biologics in- Under the pilot program, as soon as a ness are more clearly and rapidly be- cluding the fi rst two CAR T-cell therapies. sponsor locks its database and decides it coming the benefi ciary of technologic It also approved the fi rst tissue-agnostic wants to fi le with the FDA for drug ap- process,” Dr. Gottlieb said. “We are chal- cancer treatment. proval, the FDA starts sharing data. This lenging ourselves at the FDA to make “Rather than require a separate devel- informed pre-analysis gives reviewers sure we have the best approach to move opment program for each disease site, and sponsors an early opportunity to ad- “By the time the sponsor fi les the ap- these opportunities forward.” which may have taken many years, we dress data-quality issues. plication, the agency review team will –Leah Lawrence

Cell-Free DNA Assays Dr. Carlos Caldas relapse, Dr. Caldas noted. “I hope that initiative to conduct molecular profi ling Continued from page 7A within the next 12 to 18 months we will at earlier stages of disease when matched have hard data on this,” he said. therapies can be curative and treatment 0.003% and 0.2%, thus a highly sensi- There is currently great excitement morbidity is lower, Dr. Solit said. tive assay and tumor-informed approach over developing cfDNA assays as a di- Dr. Solit and colleagues have at- are required for detection, Dr. Diehn agnostic tool. There has been some in- tempted to apply their MSK-IMPACT noted. teresting research in this area suggesting assay to plasma samples to determine Dr. Diehn also discussed ongoing that copy number gains and losses in if they could analyze 468 cancer genes work to develop a urine-based cfDNA cfDNA may allow presymptomatic tu- in a cfDNA assay. In about two-thirds of assay to detect recurrence following lo- mor detection, Dr. Caldas said. cases, they are able to detect mutations calized bladder cancer treatment. Cur- in cfDNA, whereas no mutations can be rently, surveillance in these patients Bringing cfDNA Assays Into the Clinic detected in the remaining cases, suggest- requires repeated urine cytology and In his presentation, David B. Solit, ing their methods are not adequately cystoscopy, which is limited by low MD, of Memorial Sloan Kettering Can- sensitive for cfDNA assays, he said. sensitivity and high cost. He and col- cer Center, discussed how medical on- Nevertheless, Dr. Solit recounted a pa- leagues modifi ed the CAPP-Seq assay to cologists can use cfDNA assays in treat- tient case to illustrate the urgent need detect ctDNA in the cell-free compo- genome sequencing that ctDNA levels ing patients with advanced cancer either to develop cfDNA. In a young patient nent of urine samples. fall when patients respond to treatment alongside other tests or instead of ge- with cancer, tumor profi ling from a lung In a cohort of 64 patients with early- and rise when disease progresses. There- nomic profi ling of tumor tissue. biopsy failed because of inadequate tis- stage bladder cancer, ctDNA was detect- fore, they are a better biomarker of dis- Four years ago, an initiative at Memo- sue for analysis, as it does in 5%-10% of able in the urine of patients who had ease than circulating tumor cells or can- rial Sloan Kettering Cancer Center set cases. A cfDNA test was able to detect disease recurrence following treatment cer antigen 15-3. Now, they can use ultra out to molecularly profi le tumor tissue an actionable EML4-ALK fusion, but it months prior to the clinical diagnosis low pass whole-genome sequencing of for every patient with cancer to iden- was only done after the patient had died of recurrence, whereas ctDNA was de- plasma samples without any knowledge tify any actionable mutations and then from the cancer. “We didn’t have the tectable in only one patient who did of tumor mutations, Dr. Caldas noted. match those patients with the appropri- technology at the time to identify the not have recurrence. The sensitivity and In other applications, Dr. Caldas and ate therapy. For the molecular profi ling, key molecular drivers in this individual specifi city of a tumor-informed urine colleagues conducted proof-of-principle they use an assay called MSK-IMPACT, patient,” Dr. Solit said. cfDNA approach were 91% and 100%, studies that suggested they could iden- which captures regions in 468 cancer “To me, the fi rst use of cfDNA going respectively, compared with a sensitivity tify mutations associated with resistance genes of interest using biotinylated DNA forward is in this population where we of about 40% with urine cytology and in patients with mBC using whole- probes and sequences the regions for al- simply can’t get good tumor tissue to do cystoscopy. exome sequencing. They were also able terations. tumor genomic analysis, and cell-free to capture the metastatic heterogeneity To date, approximately 24,000 pa- will potentially provide an option,” Dr. Breast Cancer Monitoring and and evolution of mutations between me- tients have received MSK-IMPACT test- Solit said. “There are probably hundreds Management tastases by exome and targeted amplicon ing. There is an effort now within the to thousands of patients like this in the Clinicians are deploying cfDNA assays sequencing, “opening up the possibility country who are dying,” especially pa- to monitor disease burden in patients of liquid biopsies representing not one tients with metastatic prostate cancer. with metastatic breast cancer (mBC), and metastasis but all metastases,” Dr. Caldas –Carina Storrs, PhD there is evidence that these assays could said. be used to stratify therapy, identify drug Currently, Dr. Caldas and colleagues References: resistance–associated mutations, and de- are carrying out a study of whole- 1. Chaudhuri AA, et al. Cancer Discov. tect heterogeneity between metastases. genome sequencing to assay for structur- 2017;7:1394-403. However, the question remains whether al variants such as translocations rather 2. Dawson SJ, et al. N Engl J Med. ctDNA could be used prospectively for than point mutations. This approach has 2013;368:1199-209. early diagnosis of cancer, said Carlos the advantage of being free of PCR and 3. Adalsteinsson VA, et al. Nat Commun. Caldas, MD, FRCP, FRCPath, FMedSci, sequencing artifacts such that detection 2017;8:1324. of the University of Cambridge, United of even one copy of a structural variant 4. Murtaza M, et al. Nature. 2013;497:108-12. Kingdom, during his presentation. in cfDNA would indicate the presence 5. Murtaza M, et al. Nat Commun. In 2013, Dr. Caldas and colleagues of tumor cells and thus could be a more 2015;6:8760. demonstrated using targeted or whole- sensitive way to detect MRD and track Dr. David B. Solit 6. Amant F, et al. JAMA Oncol. 2015;1:814-9. A 22 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Karnofsky Memorial Award One important area of Dr. Weichselbaum’s research was defi ning, Patient-Reported Outcomes Continued from page 3A Continued from page 20A along with his colleague Samuel Hellman, MD, FASCO, the clinical state of that some patients so affected should be oligometastasis, which they hypothesized refers to a distinct clinical entity. outcome was feasibility (retaining 75% amenable to a curative therapeutic strat- of patients), with secondary outcomes egy.”1 Their hypothesis was published in some patients with oligometastatic dis- For the future, several avenues of in- of health care use, patient satisfaction, the Journal of Clinical Oncology in 1995, ease can be cured with ablative therapy vestigation are promising, Dr. Weich- and self-reported health. There were although it was consigned at that time and that these patients “can likely be selbaum said. These include clinical a total of 186 patients in the interven- to the editorial page. identifi ed through clinical features and and molecular classifi cation of the tion group and 102 patients in the con- The hypotheses underlying the subse- molecular parameters,” he said. Also, spectrum of metastasis, improved in- trol group. Baseline characteristics were quent research efforts were that metas- “some patients with oligo-progressive teraction of radiotherapy and immune similar between the two groups, but the tasis represents a spectrum of disease, disease may be cured.” therapy, and use of metastasis-directed intervention group had a higher risk ad- including the number of metastases, the Dr. Weichselbaum also highlighted ablative therapy to cure or decrease tu- justment factor (3.25 ± 1.78 vs. 2.80 ± involved organs, and the pace of progres- research related to the “cytoreductive mor cell burden. 1.43, respectively). sion. Additionally, subsets of patients power of radiation therapy” and said –Kathy Holliman, MEd Patients who received the proactive with limited or oligometastatic disease that radiation is a “powerful cytotoxin” symptom assessment had signifi cantly are potentially curable with metastasis- that can be used to boost antitumor im- Reference: lower mean number of emergency de- directed therapies. munity locally and “maybe systemically 1. Hellman S, et al. J Clin Oncol. 1995;13:8- partment visits per quarter (0.60 vs. Randomized research has found that as well.” 10. 0.92; p = 0.03) and lower mean number of inpatient admissions per quarter (0.72 vs. 1.02; p = 0.03). “There was an almost $10,000 differ- - ADVERTISEMENT - ence in total costs of care between the intervention group and the control group,” she said. Janssen Clinical Trials Self-reported overall health and men- Enrolling Patients with Genitourinary Cancers tal/emotional health also improved at the 5-month follow-up compared to the APALUTAMIDE* CLINICAL TRIAL 1-week post-oncology visit. KRONOS (QUROOLQJ4$OO6LWHV,GHQWLÀHG 56021927PCR2032 $Q2SHQ/DEHO0XOWLFHQWHU3KDVHEVWXG\RI-1-D3',QKLELWRU$GPLQLVWHUHGLQ ‘Important,’ But Unanswered &RPELQDWLRQZLWK$SDOXWDPLGHLQ6XEMHFWVZLWK0HWDVWDWLF&DVWUDWLRQ5HVLVWDQW3URVWDWH&DQFHU Questions Remain IROORZLQJSURJUHVVLRQDIWHUWUHDWPHQWZLWKDELUDWHURQHDFHWDWHSOXVSUHGQLVRQHSUHGQLVRORQHRU Discussant Martin J. Taphoorn, MD, of DSDOXWDPLGHRUHQ]DOXWDPLGH Haaglanden Medical Center and Leiden )RUDQ\TXHVWLRQVRQWKHVWXG\SOHDVHFRQWDFW'U6S\URV7ULDQWRVDWVWULDQWR#LWVMQMFRP University Medical Center, Netherlands, NIRAPARIB* CLINICAL TRIALS called all three papers “important,” but he said they all left some unanswered Your patient may qualify if: questions. For instance, although web- • mediated follow-up for PROs allows for 5HFHLYHGDWOHDVWOLQHRIWD[DQHEDVHGFKHPRWKHUDS\ $OOVXEMHFWVUHFHLYHGDLO\ • 5HFHLYHGDWOHDVWOLQHRI$5WDUJHWHGWKHUDS\ RUDOLQYHVWLJDWLRQPHGLFDWLRQ easy assessment and earlier detection • %LRPDUNHUSRVLWLYHVXEMHFWVLGHQWL¿HGGXULQJ QLUDSDULE and treatment of symptoms, it’s not ap- SUHVFUHHQLQJZLOOSURFHHGWRVFUHHQLQJ $3KDVH(I¿FDF\DQG3K 1 plicable for all patients. “There may be • 6DIHW\6WXG\RI1LUDSDULE (&2*36 cross-cultural differences in the use of a in Men with Metastatic • Males over the age of 18 Follow-up Castration-Resistant web-based system,” he said. 3URVWDWH&DQFHUDQG Using mobile technologies or apps DNA-Repair Anomalies &OLQLFDO7ULDOVJRYVWXG\1&7 within the technology “may reduce the response burden and increase compli- Your patient may qualify if: Treatment Phase Part I: ance,” he said. “But it is important to see QLUDSDULEPJ4'GRVH • $WOHDVWEXWQRPRUHWKDQOLQHVRIQRYHO in the longer-term follow up that there $5WDUJHWHGWKHUDS\ selection JNJ-63723283 was still a difference in OS with or with- 64091742PCR2002 • 0HDVXUDEOHGLVHDVHDVGH¿QHGE\5(&,67 1 out cross-over. This could be cost-effec- • Progression of metastatic castrate resistant prostate $3KEVWXG\RI Treatment Phase Part II: 1LUDSDULE &RPELQDWLRQ cancer tive because it may reduce the number Therapies for the QLUDSDULEPJ4'53' of CT scans.” Treatment of Men with • (&2*36 JNJ-63723283 Prostate Cancer • Male over the age of 18 Although the Apple Watch activ- 1 &RPELQDWLRQ1LUDSDULE • 1RSULRUWUHDWPHQWZLWK3$53LQKLELWRU ity data was associated with PROs and DQG-1- • 3DWLHQWVZLWKDQGZLWKRXW'1$UHSDLUDQRPDOLHV Follow-up DQWL3' emojis are showing promise for PRO assessment, Dr. Taphoorn was concerned )RUDQ\TXHVWLRQVRQWKHVWXG\SOHDVHFRQWDFW'U1LVKL.RWKDULDWQNRWKDU#LWVMQMFRP about the moderate response rate on the 1LUDSDULELVD3RO\ $GHQRVLQH'LSKRVSKDWH>$'3@5LERVH 3RO\PHUDVH 3$53 ,QKLELWRU watch and with the lack of comparative data between the three groups. ERDAFITINIB* CLINICAL TRIAL “Emojis are easily interpretable, which $3KDVH6WXG\RI(UGD¿WLQLE&RPSDUHGZLWK9LQÀXQLQHRU'RFHWD[HORU3HPEUROL]XPDE could be benefi cial for those with cog- LQ6XEMHFWVZLWK$GYDQFHG8URWKHOLDO&DQFHUDQG6HOHFWHG)*)5*HQH$EHUUDWLRQV nitive diffi culties, illiteracy, or for chil- Your patient may qualify if he or she has: Cohort 1 – prior (UGD¿WLQLEPJ dren,” Dr. Taphoorn said. 3' / WUHDWPHQW • 0HWDVWDWLFRUVXUJLFDOO\XQUHVHFWDEOH urothelial cancer 42756493BLC3001 1 Chemotherapy 'RFHWD[HOPJPRU • 5HFHLYHGRQO\OLQHRISULRUV\VWHPLF “Emojis are easily 5DQGRPL]DWLRQ treatment for metastatic urothelial cancer (OLJLELOLW\ 9LQÀXQLQHPJP • (YLGHQFHRIGLVHDVHSURJUHVVLRQ interpretable, which could be Screening 5DQGRPL]DWLRQ • ECOG performance status score 0, 1, or 2 (UGD¿WLQLEPJ benefi cial for those with cognitive 1 Cohort 2 – no prior • Tumors with at least 1 of a group of 3' / WUHDWPHQW SUHVSHFL¿HG)*)5JHQHDEHUUDWLRQV diffi culties, illiteracy, or for 3HPEUROL]XPDEPJ 1 • $GHTXDWHERQHPDUURZOLYHUDQGUHQDO children.” –DR. MARTIN J. TAPHOORN function

)RUPRUHLQIRUPDWLRQRUTXHVWLRQVFRQWDFW7LWR5RFFLDDWWURFFLD#LWVMQMFRPRU6KRQGD/LWWOHDWVOLWWO#LWVMQMFRP Using a lay health worker to assess 7KHVDIHW\DQGHI¿FDF\RIWKHLQYHVWLJDWLRQDOXVHRIWKHVHSURGXFWVKDVQRWEHHQGHWHUPLQHG7KHUHLVQRJXDUDQWHH symptoms can improve overall health WKDWWKHLQYHVWLJDWLRQDOXVHVOLVWHGZLOOEH¿OHGZLWKDQGRUDSSURYHGIRUPDUNHWLQJE\DQ\UHJXODWRU\DJHQF\ and patient satisfaction while substantially reducing health care use and costs, but the short-term results and Janssen Research & Development, LLC lack of control group should not be GU Oncology-ENG01 Version 1.0, 23MAR2018 overlooked. –Michelle Dalton, ELS COME SEE WHAT’S POSSIBLE AT THE EISAI BOOTH #7025

LENVIMA® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2018 Eisai Inc. All rights reserved. Printed in USA/May 2018 LENV-US2112 VisitVisit us us at at booth booth 21135 3085 NOW RECRUITING NewlyNewly Diagnosed FLT3-ITD Mutated(+) AML AMLin inPatients Patients aged aged 18 18- 75 - 75

Quizartinib Advancement into the Next Generation of Trials for Unmet Needs in AMLL

A Phase 3,3, Randomized,Randomized, Double-Blind,Double-Blind, Placebo-controlled Placebo-controlled Study Study of of Quizartinib Quizartinib (AC220) (AC220) Administered Administered in in Combination With InductionInduction andand ConsolidationConsolidation Chemotherapy, Chemotherapy, and and Administered Administered as as Maintenance Maintenance Therapy Therapy in Subjects 18 to 75 Years Old With Newly Diagnosed FLT3-ITD Mutated(+) Acute Acute Myeloid Myeloid Leukemia Leukemia

* * CytarabineCytarabine High-DoseHigh-Dose ++ Cytarabine Anthracycline**** Cytarabine QuizartinibQuizartinib Anthracycline ++ NEWLYNEWLY ++ Quizartinib Quizartinib Quizartinib DIAGNOSEDDIAGNOSED Quizartinib FLT3-ITD (+) FLT3-ITD ** AML InductionInduction ConsolidationConsolidation MaintenanceMaintenance Mutated AML (1-2(1-2 cycles)cycles) (up(up to to 4 4 cycles) cycles) and/or HSCTHSCT (up(up to to 1212 cycles)cycles) 18-7518-75 yearsyears ofof ageage ECOGECOG 0-20-2 * * N≈536N≈536 CytarabineCytarabine High-DoseHigh-Dose ++ Cytarabine **** Cytarabine Placebo AML=acute myeloid leukemia; FLT-3=FMS-like tyrosine kinase 3; AnthracyclineAnthracycline + Placebo HSCT=hematopoieticHSCT=hematopoietic stemstem cellcell transplant;transplant; ITD=internalITD=internal tandemtandem + + duplication; + Placebo ** Cycle Cycle 11 consistsconsists ofof 7+37+3 regimen.regimen. AlternateAlternate dosingdosing optionoption forfor Placebo Cycle 2 can include a 5 + 2 regimen. Placebo Placebo **** Daunorubicin / Idarubicin ScanScan here && PrimaryPrimary Endpoint: Event-free SurvivalSurvival (EFS) (EFS) SecondarySecondary Endpoints: tOverallOverall Survival (OS)(OS) tCompositeComposite Complete Remission (CRc)(CRc) tCompleteComplete Remission (CR)(CR) tCRCR withwith nono evidence of minimal residualresidual diseasedisease (MRD)(MRD) LearnLearn moremore Location: North America, Europe, Asia/Other Regions | ClinicalTrials.gov Identifier: NCT02668653 Location: North America, Europe, Asia/Other Regions | ClinicalTrials.gov Identifier:NCT02668653

Quizartinib is an investigational agent and is not approved by the FDA or other regulatory agencies Quizartinibworldwide isas an a treatmentinvestigational for any agent indication. that has Efficacy not been and approved safety have for anynot indicationbeen established. in any country. There is Safety no andguarantee efficacy that have quizartinib not been will established. become commercially available.

For moremore information, information, please please visit: visit: https://clinicaltrials.gov/ct2/show/study/NCT02668653, www.QuantumFirstStudy.com or or www.DSCancerEnterprise.com www.DSCancerEnterprise.com

DaiichiDaiichi Sankyo, Sankyo, Inc Inc · 211 · 211 Mt. Mt. Airy Airy Road Road · Basking · Basking Ridge, Ridge, NJ 07920-2311 NJ 07920-2311 ©© 20182017 Daiichi Daiichi Sankyo, Sankyo, Inc. Inc. All All rights rights reserved. reserved. Printed Printed in in US US 2018 2017 PP-US-QZ-0032PP-US-ON-0027 03/1803/17 www.dsi.comwww.dsi.com SUNDAY · JUNE 3, 2018 B Dr. Douglas R. Lowy to Receive Science of Oncology Award ouglas R. Lowy, MD, will receive Q: Can you talk about your previous the 2018 Science of Oncology and ongoing work in the development Award. The award recognizes out- of the technology that underlies HPV standing contributions to basic or vaccines against cervical cancer? Dtranslational research in cancer. Dr. Lowy: Almost all the research that Dr. Lowy is deputy director of the Na- I have done has been in close collabo- tional Cancer Institute (NCI) and chief ration with my longstanding colleague of the NCI’s Laboratory of Cellular On- John Schiller, PhD, NIH distinguished in- Addressing Patient cology. He is recognized for his work on vestigator and deputy chief in the NCI’s HPV infection and was instrumental in Laboratory of Cellular Oncology. He and Communication developing the technology underlying I initially did basic research, and our fi rst the HPV vaccines that have been ap- foray into translational research was the Challenges proved by the U.S. Food and Drug Ad- development of the virus-like particle ministration (FDA). His contributions vaccine used in HPV vaccination. in this fi eld have been recognized with We were fortunate that this effort paid SESSION the Lasker-DeBakey Clinical Medical off in the laboratory very quickly when Research Award in 2017 and the Szent- we determined that expressing just one PREVIEW Gyorgyi Prize for Progress in Cancer Re- gene from the papillomavirus could search in 2018. make particles that looked like papil- Dr. Douglas R. Lowy here is no question that ad- In an interview with the ASCO Daily lomaviruses. When the particles were vances in cancer diagnostics News, Dr. Lowy discussed the impact of immunized into animals and then into After that fi rst translational research, and treatment have dramati- his research efforts and ongoing investi- people, they induced very high titers of we subsequently developed the standard cally improved the cancer gations, the outlook for cancer research, neutralizing antibodies that are usually serologic assays for measuring immune Tcare landscape. However, these ad- and why this award is important to him associated with protection from preven- responses to HPV vaccination. One is vances have led to increased costs and his colleagues. tive vaccines. See Science of Oncology Award, Page 5B and more complex treatments, causing oncologists to struggle with the sheer scope of information they’re expected to know and communicate to patients. PROs Bring Value to Routine Symptom For example, should oncologists ask patients about the potential fi - Management and Clinical Trials nancial burden of their cancer treatment? Should oncologists explain ing (i.e., “valid”), that they are reliable, the results of complex genetic tests EXPERT and that the scores change as we might to patients or turn to specialists? expect (i.e., “sensitive”). These ques- ARTICLE How can oncologists manage patient EDITORIAL tionnaires can be administered through HIGHLIGHTS expectations about targeted thera- good old-fashioned pencil and paper or pies and immunotherapies when Ethan Basch, MD, MSc, FASCO electronically through the internet, an ■ Patient-reported outcomes (PROs) only a subset of patients responds app, or automated telephone systems refl ect how patients feel and func- extremely well (so-called exception- atient-reported outcomes (PROs) (Fig. 1). tion and are measured through al responders) to treatment? encompass data reported directly Depending on the context of use, PRO questionnaires. Three Education Sessions during by people about how they feel and questionnaires may be administered to ■ PROs can be collected through the 2018 Annual Meeting will delve function—for example, symptoms, patients on a regular basis, for example the internet, automated telephone into these topics, present the latest Pperformance status, and quality of life. every 1, 2, or 3 weeks during active treat- systems, or downloadable ap- research, and provide practical solu- PROs are collected through question- ment from home between visits, or every plications. tions.* naires that ideally have been rigorous- cycle of therapy at visits. There are many ■ ly developed and tested to assure that different reasonable approaches that will Multiple studies have tested Financial Burden of Cancer Care questions are clear, that they are mea- depend on the goals for using the PRO whether it is feasible to integrate During the Education Session suring what we think they are measur- data, as described below. PROs into routine cancer care (it “Communicating the Financial Bur- is) and whether outcomes are improved as a result (they are). den of Treatment With Patients” on Fig. 1. Sample Patient PRO Interfaces for Mobile and Web June 3, session Chair Ryan D. Nipp, ■ PROs are the gold standard for MD, MPH, of Massachusetts General assessing symptoms, physical Hospital Cancer Center, will pres- functioning, and quality of life in ent the clinician’s perspective on clinical trials. discussing cancer care costs with patients, concerns physicians and patients have about discussing fi nan- Using PROs for Symptom Monitoring cial issues, and practical strategies to in Routine Cancer Care alleviate fi nancial distress. Multiple studies show that clinicians “Immunotherapies and targeted miss about half of their patients’ symp- therapies are new and exciting, toms during cancer treatment.1,2 The but they can also be more expen- downstream consequences of missing sive than the older treatments symptoms include patient suffering due such as chemotherapy,” Dr. Nipp to poor symptom control, missed treat- See Patient Communication, Page 3B ments, emergency room (ER) visits and See Patient-Reported Outcomes, Page 13B EXPERIENCE IMBRUVICA®

Visit Booth 13081 to learn more

Patient Communication Next-Generation Sequencing Continued from page 1B Technology has dramatically improved the pace of genetic testing using said. From 1965 to 2013, the aver- DNA. It took more than a decade to se- age monthly cost of cancer treatment quence the fi rst human genome; now a increased from $100 to $10,000.1 “Al- human genome can be sequenced in 1 though patients with a good prognosis or 2 days. live longer, they may need to take their “We have seen a confl uence of bet- medications over a longer period of ter, faster, and cheaper next-generation time, which can add to their fi nancial sequencing (NGS) technologies and burden,” he explained. more targeted therapies approved for Dr. Ryan D. Nipp Dr. Ben H. Park Dr. Thomas W. LeBlanc To better understand the fi nancial cancers,” Ben H. Park, MD, PhD, of the burdens faced by patients and their fam- Johns Hopkins Sidney Kimmel Compre- ilies, Gery P. Guy Jr., PhD, MPH, of the hensive Cancer Center, said. “However, FDA-approved therapies, label versus notherapies. “Because we can’t predict Centers for Disease Control and Preven- NGS is a fast-moving target. Although off-label use, clinical trials, and how to with any degree of certainty who will tion, will present the latest research on some NGS platforms are now U.S. identify and prioritize molecular trials respond well, we may further avoid the costs of cancer care, share the pub- Food and Drug Administration (FDA)– during his talk, “Identifying Appropri- communicating prognostic informa- licly available data sources to examine approved to screen for many abnormal- ate Trials for Our Patients and Consid- tion,” Dr. LeBlanc said. the fi nancial burden, and emphasize the ities, NGS technologies have outpaced ering Compassionate Use Programs.” During her presentation, “Excep- need for more research in this area dur- FDA-approved therapies and are being tional Responders, Hope, and Prog- ing his presentation, “Cost in the Era of used to guide therapeutic decision- Communicating Prognosis nostication: Making a Tough Problem Targeted Therapies and Immunothera- making outside of these intended uses.” Shared decision-making requires that Even Tougher,” Jennifer S. Temel, MD, pies for Cancer.” Dr. Park will chair the Education Ses- patients be informed azbout their prog- of Massachusetts General Hospital, Studies show that when patients delay sion “Helping Our Patients Understand nosis. Although all oncologists talk with will discuss the impact of novel im- or forego care to defray costs, they may Molecular Testing and Its Implications” patients about what to expect, studies munotherapies on oncologists’ ability experience decreased quality of life, in- on June 4. He will discuss how academic show that more than half of patients to formulate and communicate a prog- creased risk of depressed mood, and high- medical centers and community mo- with advanced cancer surveyed have in- nostic estimate to their patients with er frequency of worrying about cancer lecular tumor boards can guide inter- accurate perceptions of their prognosis advanced disease. recurrence.2 However, research also shows pretation and analysis of test results and and tend to overestimate the likelihood Paul R. Helft, MD, of Indiana Uni- that patients want to discuss the fi nancial the differences between germline and of a cure and their survival.5-7 versity Melvin and Bren Simon Cancer impact of care with their oncology team.3,4 somatic testing techniques, their limita- “Other studies suggest that some Center, will present various strategies to Therefore, medical organizations, includ- tions, and his recommendations. oncologists avoid or rarely engage improve communication skills, including ASCO, recommend that clinicians dis- “The results from NGS testing can vary patients in these conversations un- ing training programs and pairing with cuss the cost of care with patients. signifi cantly depending on the exact test less patients explicitly ask about their palliative care specialists during his pre- “We need to think of cost information performed and analysis of sequencing prognosis,” Thomas W. LeBlanc, MD, sentation, “Necessary Collusion: Prog- as another piece of informed decision- data,” he said. “For example, the germ- MA, MHS, FAAHPM, of Duke Univer- nostic Communication With Advanced making, which ultimately empowers pa- line tests we do with a cheek swab speci- sity School of Medicine, said. As chair Cancer Patients.” tients,” Dr. Nipp said. men only look for heritable mutations, of the session “How Much Time Do I –Christine Lehmann, MA Although oncologists can’t be expect- but the tumor tests we conduct predom- Have, Doc? Communicating Prognosis ed to navigate the maze of insurance inantly look for mutations within the in the Era of Exceptional Responders,” References: coverage, just knowing which medica- cancer. Using only one test can result in on June 4, Dr. LeBlanc will set the stage 1. Institute of Medicine. Ensuring Pa- tions are more expensive than others can incomplete information.” for these topics by presenting research tient Access to Affordable Cancer Drugs. jumpstart the conversation. For example, Even when genetic mutations are on prognostication involving patients Washington, D.C. National Academies Dr. Nipp may say to a patient, “I have identifi ed, though, they may not have and physicians’ perceptions and biases. Press;2014:3. heard this is an expensive medication. FDA-approved therapies. During his For example, oncologists may be re- 2. Kale HP, et al. Cancer. 2016;122:283-9. Let me know if you have any problems presentation, “Discussing Test Results: luctant to communicate a negative prog- 3. Irwin B, et al. Oncologist. 2014;19:1135-40. with your insurance coverage or trouble Understanding Actionable and Nonac- nosis when they have seen even a small 4. Bullock AJ, et al. J Oncol Pract. 2012;8:e50- affording this prescription.” tionable Mutations,” Michael P. Mul- number of patients in similar situations 8. To round out the session, Ellen M. lane, MD, of Aurora Cancer Care, will do much better than expected. “The re- 5. Applebaum AJ, et al. J Health Psychol. Sonet, MBA, JD, of CancerCare, will dis- discuss how to prioritize actionable ver- search also shows that as oncologists get 2014;19:1103-19. cuss several strategies for assisting pa- sus nonactionable mutations based on closer to patients and develop long-term 6. Weeks JC, et al. N Engl J Med. tients experiencing fi nancial burdens different levels of evidence, the chal- relationships, they become less accurate 2012;367:1616-25. including assessments, referrals, and lenges of false positives, and the reports in estimating patients’ survival,” Dr. 7. Sekeres, et al. Leukemia. 2004;18:809-16. interventions during her presentation, that molecular tumor boards provide to LeBlanc said. “Assisting Patients With the Cost Bur- referring physicians and their patients. Communicating prognosis to pa- *Program information updated as of February den of Cancer Diagnosis and Treatment: Finally, Aaron S. Mansfi eld, MD, of tients is further complicated by the 22. For session time and location information, Next-Generation Sequencing Testing, the Mayo Clinic, will discuss treatment fact that only a minority of patients please refer to the ASCO iPlanner on the Off-Label Medications, and More.” recommendations, the identifi cation of respond exceptionally well to immu- Attendee Resource Center (am.asco.org/arc).

Education Session to Highlight Novel Molecular Diagnostic Platforms Patrick C. Ma, MD, MSc, of the WVU recent years because of practical limita- Liquid Biopsies SESSION Cancer Institute, said. tions and risks associated with tissue- A recent review article highlighted the “We have seen an unprecedented based biopsy diagnostics, Dr. Ma said. potential and challenge of liquid biopsies PREVIEW pace of progress in expansion of cancer These next-generation molecular di- for early detection of cancer.1 Liquid biop- diagnostics on tumor tissues as well as agnostic assays—such as liquid biopsy sies are intended to provide information he Education Session “Next- beyond tissues in novel noninvasive mo- interrogating circulating tumor DNA or about the response to therapies, to detect Generation Diagnostics Beyond lecular assays,” he said. circulating tumor cells; proteomics, me- relapse with lead time compared to stan- Tissue” on June 4* promises to Other speakers at the Education Ses- tabolomics, and exosomes; urine biopsy dard measures, and to reveal mechanisms provide an in-depth look at the sion will be Sai-Hong Ignatius Ou, MD, to assay circulating tumor DNA; saliva of resistance. The use of these biopsies for Tnovel innovations in noninvasive can- PhD, of the University of California Irvine and stool biopsies for molecular-genom- detection of early malignant disease stag- cer molecular diagnostic platforms as Chao Family Comprehensive Cancer Cen- ic assays; and breath biopsy measures, however, is not as well documented well as their potential and challenges. ter, whose topic will be “Liquid Biopsy to ing volatile organic compounds—have as the research and data available for ad- The need for improvement of molecu- Identify Actionable Genomic Alterations”; transformed the utility of cancer diag- vanced tumor stages.1 lar cancer diagnostics “has never been and Peter Kuhn, PhD, of the USC Michel- nostics, according to Dr. Ma. Novel diag- Dr. Ou’s presentation will focus on the more important” given the advent of son Center, whose topic will be “Noninva- nostic tools are being used to longitudi- innovations in liquid biopsies that can cancer genomics and genomics-guided sive Biomarkers for Immunotherapy.” nally monitor therapy for early disease identify actionable genomic alterations, precision medicine and the arrival of Noninvasive cancer diagnostics plat- detection and for therapeutic response- the approved tests, next-generation plat- cancer immunotherapies, session Chair forms have evolved and expanded in resistance monitoring, he said. See Molecular Diagnostic Platforms, Page 13B B 4 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

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multiple myeloma who are receiving maintenance therapy, an every 3-month ASCO Updates Guidelines for Use of interval of bisphosphonates can be considered rather than monthly administra- Bone-Modifying Agents in Multiple Myeloma tion. Data from the single-arm Z-MARK study suggested that less-frequent dosing of zoledronic acid is associated n January, members of an Expert approximately zoledronic acid over clodronate (only with a low incidence of skeletal-related Panel updated ASCO Clinical Practice 80% of patients approved outside the United States) for events. G uidelines on the role of bone-modi- with myeloma preventing skeletal complications. In terms of duration of therapy, previ- fying agents in patients with multiple have osteopo- ous guidelines had suggested continuing Imyeloma.1 The update incorporates evi- rosis or lytic Inclusion of Denosumab in Guidelines bisphosphonates for 2 years, after which dence that has become available since disease of bone Denosumab received U.S. Food and point discontinuation should be consid- the guidelines were last published, in- at diagnosis. Drug Administration approval in Janu- ered and further use should be left up to cluding new information about deno- The expan- ary for the prevention of skeletal-related the physician’s discretion. Recent data sumab and updated recommendations sion of the events in patients with multiple myelo- suggest a potential benefi t with contin- regarding indications for bone-modify- recommen- ma.2 The approval was based on a large, ued dosing beyond 2 years, although ing agents, duration of treatment, and dation to use Dr. Kenneth Anderson international, phase III trial in which this has not been evaluated in a ran- potential complications. bone-modi- denosumab demonstrated noninferior- domized study. The new guidelines note fying agents ity to zoledronic acid and was associat- there are insuffi cient data to recommend Indications for Bone-Modifying Agents was based on ed with less renal toxicity. The updated a specifi c duration of bisphosphonate The updated guidelines have expand- the MRC IX guidelines for bone-modifying agents therapy. Therefore, it is recommended ed the indications for bisphosphonate trial, which note that denosumab provides an ad- that bone-targeted treatment is contin- treatment. Whereas the previous guide- demonstrated ditional option, but it is substantially ued for up to 2 years, resuming monthly lines recommended bone-modifying the benefi t of more expensive than zoledronic acid. treatment upon relapse with new-onset agents only for patients with lytic dis- bisphospho- “I would restrict denosumab to patients skeletal-related events. ease, the new guidelines state that any nate therapy with myeloma with renal compromise,” For the subset of patients in remis- patient who receives treatment for ac- in patients Dr. Anderson said. sion who are not receiving maintenance tive multiple myeloma should receive without lytic therapy, “it is reasonable to discontin- bisphosphonate therapy. bone disease. Duration and Frequency of ue bisphosphonates after 2 years, pro- The benefi t of the new recommen- In that trial, Dr. Robert A. Kyle Bone-Modifying Agents vided that the patient is in remission, Credit Mayo Clinic dation is to decrease skeletal complica- zoledronic acid The updated guidelines also discuss [although] bisphosphonates should be tions in patients with myeloma who was associated with a reduction in the feasibility of less frequent dosing reinstituted when the patient relapses,” have osteoporosis but no lytic disease, skeletal-related events at relapse and an of bone-targeted treatments in selected guideline co-author Robert A. Kyle, MD, Expert Panel Co-Chair Kenneth Ander- improvement in progression-free sur- patients, given the risk of osteonecrosis of the Mayo Clinic, said. son, MD, of the Dana-Farber Cancer vival. The MRC IX trial also demon- of the jaw associated with bone-target- Institute, said. Dr. Anderson added that strated the superiority of intravenous ing agents. For patients without active See Bone-Modifying Agents, Page 30B am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 5 B

We are shaping the future of immuno-oncology by researching innovative therapies targeting a wide range of immune cell types across numerous diseases. We are the forefront of investigating CAR T therapies across multiple targets, including BCMA and CD19, while evaluating new ways to leverage the PD-1/PD-L1 pathway and many other immunologic approaches.

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Science of Oncology Award just one or two doses of the vaccine were Q: What is the focus of other research Q: What is the importance of the Continued from page 1B as well protected as the women who re- at the NCI, including the impact of Science of Oncology Award to you? ceived all three doses. Those fi ndings led funding due to the Cancer Moonshot? Dr. Lowy: One reason I am so pleased the ELISA, and the other is a neutraliza- to the approval and recommendation of Dr. Lowy: The NCI supports a broad to accept this award is that it highlights tion assay. The neutralization assay was only two doses of HPV vaccination for range of research, including basic and how precision medicine and immunol- enabled by another technology that we young adolescents. investigator-initiated research. We sup- ogy can come together in important developed, papillomavirus pseudovirus- The NCI began another clinical trial port research on the causes of cancer, ways to prevent cancer from developing es, which are authentic papillomavirus in Costa Rica in November 2017 with pathogenesis of cancer, the training of in the fi rst place. Because ASCO is an or- capsids or particles that can encapsidate support from the Bill and Melinda the next-generation cancer researchers, ganization of oncologists and oncology any DNA. Both have become mainstay Gates Foundation, which will determine cancer health disparities, and a broad care providers, it is principally focused assays for measuring the immune re- whether one dose of the HPV vaccine in range of research in cancer prevention, on the treatment of cancer. I am espe- sponse to papillomaviruses. young adolescents is suffi cient to induce screening, treatment, and survivorship. cially grateful to ASCO for highlighting Using the papillomavirus pseudovirus strong, long-term protection. The trial Fortunately, there is strong bipartisan our translational research, which is out- technology, we developed a mouse geni- will include about 20,000 adolescent support in Congress for biomedical re- side the area of treatment but instead tal tract challenge model for measuring girls who will be followed for 4 years af- search. In addition, our strong and com- is in an area earlier than treatment—in the protection and immune response to ter vaccination. Two FDA-approved HPV mitted cancer advocacy community this case, primary prevention. papillomavirus challenge in the female vaccines are being tested: the bivalent plays an indispensable role in advocat- Although these awards are given to mouse genital tract. The responses we saw (types 16 and 18) vaccine1 and the HPV ing strongly and effectively for funding individuals, research is a group activ- were virtually identical to what we have 9-valent vaccine.2 on behalf of cancer research. ity. I wouldn’t be here if it were not for seen in the international clinical trials The NCI has been going full-tilt on im- the excellent research that came before that led to licensure for both vaccines. Q: What are the potential plementing the recommendations of the the research that Dr. Schiller and I have implications of this trial? Cancer Moonshot Blue Ribbon Panel , done. Q: What did those clinical trials Dr. Lowy: Although the vaccine is high- and we have created numerous funding –Tim Donald, ELS demonstrate? ly effective, costs and logistics combine opportunities that can be found on the Dr. Lowy: Early-phase trials demon- to make the HPV vaccine less widely de- NCI website at cancer.gov. References: strated that the HPV vaccine was highly ployed in low- and middle-income coun- We have been going out regularly to 1. U.S. Food and Drug Administration. immunogenic and well tolerated in both tries. This is where the big public health our extramural colleagues to get their in- Cervarix. www.fda.gov/Biologics young men and women. We subsequent- problem resides for HPV-associated can- put on how to prioritize funding. Those BloodVaccines/Vaccines/Approved ly worked with colleagues at the NCI cer, mainly cervical cancer. If one dose efforts have led directly to a public-pri- Products/ucm186957.htm. Updated who led a trial of the vaccine made by were shown to be effective, it would be vate partnership between the NCI and February 26, 2018. Accessed March 23, GlaxoSmithKline (GSK), a bivalent vac- far easier and much less expensive. That more than a dozen pharmaceutical com- 2018. cine made of virus-like particles from could expand the widespread deploy- panies to conduct research in the area of 2. U.S. Food and Drug Administration. different HPV types: HPV 16 and 18. The ment of the vaccine in less-developed immunotherapy in what we call precom- Gardasil 9. www.fda.gov/Biologics trial, conducted in Costa Rica, demon- countries, while at the same time saving petitive collaboration. We are developing BloodVaccines/Vaccines/Approved strated that the vaccine had a high rate a tremendous amount of money in the standard operating procedures and stan- Products/ucm426445.htm. Updated of effi cacy. We also found in post-hoc industrialized world, because you would dardized assays that we are confi dent will February 26, 2018. Accessed March 23, analyses that the women who received not need to give as many doses. be able to move the fi eld forward. 2018. B 6 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

follow-up of 4.1 years, the recurrence- 2018 GU Cancers Symposium Focuses on free survival was nonsignifi cantly better with daily IGRT (HR 0.81, 95% CI [0.52, 1.25]; p = 0.330). The second Translating Evidence to Multidisciplinary Care cancer-free interval was worse with daily IGRT (HR 2.21, 95% CI [1.10, he 2018 Genitourinary Cancers 0.35]; p < 0.0001). Subgroup analyses 4.44]; p = 0.026). OS was also worse More than 4,000 individuals attended the Symposium took place on Febru- showed benefi t across all subgroups, with daily IGRT. 2018 Genitourinary Cancers Symposium. ary 8-10, in San Francisco, and fea- and there is an early, though nonsig- tured the most up-to-date research nifi cant, trend toward an overall sur- Advances in Bladder Cancer Treatment Tand its translation to clinical, multidisci- vival (OS) benefi t with enzalutamide Several studies highlighted major ad- plinary care for prostate, renal, urothe- as well. vances in the treatment of urothelial lial, testicular, and adrenal cancers. ■ Similarly, the phase III SPARTAN trial carcinoma, including some that should Read on for a summary of some of the (Abstract 161) demonstrated that the change standards of care. top research presented at the meeting, next-generation androgen signaling ■ Adjuvant chemotherapy following including data from long-term phase inhibitor apalutamide also offered nephroureterectomy signifi cantly III trials, early-phase results of novel ap- much better MFS than placebo. In the improves outcomes in upper tract proaches, and the newest genomic and study of 1,207 patients, the median urothelial cancer. The phase III POUT biomarker studies. MFS was 40.5 months with the study trial (Abstract 407), the largest ran- drug and 16.2 months with placebo domized study in this setting to date, Advances in Prostate Cancer Therapy (HR 0.28, 95% CI [0.23, 0.35]; p < responses greater than 50%; notably, included 248 patients who were ran- Prostate cancer therapy continues to 0.0001). The median time to symp- six of those patients had mutations domly assigned to either surveillance evolve. Several abstracts focused on an- tomatic progression was also bet- in the DNA damage repair pathways. or chemotherapy with four cycles of drogen signaling inhibition, the use of ter with apalutamide. The trial was The combination was reasonably well gemcitabine-cisplatin or gemcitabine- immunotherapy options, and some of unblinded, allowing patients who tolerated, with the most common carboplatin. After a median follow-up the specifi cs of radiotherapy in this ma- originally received the placebo to grade 3/4 adverse events including of 17.6 months, progression-free sur- lignancy. receive apalutamide. anemia (24%), lymphopenia (12%), vival (PFS) favored chemotherapy (HR ■ The phase III PROSPER trial (Abstract ■ As the era of immunotherapy has and infection (12%). 0.49, 95% CI [0.30, 0.79]; p = 0.003). 3) showed that the androgen signal- progressed, prostate cancer has ■ Daily image-guided radiation therapy The 2-year disease-free survival rate ing inhibitor enzalutamide resulted proved a diffi cult malignancy for (IGRT) resulted in a lower risk of was 51% with surveillance and 70% in signifi cantly better metastasis-free this fi eld. A phase II study of mCRPC recurrence and late rectal toxic- with chemotherapy; the trial stopped survival (MFS) compared with placebo (Abstract 163) found that combining ity compared with weekly IGRT in early due to the signifi cant benefi t in patients with metastatic castration- the immune checkpoint inhibitor localized prostate cancer, but it was seen with chemotherapy. resistant prostate cancer (mCRPC). durvalumab with the PARP inhibitor also associated with an increased risk ■ Two bladder-sparing chemoradiation It included 1,401 patients, and the olaparib is well tolerated with some of second cancer. A phase III trial therapy regimens showed promise median MFS was 36.6 months with promising activity. Among 17 un- (Abstract 4) randomly assigned 470 in a phase II trial of muscle invasive enzalutamide and only 14.7 months selected patients with mCRPC, eight patients with N0 localized disease to bladder cancer. The study (Abstract with placebo (HR 0.29, 95% CI [0.24, (47%) had prostate-specifi c antigen daily or weekly IGRT. After a median See 2018 GU Cancers Symposium, Page 15B

2018 HIGHLIGHTS gucasym.org

The Genitourinary (GU) Cancers Symposium brings together DOMESTIC VS. ATTENDEE FEEDBACK a diverse group of international leaders in GU cancers from multiple specialties to debate and exchange the latest INTERNATIONAL ATTENDANCE strategies in the prevention, screening, diagnosis, and multidisciplinary management of prostate, renal, testicular, penile, urethral, and urothelial cancers. Marking the Symposium’s 14th year, the 2018 meeting had record-break- 2,057 “I have attended for several ing abstract submissions and registration and featured the Domestic Professional Attendees years, and this was one of the latest in systemic therapy, exploration of biomarkers, and 50% 50% genomic analysis. The Symposium was cosponsored by best conferences.” ASCO, ASTRO, and the Society of Urologic Oncology. 2,083 ABSTRACT SUBMISSIONS: International Professional Attendees “It is a great TOP 5 COUNTRIES meeting and TOTAL ATTENDANCE OVER TIME organized USA 452 very well.” 5,000 JAPAN 47 4,000 4,500 CANADA 46 3,000 3,320 3,410 3,190 2,950 UNITED KINGDOM 3636 2,000

FRANCE 8828 1,000 0 ABSTRACTS SUBMITTED BY YEAR 2014 2015 2016 2017 2018 SOCIAL MEDIA #GU18 800 688 763 During the meeting, 600 630 642 648 400 2,020 users sent 7,928 tweets using the hashtag #GU18, 200

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PATIENTS WHOSE DISEASE HAS PROGRESSED ON PRIOR TREATMENT.*

PATIENTS WHO KNOW THEIR SITUATION, BUT ARE NOT SURRENDERING TO IT.

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SELECT IMPORTANT SAFETY INFORMATION FOR CYRAMZA

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Please see additional Important Safety Information for CYRAMZA, including Boxed Warning for hemorrhage, gastrointestinal perforation, and impaired wound healing, on adjacent page. Also see the Brief Summary of Prescribing Information for CYRAMZA on subsequent pages. ”We have some unfinished business.”

METASTATIC GASTRIC OR GEJ ADENOCARCINOMA INDICATION CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

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METASTATIC NON-SMALL CELL LUNG CANCER INDICATION CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

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METASTATIC COLORECTAL CANCER INDICATION CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. INDICATIONS Most Common Adverse Reactions—Single Agent CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with hyponatremia (6% vs 2%; 3% vs 1%). disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase • The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo. CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients vs placebo in study 1 were: neutropenia (4.7% vs colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%). • Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in IMPORTANT SAFETY INFORMATION FOR CYRAMZA CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusion-related reactions was 0.4%. Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Most Common Adverse Reactions—Combination With Paclitaxel severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and experience severe bleeding. ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%). gastrointestinal perforation. • The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA • Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications. were neutropenia (4%) and thrombocytopenia (3%). • Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for Warnings and Precautions CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel). Hemorrhage • In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and Most Common Adverse Reactions—Combination With Docetaxel ≥ 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel in advanced gastric cancer, the incidence of severe bleeding was 4.3% • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in 5% of patients receiving CYRAMZA plus docetaxel and ≥ for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal 2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2. In study 3, which evaluated CYRAMZA plus docetaxel in stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than and hypertension (11% vs 5%; 6% vs 2%). once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3. In • The most common serious adverse events with CYRAMZA plus docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and study 4, which evaluated CYRAMZA plus FOLFIRI in metastatic colorectal cancer, the incidence of severe bleeding was 2.5% for CYRAMZA plus neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding. patients who received placebo plus docetaxel. ≥ Arterial Thromboembolic Events (ATEs) • In patients 65 years of age, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years of age, there were 13 (3%) deaths on treatment or within 30 days of • Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE. • Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo Hypertension plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA in study 3 were • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%), in infusion-related reaction (0.5%) and epistaxis (0.3%). patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), and in patients receiving CYRAMZA plus • For patients with nonsquamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of grade ≥3 pulmonary docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade ≥3 pulmonary hemorrhage for placebo plus FOLFIRI (3%). Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of grade ≥3 severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. for placebo plus docetaxel. Infusion-Related Reactions (IRRs) • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel). including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Monitor patients Most Common Adverse Reactions—Combination With FOLFIRI during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus FOLFIRI and discontinue CYRAMZA for grade 3 or 4 IRRs. ≥2% higher than placebo plus FOLFIRI in study 4 were diarrhea (60% vs 51%; 11% vs 10%), neutropenia (59% vs 46%; 38% vs 23%), decreased Gastrointestinal Perforations appetite (37% vs 27%; 2% vs 2%), epistaxis (33% vs 15%; 0% vs 0%), stomatitis (31% vs 21%; 4% vs 2%), thrombocytopenia (28% vs 14%; • Four of 570 patients (0.7%) who received CYRAMZA as a single agent in advanced gastric cancer clinical trials experienced gastrointestinal 3% vs <1%), hypertension (26% vs 9%; 11% vs 3%), peripheral edema (20% vs 9%; <1% vs 0%), proteinuria (17% vs 5%; 3% vs <1%), perforation. In study 2, the incidence of gastrointestinal perforation was 1.2% for CYRAMZA plus paclitaxel as compared to 0.3% for placebo plus palmar-plantar erythrodysesthesia syndrome (13% vs 5%; 1% vs <1%), gastrointestinal hemorrhage events (12% vs 7%; 2% vs 1%), paclitaxel. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel as compared to 0.3% for placebo plus hypoalbuminemia (6% vs 2%; 1% vs 0%). Twenty percent of patients treated with CYRAMZA plus FOLFIRI received granulocyte colony- docetaxel. In study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. stimulating factors. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. • The most common serious adverse events with CYRAMZA plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile Impaired Wound Healing neutropenia (2.8%). • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA has the potential to adversely affect wound healing. • Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA plus FOLFIRI-treated patients (29%) Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the than in placebo plus FOLFIRI-treated patients (13%). The most common adverse reactions leading to discontinuation of any component of surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, CYRAMZA plus FOLFIRI as compared to placebo plus FOLFIRI were neutropenia (12.5% versus 5.3%) and thrombocytopenia (4.2% versus 0.8%). discontinue CYRAMZA until the wound is fully healed. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%). ≥ Clinical Deterioration in Child-Pugh B or C Cirrhosis • Clinically relevant adverse reactions reported in 1% and <5% of CYRAMZA plus FOLFIRI-treated patients in study 4 consisted of gastrointestinal perforation (1.7% CYRAMZA plus FOLFIRI versus 0.6% for placebo plus FOLFIRI). • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. • Thyroid-stimulating hormone (TSH) was evaluated in 224 patients (115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo plus FOLFIRI-treated patients) with normal baseline TSH levels. Increased TSH was observed in 53 (46%) patients treated with CYRAMZA plus Reversible Posterior Leukoencephalopathy Syndrome (RPLS) FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI. • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Discontinue CYRAMZA in patients who develop RPLS. Symptoms Drug Interactions may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. • No pharmacokinetic interactions were observed between ramucirumab and paclitaxel, between ramucirumab and docetaxel, or between Proteinuria Including Nephrotic Syndrome ramucirumab and irinotecan or its active metabolite, SN-38. • In study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo Use in Specific Populations plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein • Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on ≥2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome. ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and pediatric development, and to use effective contraception during CYRAMZA therapy and for at least 3 Thyroid Dysfunction months following the last dose of CYRAMZA. • Monitor thyroid function during treatment with CYRAMZA. In study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in • Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is the CYRAMZA plus FOLFIRI-treated patients and 0.9% in the placebo plus FOLFIRI-treated patients. not recommended during treatment with CYRAMZA. Embryofetal Toxicity • Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility. • Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with gastrointestinal perforation, and impaired wound healing, on adjacent pages. CYRAMZA and for at least 3 months after the last dose of CYRAMZA. RB-P-HCP ISI 16FEB2017

CYRAMZA® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or afﬁ liates. PP-RB-US-1405 03/2018 PRINTED IN USA © Lilly USA, LLC 2018. All rights reserved. CYRAMZA® (ramucirumab) injection Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% INDICATIONS AND USAGE CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% Gastric Cancer CYRAMZA versus 0% placebo). CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of Non-Small Cell Lung Cancer placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related CYRAMZA in combination with docetaxel, is indicated for treatment of metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy. reactions was 0.4%. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. CYRAMZA Administered in Combination with Paclitaxel Among 327 patients who received CYRAMZA (safety population) in Study 2, median age was 61 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 Colorectal Cancer received a median of 9 doses of CYRAMZA; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months. CYRAMZA in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of metastatic colorectal cancer with disease progression on or after In Study 2, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with CYRAMZA plus paclitaxel were neutropenia (3.7%) and febrile neutropenia CONTRAINDICATIONS (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the None. CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%). Table 2 provides the frequency and severity of adverse reactions in Study 2. WARNINGS AND PRECAUTIONS Hemorrhage Table 2: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA plus Paclitaxel in Study 2 CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA- treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Hypoalbuminemia Impaired Wound Healing Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. Proteinuria Including Nephrotic Syndrome Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel treated patients in Study 2 were sepsis (3.1% CYRAMZA plus paclitaxel versus 1.8% In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was placebo plus paclitaxel) and gastrointestinal perforations (1.2% CYRAMZA plus paclitaxel versus 0.3% for placebo plus paclitaxel). reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine Non-Small Cell Lung Cancer protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently CYRAMZA Administered in Combination with Docetaxel discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome. Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 Thyroid Dysfunction intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS patients and 0.9% in the placebo plus FOLFIRI treated patients. of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel Embryofetal Toxicity invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA. baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% ADVERSE REACTIONS of 627) patients received CYRAMZA for at least six months. Clinical Trials Experience In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus trials of another drug and may not reflect the rates observed in practice. docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were Gastric Cancer infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of Safety data are presented from two randomized, placebo controlled clinical trials in which patients received CYRAMZA: Study 1, a randomized (2:1), double-blind, clinical trial in which ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. 351 patients received either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks. Both trials docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA upper limit of normal. plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus CYRAMZA Administered as a Single Agent docetaxel and 26 (6%) deaths for placebo plus docetaxel. Among 236 patients who received CYRAMZA (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 Table 3 provides the frequency and severity of adverse reactions in Study 3. received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months. In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo. Table 1 provides the frequency and severity of adverse reactions in Study 1. Table 3: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3 Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). Of the 529 patients who received CYRAMZA plus FOLFIRI in Study 4, 209 (40%) were 65 and over, while 51 (10%) were 75 and over. Overall, no differences in safety or effectiveness were observed between these subjects and younger subjects.

Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel Renal Impairment versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel). No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis. Colorectal Cancer Hepatic Impairment CYRAMZA Administered in Combination with FOLFIRI No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 Study 4 was a multinational, randomized, double-blind study conducted in patients with metastatic colorectal cancer with disease progression on or after therapy with times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients received either CYRAMZA 8 mg/kg intravenously plus FOLFIRI intravenously every 2 weeks or placebo plus FOLFIRI reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. intravenously every 2 weeks. DOSAGE AND ADMINISTRATION Study 4 excluded patients with an ECOG PS of 2 or greater, uncontrolled hypertension, major surgery within 28 days, and those who experienced any of the following during Do not administer CYRAMZA as an intravenous push or bolus. first-line therapy with a bevacizumab-containing regimen: an arterial thrombotic/thromboembolic event; Grade 4 hypertension; Grade 3 proteinuria; a Grade 3-4 bleeding Recommended Dose and Schedule event; or bowel perforation. Gastric Cancer Demographics and baseline characteristics for the treated population were similar between treatment arms (n=1057). Median age was 62 years; 57% of patients were men; The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 76% were White and 20% were Asian; 48% had ECOG PS 0. minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination, administer CYRAMZA prior to administration of paclitaxel. The data described in this section reflect exposure to CYRAMZA plus FOLFIRI in 529 patients in Study 4. Patients received a median of 8 doses (range 1-68) of CYRAMZA; the Non-Small Cell Lung Cancer median duration of exposure was 4.4 months, and 169 (32% of 529) patients received CYRAMZA for at least six months. The most common adverse reactions (all grades) The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until observed in CYRAMZA plus FOLFIRI-treated patients at a rate of ≥30% and ≥2% higher than placebo plus FOLFIRI were diarrhea, neutropenia, decreased appetite, epistaxis, disease progression or unacceptable toxicity. and stomatitis. Twenty percent of patients treated with CYRAMZA plus FOLFIRI received granulocyte colony-stimulating factors. Treatment discontinuation of any study drug Colorectal Cancer due to adverse reactions occurred more frequently in CYRAMZA plus FOLFIRI-treated patients (29%) than in placebo plus FOLFIRI-treated patients (13%). The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. Continue CYRAMZA until disease The most common adverse reactions leading to discontinuation of any component of CYRAMZA plus FOLFIRI as compared to placebo plus FOLFIRI, were neutropenia (12.5% progression or unacceptable toxicity. versus 5.3%) and thrombocytopenia (4.2% versus 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and Premedication gastrointestinal perforation (1.7%). Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). The most common serious adverse events with CYRAMZA plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%). For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Table 4 provides the frequency and severity of adverse reactions in Study 4. Dose Modifications Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 4 Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose (see Table 5) once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose (see Table 5) once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Table 5: CYRAMZA Dose Reductions for Proteinuria

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to paclitaxel, docetaxel, or the components of FOLFIRI, refer to the current prescribing information. PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event. aIncludes 3 patients with nephrotic syndrome in the CYRAMZA plus FOLFIRI treatment group. • Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus FOLFIRI-treated patients in Study 4 consisted of gastrointestinal perforation (1.7% CYRAMZA plus severe headache, lightheadedness, or neurologic symptoms. FOLFIRI versus 0.6% for placebo plus FOLFIRI). • Gastrointestinal perforations: Thyroid stimulating hormone (TSH) levels were evaluated in 224 patients (115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo plus FOLFIRI-treated patients) with normal Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. baseline TSH levels. Patients underwent periodic TSH laboratory assessments until 30 days after the last dose of study treatment. Increased TSH levels were observed in 53 (46%) patients treated with CYRAMZA plus FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI. • Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent • Pregnancy and fetal harm: anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development and to use effective contraception treatment-emergent anti-ramucirumab antibodies. during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) • Lactation: positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying Advise patients not to breastfeed during CYRAMZA treatment. disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. • Infertility: DRUG INTERACTIONS Advise females of reproductive potential regarding potential infertility effects of CYRAMZA. No pharmacokinetic interactions were observed between ramucirumab and paclitaxel, between ramucirumab and docetaxel, or between ramucirumab and irinotecan or its active metabolite, SN-38. Additional information can be found at www.CYRAMZAHCP.com. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Eli Lilly and Company, Indianapolis, IN 46285, USA Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, Copyright © 2017, Eli Lilly and Company. All rights reserved. embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are RB-P HCP BS 27MAR2017 unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 13 B

Patient-Reported Outcomes Fig. 2. Generic Model for Integrating Patient-Reported Outcomes success. It should be clear to patients Continued from page 1B Into Clinical Workfl ow that this is something that is important to the center and to the clinicians. Invi- hospitalizations, and physical debility. tations to patients to participate should Indeed, poorly controlled symptoms are come from a clinician or staff member a principal driver of preventable ER vis- they know or recognize. Staff should its for pain, dyspnea, dehydration, nau- remind patients at all visits about self- sea/vomiting, diarrhea, and fatigue.3,4 reporting. Clinicians should use the in- Multiple studies show that system- formation and make it clear to patients atic monitoring of patients’ symptoms that they are referencing it for care. using PROs closes this gap, improving Technical support should be available patient-clinician communication, clini- for patients and clinicians. cian awareness of symptoms, symptom A question that many institutions management, patient satisfaction, and ponder is whether to use a PRO func- quality of life.5,6 Most patients with can- tionality native to their EHR system cer (about 80%) are willing and able to patient portal or to build or license a self-report PROs on a regular basis during free-standing PRO system. There is no treatment. Presentations during the 2016 right answer, and the decision will de- and 2017 ASCO Annual Meetings report- Abbreviation: ePRO, electronic patient-reported outcomes. pend on the desired use of the data and ed that PRO monitoring can signifi cantly the quality of the available EHR PRO reduce ER visits and improve survival: in the PRO arm experienced signifi - reported (usually to nurses, via email functionality. Unfortunately, many of ■ In 2016, Fabrice Denis, MD, PhD, cantly better quality of life, reduced or EHR in-basket messages); and the widely used EHR systems still only presented “Overall survival in pa- ER visits by 7%, longer tolerability ❑ The ability to visualize PRO values include rudimentary PRO functionality, tients with lung cancer using a web of cancer treatment by 2 months, longitudinally (either through the with unappealing clinician visualization application–guided follow-up com- improved physical functioning, and a EHR or a free-standing PRO system). of patient-reported data. Hopefully this pared to standard modalities: Results 5-month overall survival benefi t.8 3. A standardized quality improvement will change in the near future. of phase III randomized trial” during process for implementing PROs in the There is support for research on im- the ASCO Annual Meeting (Abstract How does this all work in a practice? workfl ow, including patient training plementing PROs in clinical practice LBA9006). In this multicenter French Figure 2 illustrates a model for bringing and monitoring, staff training, and and within EHR systems from multiple study, 121 patients were randomly PROs into usual workfl ow processes for project monitoring. agencies, including the National Cancer assigned to one of two post-treatment symptom management in cancer care. Institute (NCI), PCORI, and the Agency surveillance strategies: PRO symptom There are many variations of workfl ow A more in-depth description of the for Healthcare Research and Quality. monitoring versus standard care with considerations when bringing PROs on- various considerations for bringing Notably, one of the recent NCI Cancer scheduled follow-up scans. Compared line in a practice, but most models share PROs into a practice can be found in Moonshot announcements specifi cally to standard care, survival was signifi - three common elements: two excellent Users’ Guides, which are focused on implementing PROs into cantly improved by 8 months among 1. A cross-disciplinary governance group freely available online and are highly EHRs and clinical workfl ow of practice patients in the PRO arm.7 to make decisions and implement the recommended: the “User’s Guide to Im- networks.11 ■ In 2017, my research group presented system (usually including clinicians, plementing Patient-Reported Outcomes “Overall survival results of a random- administrators, patient representa- Assessment in Clinical Practice,” from Increasing Focus on PROs in Clinical ized trial assessing patient-reported tives, and information technology the International Society for Quality of Trials and Drug Development outcomes for symptom monitoring experts). Life Research,9 and the “Users’ Guide to Drug development trials are perhaps during routine cancer treatment” dur- 2. A PRO software system that includes: Integrating Patient-Reported Outcomes the most well-traveled context in which ing the ASCO Annual Meeting Plenary ❑ An interface for patients to self- in Electronic Health Records” supported PROs have been used in oncology. Many Session (Abstract LBA2). In this study, report (connected to the electronic by the Patient-Centered Outcomes Re- of the PRO questionnaires in use today 766 patients with metastatic solid health record [EHR]/patient portal search Institute (PCORI).10 were developed for trials. PROs are com- tumors at Memorial Sloan Kettering or free-standing); Like any quality improvement proj- monly collected in publicly funded re- Cancer Center were randomly as- ❑ Automated reminders to patients ect, there is a risk of failure if implemen- search (e.g., through the NCI-supported signed to weekly PRO symptom moni- to self-report (usually by email, text tation is not done thoughtfully with National Clinical Trials Network of co- toring with alerts to nurses for severe/ message, or automated phone call); ongoing monitoring and adjustment— operative groups) and in industry spon- worsening symptoms versus usual ❑ Automated alerts to clinicians when particularly in early phases. There are sored research. care. Compared to usual care, patients severe or worsening symptoms are a few steps that can be helpful toward See Patient-Reported Outcomes, Page 15B

Molecular Diagnostic Platforms patient. There are two distinct steps: sepa- created detailed digital facsimiles of can- research of Bernd Bodenmiller, PhD, of Continued from page 3B rating consequential from inconsequen- cer cells. The researchers established the the University of Zurich, in Switzerland, tial and treating effectively, which both proof of concept for the metal-detection by using his approach with the liquid bi- forms, and other mutations that are out- have a time-space challenge. The disease technique that allows for detection of opsy he had previously developed.3 “We side lung and colon cancers, he said. evolves over time and through ‘space’; tumor cells at a molecular level, he said. simply add the antibody cocktail, wait “The future is next-generation se- i.e., the body as a system,” he said. “As- According to Dr. Kuhn, the research pub- for binding, and then wash off the ex- quencing,” he said. His presentation will sessing this time-space correlation and lished recently in Convergent Science Phys- cess and see what sticks. Then we use a give an overview of the two most com- tracking its evolution requires an exten- ical Oncology will help researchers under- laser to atomize the sample and a mass mon next-generation sequencing plat- sion of our traditional approach to the stand how cancer moves from its initial spectrometer to look for each of the met- forms used in the United States, as well tissue biopsy.” location to other organs and will hope- als,” Dr. Kuhn said. as others, and “the genes they are testing, Dr. Kuhn noted that next-generation fully lead toward development of more −Kathy Holliman, MEd when they were launched, and the types diagnostic methods “have to support each precise treatment plans for patients.2 of alterations they target,” he said. “This and every decision point that a patient is Using the Fluidigm Hyperion Imaging References: ﬁ eld is moving so fast. New tests are be- facing with both accuracy and precision. System , Dr. Kuhn and his team could see 1. Heitzer E, et al. npj Precision Oncology. The ing approved and developed, and they This can be achieved with the appropri- protein biomarkers that may determine potential of liquid biopsies for the early keep improving the current platforms.” ate implementation of high-content liq- how a tumor cell would potentially re- detection of cancer. nature.com/articles/ His talk will update attendees with the uid biopsy approaches that use single-cell spond or not to therapy, how it could s41698-017-0039-5. Published October 17, latest information about these emerging proteogenomics. The results can be vali- metastasize, and how it could affect the 2017. Accessed March 12, 2018. platforms. dated and reproduced, and the ﬁ nal tests patient’s immune system response. This 2. Malihi PD, et al. Converg Sci Phys Oncol. can be shrink-wrapped and launched to new approach, now a technique avail- 2018;4:015003. Noninvasive Biomarkers impact globally,” he said. able with Fluidigm, uses metal-tagged 3. Wang HA, et al. Anal Chem. Dr. Kuhn, the third speaker at the ses- Dr. Kuhn will discuss recent research antibodies and a laser ablation system, 2013:85:10107-16. sion, will focus on noninvasive biomark- by the USC Michelson Center for Con- along with a mass spectrometer, which ers for immunotherapy. “Our goal in can- vergent Bioscience Bridge Institute. By can provide 35 distinct views of the can- *Program information updated as of March cer therapy is to identify consequential imaging metal-tagged antibodies on cer cell’s biology, Dr. Kuhn said. 12. For session time and location information, cancer and treat effectively to avoid its biopsies from patients with metastatic Their research using metal-targeted please refer to the ASCO iPlanner on the lethality within the healthy lifespan of a prostate cancer, Dr. Kuhn and colleagues antibodies expands on the pioneering Attendee Resource Center (am.asco.org/arc). B 14 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn CLINICAL CORNER Duration of Adjuvant Chemotherapy for Early-Stage Breast Cancer

ayeh Lavasani, MD, MSc, FRCPC, for four cycles (AC4) with the primary Cancer (ABC) trials reported by Blum et we know from answers a question posed by an endpoint of disease-free survival (DFS). al pooled patients from three large ran- the recent data attendee during a Best of ASCO® In this report, TC was associated with a domized trials to compare TaxAC with a that TC6 is in- Meeting. Dr. Lavasani is a breast superior DFS and different toxicity pro- nonanthracycline taxane-based control ferior to AC/ Smedical oncologist at Memorial Cancer fi le compared to AC. arm (TC6).4 The study’s primary end- paclitaxel. The Institute. The 7-year follow-up showed that TC4 point was invasive DFS. Four-year inva- truth is that was superior to AC4.2 DFS was 81% ver- sive DFS was 88.2% in the TC arm versus we do not have Question: How many cycles sus 75%, respectively (HR 0.74, 95% CI 90.7% for the TaxAC arm (HR 1.23; p = any scientifi c of combination docetaxel/ [0.56, 0.98]; p = 0.03). The overall sur- 0.04), demonstrating that TC6 is inferior evidence that cyclophosphamide do you vival (OS) was 87% versus 82%, respec- to TaxAC. TC needs to be recommend in the adjuvant setting tively (HR 0.69, 95% CI [0.50, 0.97]; p According to the ASCO adaptation Dr. Sayeh Lavasani given for six for patients with breast cancer? = 0.032). of the Cancer Care Ontario Program in cycles. In my Answer: This remains an area of con- There are no head-to-head compari- Evidence-Based Care guideline, TC4 is practice, if I feel troversy. Many studies have compared sons between TC4 versus TC for six recommended as an alternative to AC4 that I can avoid anthracyclines and de- standard-dose doxorubicin/cyclophos- cycles (TC6). The fi rst study comparing and offers improved DFS and OS.5 The cide that I want to use the TC regimen, I phamide (AC) to docetaxel/cyclophos- four versus six cycles of therapy of the National Comprehensive Cancer Net- use four cycles only—otherwise I use the phamide (TC; 75 mg/m2 and 600 mg/ same regimen was the CALGB 40101 work guideline also recommends TC4.6 TaxAC combination regimen. m2, respectively) at four and six cycles. trial.3 Using a 2 x 2 factorial design, the In summary, current data illustrates TC administered every 3 weeks for four study compared four and six cycles of AC that TC4 is better than AC4. We also References: cycles (TC4) is a chemotherapy regimen (AC4 vs. AC6) or single-agent paclitaxel know that AC6 is equal to AC4 with 1. Jones S, et al. J Clin Oncol. 2006;24:5381-7. used for the treatment of early-stage in early-stage breast cancer and zero to more toxicities, and we know that TC6 2. Jones S, et al. J Clin Oncol. 2009;27:1177- breast cancer in an adjuvant setting and three positive axillary nodes. The study is inferior to TaxAC, particularly in pa- 83. is gaining popularity due to the lack found no difference in 4-year relapse- tients who are triple-negative or hor- 3. Shulman L, et al. J Clin Oncol. of cardiotoxicity and decreased risk of free survival or OS between four and six mone-positive and who have multiple 2012;30:4071-6. acute leukemia compared to an anthra- cycles with more toxicities in six-cycle positive axillary nodes. 4. Blum J, et al. J Clin Oncol. 2017;35:2647-55. cycline-based regimen. treatment arms. Some medical oncologists believe that 5. Denduluri N, et al. J Oncol Pract. USOR 9735 was the fi rst trial to reveal TC6 has been compared to the tax- by adding two more cycles to TC4, they 2016;12:485-8. effi cacy and improved toxicity of TC ane anthracycline (TaxAC) combination can compensate for the TaxAC regimen; 6. National Comprehensive Cancer Network over AC.1 This phase III study by Jones et chemotherapy regimen. The joint analy- therefore, they are replacing the dose- (NCCN) Guidelines in Oncology. Breast al compared TC4 with standard-dose AC sis of the Anthracyclines in Early Breast dense AC/paclitaxel with TC6. However, Cancer (version 3.2017).

Tantalizingly Close: Global Health Equity and the Inﬂ uence of Socioeconomic Disparities on Cancer Care Outcomes

arm to pick an apple, and the water will the low- and middle-income strata, these particular type of health difference that seep through the rock while the branch- advancements remain an aspiration. is closely linked with social, economic, EXPERT es move away. Close enough, but always This editorial focuses on health dispari- and/or environmental disadvantage.”1 EDITORIAL tantalizingly out of reach. ties using specifi c countries across the It includes differences among the most Such is the current situation in re- income spectrum to highlight the chal- advantaged group in a given category, source-constrained settings when we lenges encountered by health offi cials, such as the most wealthy or powerful, Robert Ali, MBBS; Jonas A. de Souza, MD; fi ght for cancer control. The last few physicians, and patients at each level. and all others, not only between the Bijou Hunt, MA; Fredrick Chite Asirwa, MD; decades have been brimming with ma- best- and worst-off groups. Furthermore, Clement Adebamowo, BM, ChB Hons, FACS, jor breakthroughs in care initiatives in- Defi ning Health Care Disparities and inherent in this designation is that those FWACS, ScD; and Gilberto Lopes Jr., MD, cluding novel immunotherapy options, Cancer Control disadvantaged social groups who persis- MBA, FAMS molecular testing, targeted therapies, Multiple defi nitions for health care tently experience social discrimination greater public awareness, and improved disparities have been proposed; howev- systematically experience worse health t is an easy place to reach; the problem national cancer control plans. Nonethe- er, the consensus put forward by Healthy or greater health risks than their more has always been returning home. From less, a signifi cant disparity in the acces- People 2020 offers a nicely rounded de- advantaged social counterparts. Pursu- most world capitals, airliners will take sibility to care among various socioeco- scription. The Healthy People 2020 pro- ing health equity implies pursuing the you to Athens, Greece, and from there nomic settings exists. For those among gram defi nes a health disparity as “a elimination of such health disparities Ia short fl ight north will get you to Thes- and inequalities. protia in the region of Epirus. Locals will Per the Union for International Can- be happy to point you in the direction cer Control (UICC), cancer control is of the cave known as Charonium, one defi ned as “a public health approach of the gates to our destination. Do not ARTICLE HIGHLIGHTS aimed at reducing the burden of cancer forget to bring a gold coin or two to pay in a population.”2 This concept includes the ferryman, Charon (yes, you guessed ■ A signifi cant disparity exists in the accessibility to cancer care among various the planning of integrated, evidence- where his name comes from). Once on socioeconomic settings. based, and cost-effective interventions the river Styx, at the bifurcation, do across the cancer continuum, including ■ Only one in fi ve low- or middle-income countries have the data needed to not take the road to Elysium (appropri- research, prevention, early detection, drive cancer policies. ately for our story, in Greek mythology, treatment, and palliation. heaven was actually in the underworld ■ Although a considerable fi nancial emphasis is placed on health care initiatives, So why bother with a global initiative? as well); keep going. Hades’ most appro- high-income countries still face challenges with ensuring equitable distribution During the 2014 World Cancer Lead- priate metaphor for cancer control in of cancer care resources. ers’ Summit, cancer advocates argued low-resource settings in both rich and ■ Middle-income countries have been partially successful through measures that it makes economic sense to invest poor countries alike is Tantalus. Here, such as tax-funded health care. However, low-income countries continue to in global cancer control, particularly there is water to quench your thirst and struggle with providing suffi cient resources and may require international in low- and middle-income countries sweet fruit to satiate your hunger. But try support. (LMICs). In 2010, the annual global to bow down and drink or stretch your See Global Health Equity, Page 18B am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 15 B

2018 GU Cancers Symposium The 2018 Genitourinary Cancers fi ndings reinforce the importance Continued from page 6B Symposium featured robust panel of surveillance in this survivor discussions, putting the science population. presented into real-world context. 408) included 66 patients with T2-4a ■ A prospective study found that bladder cancer, randomly assigned to treatment for germ cell tumors can receive either twice-daily radiation result in long-term sexual function plus 5-fl uorouracil/cisplatin (FCT) problems (Abstract 549). The study or daily radiation plus gemcitabine included 155 survivors who fi lled out (GD). The rate of distant metastasis at a Sexual Function Questionnaire after 3 years was 22% with FCT and 16% a median of 10 years of follow-up. with GD (the study was not designed Survivors who were treated with che- for direct comparisons of the two motherapy and radiotherapy, or with groups). Complete response rates in any therapy, had diffi culty maintain- the two groups were 88% and 78%, ing erection during intercourse com- respectively, and there was less toxic- pared to control patients (p = 0.04), ity seen in the GD arm of the study. and those treated with the combina- ■ Interim results of the KEYNOTE-045 tion reported diffi culty in achieving trial led to the approval of pem- orgasm during intercourse (p = 0.04). brolizumab for treatment of locally patients who underwent cytoreduc- with advanced clear cell RCC of inter- Those patients treated with both advanced or metastatic urothelial tive nephrectomy was 16.3 months, mediate or poor risk (Abstract 583). chemotherapy and radiotherapy also carcinoma that progressed during compared with 8.6 months in those The TemPa trial included 69 patients, reported disappointment with overall or after platinum-based chemo- who did not (p < 0.0001). After ad- and the median PFS was 5.2 months quality of sex life (p = 0.002). therapy. Now, 2-year results confi rm justment for individual risk factors, with pazopanib and 2.6 months with ■ The expansion of Medicaid has had the benefi ts (Abstract 410). Among the hazard ratio for death was 0.62 temsirolimus. The median OS was an effect on the diagnosis of testicular the 542 patients randomly assigned (95% CI [0.45, 0.85]; p = 0.0031). 12.0 months with pazopanib, com- cancer. An analysis using the Surveil- to pembrolizumab or investigator’s ■ Combining a PD-1/PD-L1 pathway pared with 7.4 months with temsiroli- lance Epidemiology and End Results choice chemotherapy and followed inhibitor with an anti-VEGF agent of- mus (p = 0.61). The response rate was database identifi ed 12,731 cases of for a median of 27.7 months, the fered improved outcomes in patients signifi cantly better with pazopanib, at testicular cancer from 2010 to 2014 median OS was 10.3 months with the with metastatic RCC, especially in 26%, compared with 6% with tem- (Abstract 551). In the states that ex- immune checkpoint inhibitor and 7.3 those who are PD-L1–positive. The sirolimus (p = 0.046). Safety profi les panded Medicaid after passage of the months with chemotherapy (HR 0.70; phase III IMmotion151 trial (Abstract were similar to that seen with these Affordable Care Act, Medicaid cover- p < 0.0002). The benefi t was seen in 578) included 915 patients in an in- drugs in other trials. age for testicular cancer increased all PD-L1 expression subgroups, and tention-to-treat analysis, and 362 who from 14.8% to 19.4% of patients (p adjustments for multiple variables did were PD-L1–positive were randomly Testicular Cancer Therapies and < 0.001), and the uninsured rate for not change the fi ndings, confi rming assigned to receive either sunitinib or Phenotypes these patients decreased from 8.7% the use of this agent in this setting. atezolizumab plus bevacizumab. The ■ A case control study of 30 individuals to 4.3% (p < 0.001). No such trends median PFS was 11.2 months with including 15 with testicular cancer were seen in states that did not ex- Renal Cell Carcinoma Highlights the combination compared with 7.7 treated with chemotherapy found pand Medicaid. The number of cases Studies were also presented that dem- months with sunitinib in patients a “senescence phenotype” in the diagnosed at stage I also increased in onstrate advances in renal cell carcinoma who were PD-L1–positive (HR 0.74, survivors of the malignancy (Abstract expansion states, whereas in nonex- (RCC), including less well-understood 95% CI [0.57, 0.96]; p = 0.0217). In 548). They had a signifi cantly higher pansion states there was an increase settings such as patients with papillary the intention-to-treat population, the expression of p16INK4a, which has in stage III cases. No change in man- histology. median PFS was 11.2 months and 8.4 been dubbed a biomarker of aging, agement of the malignancy has yet ■ A retrospective analysis of 353 pa- months, respectively (HR 0.83, 95% than the control individuals (p = been observed. tients with papillary metastatic RCC CI [0.70, 0.97]; p = 0.0219). OS data 0.031). Differences in lymphocyte found that cytoreductive nephrecto- were not yet mature. populations were also observed, Save the date for the 2019 Genitouri- my could improve survival outcomes ■ The VEGFR tyrosine-kinase inhibitor suggesting survivors of these cancers nary Cancers Symposium, to be held (Abstract 581). After a median follow- pazopanib improved outcomes over treated with chemotherapy could February 14-16, in San Francisco. up of 57.1 months, the median OS in temsirolimus in a study of patients be at increased risk of infection; the –David Levitan

Patient-Reported Outcomes tioning can refl ect tolerability and in- PRO-CTCAE). The PRO-CTCAE is a About the Author Continued from page 13B form decisions about dosing. In phase III library of items for patient self- trials, PROs can be useful to understand reporting of 78 different symp- Dr. Basch is a UNC Line- For more than a decade, regulatory the impact of therapy on disease-related tomatic adverse events that are berger Comprehensive Cancer Center member, agencies, particularly the U.S. Food and symptoms, such as pain or fatigue. common in cancer care such director of Cancer Out- Drug Administration (FDA) and Europe- Ideally, the PRO component of a as nausea, diarrhea, dyspnea, comes Research Program, an Medicines Agency (EMA), have cham- clinical trial will be planned early. This etc. Like the CTCAE, individual and professor of medicine pioned the value of directly collecting starts with identifying outcomes that adverse events can be elicited in at the University of North information from patients through PRO are meaningful in a given context or trials or during routine care de- Carolina, Chapel Hill. questionnaires. Indeed, the term “pa- population through literature reviews pending on the context of use. The tient-reported outcome” was popular- or qualitative (patient interview) work, PRO-CTCAE was rigorously developed erally have an incomplete picture of the ized by the FDA in the late 2000s when it then choosing or developing a rigorous for the NCI by a group of multidisci- patient experience, which can impair our published a highly infl uential PRO meth- questionnaire that maps to those out- plinary investigators, including myself.15 ability to make informed decisions about ods guidance,12 which was reinforced by comes. Investigators should ideally part- The PRO-CTCAE is free and avail- treatments. Technologies for collecting an equally infl uential refl ections docu- ner with an expert in PRO methods to able from the NCI for use in any clini- PROs are improving, and there is rapid- ment from the EMA.13 A recent accom- assist with the design. Increasingly, there cal trial or real-world setting, and it ly growing interest to routinely include plishment is a framework for PRO data are efforts to standardize approaches to can be downloaded in multiple lan- PROs in care and research processes. collection presented by the FDA, which PROs in various contexts side by side guages at healthcaredelivery.cancer.gov/ focuses on three domains: cancer-related with other endpoints. For example, the pro-ctcae. This tool is designed to bring References: symptoms, physical functioning, and Prostate Cancer Clinical Trials Working the patient voice into research and care 1. Laugsand EA, et al. Health Qual Life Out- symptomatic adverse events.14 Group has recommended standards for and to reduce the frequency of missing comes. 2010;8:104. Understanding patients’ symptom and outcomes in clinical trials, including vital symptoms experienced by patients. 2. Basch E, et al. J Natl Cancer Inst. physical functioning experiences is vital biomarkers, imaging, and PROs. 2009;101:1624-32. to appreciating the properties of cancer Summary 3. Panattoni L, et al. J Oncol Pract. 2018;Feb 8 treatments, and PRO questionnaires are The Patient Version of the CTCAE PROs enable patients to report how [Epub ahead of print]. the gold standard for assessing these ar- Recently, the NCI released a patient- they are feeling and functioning. This is 4. Mayer DK, et al. J Clin Oncol. eas. For example, in early-phase trials, reported version of the Common Termi- essential information for cancer clinicians 2011;29:2683-8. patient symptoms and physical func- nology Criteria for Adverse Events (the and investigators. Without PROs, we gen- See Patient-Reported Outcomes, Page 28B B 16 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Do you have patients receiving AC who may potentially develop chemotherapy induced nausea and vomiting?

IV NEPA phase 3b Clinical trial the CYCLAMEN Study

Now enrolling IV NEPA (fosnetupitant 235mg/palonosetron 0.25mg) in the prevention of chemotherapy-induced nausea and vomiting: A multicenter, randomized, double-blind, double-dummy, active-controlled, parallel group phase 3b study to assess the safety and to describe the efﬁcacy of IV NEPA compared to oral NEPA (netupitant 300mg/palonosetron 0.5mg, Akynzeo®) for the prevention of chemotherapy-induced nausea and vomiting in initial and repeated cycles of anthracycline- cyclophosphamide (AC) chemotherapy (CT) in women with breast cancer. Key Inclusion criteria: • Adult patients with breast cancer • Naïve to moderately or highly emetogenic CT

For additional information regarding the trial, or if you are interested in becoming an investigator contact us at: [email protected]

NEPA IV in an AC patient population for CINV has not been approved for https://clinicaltrials. gov/show/ NEPA-US-0008 commercial use by FDA or any other regulatory authority in any part of the world. NCT03403712

ASCO Guideline Addresses Palliative Care in the Global Setting

ntegrating palliative care into overall Public Health, said. “The previous guide- may be,” Dr. spiritual care. oncology care is critical, and ASCO lines work well in countries that already Osman said. ASCO’s guide- has published a new resource-strat- have excellent oncology care and the re- “This makes it line recom- ifi ed guideline to address this issue sources to provide that care.” Dr. Cleary an extremely mends a coor- Iworldwide. The new “Palliative Care co-chaired the guideline Expert Panel useful tool for dinated system in the Global Setting: American So- along with Hibah Osman, MD, MPH, of palliative care where the palli- ciety of Clinical Oncology Resource- the Lebanese Center for Palliative Care- advocates glob- ative care needs Stratifi ed Practice Guideline,” is intend- Balsam. ally and will of patients and ed to complement the “Integration of When the nonresource-stratifi ed encourage poli- families are Palliative Care Into Standard Oncology guidelines were fi rst published, every- cymakers to identifi ed and Care: American Society of Clinical On- one agreed they were useful. “They rede- implement the Dr. James F. Cleary Dr. Hibah Osman met at all levels, cology Clinical Practice Guideline Up- fi ned the role of palliative care in cancer recommenda- in collaboration date” of 2016. The purpose of the new treatment, and they were an extremely tions in the with the team resource-stratifi ed guideline “is to pro- helpful resource in our advocacy efforts guideline.” providing oncology care. The health vide expert guidance to clinician policy- as we work to get palliative care inte- She added a key point of the ASCO care system “should have trained per- makers on implementing palliative care grated into our health care systems,” Dr. guideline is that palliative care “should sonnel who are licensed to prescribe, de- in resource-constrained settings.”1 Osman said. “Unfortunately, it was easy be initiated as early as possible and liver, and dispense opioids at all levels.”1 “It came to our attention that the for decision-makers in countries with should not be reserved until the patient According to Dr. Cleary, 80% of the 2016 guidelines were benefi cial for very limited resources like mine [Lebanon] is no longer a candidate for curative world’s population lacks access to mor- well-resourced, high-income countries,” to dismiss the U.S.-based guidelines as therapies.” phine, making palliative care crucial in James F. Cleary, MD, of the University standards that cannot be realistically ap- Although clinician mindset is slowly areas where oncology care resources are of Wisconsin School of Medicine and plied in our setting.” embracing that philosophy, Dr. Osman stretched by budgetary constraints. Globally, the push for palliative care said it’s still common to hear oncolo- These guidelines are “the very basic has increased over the years, Dr. Cleary gists say a patient “isn’t at the palliative level that should actually come, or be Palliative care “should be said. For example, a World Health Or- stage yet,” even as patients are receiving provided, for the low-income countries initiated as early as possible ganization resolution in 2014 recom- second-, third-, and fourth-line chemo- or least-resourced countries,” he said. mended that nations look to improve therapy treatments. “I’m hopeful that “This provides a roadmap for countries and should not be reserved their palliative care efforts.2 Last year, a this guideline will help us change that,” as they develop health care policies.” until the patient is no longer Lancet Commission report noted an “ac- she said. Accessibility of opioids remains a ma- cess abyss in palliative care,” saying the jor issue in lower-income parts of the a candidate for curative lack of global access is a global crisis.3 Key Concepts world. therapies.” ASCO’s resource-stratifi ed guideline This guideline addresses two critical “The Lancet Commission report on “sets an achievable standard for any set- components: accessibility of opioids in palliative care and pain relief estimated –DR. HIBAH OSMAN ting, regardless of how limited resources lower-income countries and the role of See Guideline Addresses Palliative Care, Page 30B WE ARE WORKING TO BRING IMMUNE RESPONSE TO THE SURFACE

≈5% of stage IV CRC tumors are The remaining ≈95% are microsatellite microsatellite instability-high (MSI-H) stable (MSS) or microsatellite instability- and exhibit high mutational burden1-5 low (MSI-L) and exhibit low mutational burden. This leads to limited generation of tumor-directed T cells, allowing tumors to escape immune surveillance2-4,6,7

Genentech is leading cancer immunotherapy research to enhance immune detection of CRC tumors regardless of mutational burden • MEK pathway inhibition may expose tumors by increasing antigen presentation on the surface of tumor cells8 • PD-L1 pathway inhibition may activate T cells to attack tumor cells9

PD-L1=programmed death-ligand 1.

References: 1. Vilar E, Gruber SB. Nat Rev Clin Oncol. 2010;7:153-162. 2. Venderbosch S, et al. Clin Cancer Res. 2014;20:5322-5330. 3. Müller CI, et al; AIO Colorectal Study Group. Int J Colorectal Dis. 2008;23:1033-1039. 4. Timmermann B, et al. PLoS One. 2010;5:e15661. 5. Banerjea A, et al. World J Surg Oncol. 2005;3:26. 6. de Vries NL, et al. Int J Mol Sci. 2016;17:1-21. 7. Angelova M, et al. Oncoimmunology. 2016;5:e1078058. 8. Reddy SM, et al. Curr Oncol Rep. 2016;18:42. 9. Kim JM, Chen DS. Ann Oncol. 2016;27:1492-1504.

WHY I ATTEND DR. LESLIE SAMUEL Q: Have you made any connections Q: What do you always make sure at the Meeting that have impacted to include when packing for the ong-time ASCO Annual Meeting at- Q: Do you have any tips for new your career? Meeting? tendee Leslie Samuel, MD, provides attendees who may feel overwhelmed Dr. Samuel: I’ve made some very in- Dr. Samuel: As I’m coming from the advice to new attendees on how to by all the on-site options? teresting connections that have led to United Kingdom with a 5- to 6-hour get the most out of the Meeting. Dr. Samuel: There are bound to be clinical trial collaborations, which have time difference, I always make sure to L times where you want to be in two enriched my career. If you know of a pack some melatonin tablets. I usually Q: Why are you attending the ASCO places at once. My advice is to use the study that you would like to be involved also bring my cycling shorts, as there Annual Meeting this year? Annual Meeting Videos & Slides tool to with, contact the sponsor, commercial are some great urban cycling routes in Dr. Samuel: It is an opportunity to help prioritize. You can watch recorded company, or a lead investigator, and ask Chicago. I also bring business cards. hear the results from a number of clini- presentations of sessions you may have to meet for coffee. You may fi nd oppor- cal trials, some of which I’ve been in- missed in person. tunities fl ow from these meetings. Q: Any other tips for attendees? volved with, being presented and dis- Dr. Samuel: The Poster Sessions can cussed. It is also an opportunity to catch Q: Apart from the science presented, Q: This year’s theme is focused on be an excellent opportunity to get up- up with oncologists whom I know, as what are the benefi ts of attending precision medicine. What do you to-date information about studies from well as industry colleagues about pres- the Meeting? think the Meeting will be most someone involved. Engage the present- ent or future trials. Dr. Samuel: There are quite a few, focused on 10 years from now? ers, and make sure to bring some busi- apart from the obvious one of spend- Dr. Samuel: That’s a very good ques- ness cards to exchange. Q: How do you plan your time ing a few days in Chicago. It is an option, particularly given the rapid change during the Meeting? portunity to meet other oncologists, in knowledge over the past few years. Dr. Samuel: I use the iPlanner app and particularly at the Poster Sessions, and Our understanding of the interaction online abstracts for planning. It’s impor- discuss results, which may lead to oth- between cancer cells and other normal tant to spend time going through the er studies. In the same vein, it is an op- tissue function, such as stromal tissue, Leslie Samuel, MD, is the Macmillan program and note what is happening portunity to meet industry colleagues, for example, will increase yet pose chal- Consultant Oncologist at the Aberdeen and when, as well as the location within as it is always good to put a face to a lenges to how we interpret the informa- Royal Infi rmary, United Kingdom, and McCormick Place. The silver lining for name. This may lead to future trial col- tion from biopsies. Bioinformatics will honorary senior lecturer in the Health those of us with long wait times in air- laborations to the benefi t of your pa- need to be (and I’m sure will be) more Service Research Unit, Aberdeen Uni- versity. He’s involved with academic and port departure lounges or long fl ights to tients and your career. user-friendly for clinicians, but I suspect commercial clinical research, particu- Chicago is that there is plenty of time to our training will need to embrace the larly in lower gastrointestinal cancers. make plans. bioinformatic analysis and pitfalls.

Global Health Equity countries, an inequitable distribution of cal, breast, and colon cancer screening is public places, federal policies have been Continued from page 14B fi nances, expertise, and resources por- also impaired because of a lack of com- implemented to combat obesity and tends a poor health care foundation. In munity awareness on the importance of the harmful effects of alcohol. HPV and cost of cancer was up to $2.5 trillion, ac- 2004, the country’s health care policy screening, as well as low levels of health hepatitis B vaccines are freely available. counting for costs related to prevention was revised, mandating free basic health literacy. Other contributing factors in- Additionally, screening for both cervical and treatment, economic value of mor- care at the primary level to all citizens. clude inadequate skill among service and breast cancers has been advocated, bidity and mortality, and longer-term That being said, cancer screening, diag- providers, lack of equipment and sup- and protocols comply with standard in- costs to patients and families.3 By 2012, nostics, and treatment are still not cov- plies, and scant monitoring. ternational guidelines. there was an estimated 14.1 million new ered by the government-funded insur- As is typical of many middle-income Despite implementation of these ini- cases of cancer, with 8.2 million cancer ance, and routine vaccinations for HPV countries, health policy and resources tiatives, there are still signifi cant prob- deaths occurring worldwide. Sixty-fi ve and hepatitis B are not included in the are primarily focused on communicable lems with access to cancer care. For percent of these occurred in low-income immunization schema. By 2013, only diseases. The most common cancers instance, the average time between countries.4 Cancer has been designated 4.5 million (11%) of the Kenyan popula- are breast and cervical—malignancies mammography and diagnostic biopsy the second leading cause of death inter- tion had health care coverage.7 that can be prevented or detected early, is 72 days.7 Or, in the case of patients nationally and is responsible for nearly Access to medications, surgery, and benefi ting from the implementation of diagnosed with oral cancer, it takes an one in six deaths.5 In 2015, the World radiation therapy is cost-prohibitive. Ke- dedicated vaccination and screening average of 41 days to commence treat- Health Organization (WHO) estimated nya’s oncology drug list consists of only programs. Cancer-related mortality is ment. Traditional imaging and surgical that 8.8 million deaths related to cancer 18 of the 52 essential cancer medicines the third most common cause of death and pathology services are available, but occurred, with 70% of these in LMICs.5 outlined by WHO.7 Chemotherapy is in Kenya.7 Circumstances such as inad- delays are common and molecular anal- More than 90% of high-income coun- available, but because of the high cost of equate public education and awareness, yses are not always available. Similarly, tries report available treatment services drugs and lack of coverage of the cost of scarce oncology services, and poorly while there are more than 250 radiation versus less than 30% in low-income cancer treatments by the National Hos- trained personnel, compounded by low machines in the country, access is limit- settings. Furthermore, only one in fi ve pital Insurance Fund, it is inaccessible prioritization by political parties have ed based on geography and income, and LMICs have the necessary data to drive to most. This quandary also extends to resulted in these inferior outcomes. wait times can be up to 3 months. cancer policies. Implementing preven- narcotic agents, making pain control a Policies differ in terms of the provi- tion, early detection, and treatment major obstacle. Use of other complimen- Brazil sion of anticancer medicines. The strategies could potentially save between tary services is also curtailed by cost re- Brazil is an Brazilian essential medicine list is 2.4 to 3.7 million lives annually, trans- straints. Kenya has only two cobalt radi- upper-middle- mostly congruent with the WHO lating to an economic benefi t in excess ation machines for patients with public income country, essential medicine list.7 Moreover, of $400 billion.3 health care, with appointments booked with a popula- once a drug is approved by the for several months in advance. For pa- tion of 200 million, a local regulatory agency, coverage Kenya tients with private health care, there GDP per capita of $8,650 is mandatory in the private health Kenya is a lower- are four linear accelerators in Nairobi, (in 2016), and a general care system. As such, citizens (usually middle income East with prompt initiation of therapy for life expectancy of 70 years the more affl uent) can sue the federal African country in those who can afford it. for men and 77 years for government for access to cancer medi- sub-Saharan Africa This lack of resources is compounded women.7 Total health expen- cations. This creates the conundrum with a population by limited education and exacerbates diture accounts for about 9.3% of the where distribution of scarce resources in of about 48.5 mil- the diffi culty in accessing effi cient GDP, with 46% of this in the public sec- the public system becomes imbalanced lion.6 As of 2016, the health care. In 2011, the National Can- tor. Sistema Único de Saúde is a public, in favor of those belonging to higher so- gross domestic product cer Prevention and Control Programme tax-funded health scheme that covers cioeconomic levels. (GDP) per capita is $1,455, stipulated provisions to making preven- the population; however, about one- Brazil is a model for health care in life expectancy was 61 years for tive, curative, and palliative care services quarter of the population still subscribes middle-income countries. Execution of men and 66 years for women, and accessible to all Kenyans.7 Unfortunate- to private medical insurance. Brazil in- screening programs and public educa- health expenditures accounted for 4.7% ly, such an undertaking proved overly stituted a national cancer control plan tion emphasizing risk reduction strat- GDP.7 The estimated annual incidence ambitious; screening occurs only in a in 2005, with a heavy emphasis on pub- egies constitute the mainstay of their of cancer is 28,000 cases, with 22,000 few selected sites, rather than as a cohe- lic education and screening. Smoking, cancer control plan.7 Establishment deaths. As with many middle-income sive national program. Access to cervi- as well as its advertising, is banned in See Global Health Equity, Page 20B 100% FREE

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Global Health Equity than those of whites and nearly twice available and high-quality pathologic About the Authors Continued from page 18B the rates among Asians/Pacifi c Island- and imaging studies. Treatments often ers. Conversely, non-Hispanic and white include a careful mixture of surgery, ra- Dr. Ali is a of this basic health care system has re- women have the highest overall cancer diation, and chemotherapy, followed by hematology-oncology sulted in improved outcomes and de- incidence rates among females. These a long period of follow-up. The typical fellow at the Univer- creased cancer mortality over the past disparities among racial groups are also health care coverage that is available is sity of Miami and Sylvester Compre- decade. Nonetheless, challenges still refl ected in the all-cancer mortality not always able to accommodate these hensive Cancer exist with the distribution of resources rates. The highest rate is noted among expenses, causing patients to forfeit Center. among various social echelons, as well non-Hispanic blacks (208.8 per 100,000 some components of their care. as geographic locations. Also, the rou- population), followed by whites (176.5), The distribution of screening and tine acquisition and implementation of Hispanics (119.7), and Asians (108.9). treatment centers are not always even advanced technologies and medicines within countries because of funding and Dr. de Souza is an continues to be a struggle. Mitigating Disparities Moving Forward geography. Accessibility to cancer care is oncologist with Although considerable emphasis is often worse in rural compared to urban the University of The United States placed on the role of fi nances on health communities, regardless of the income Chicago. The United States is a federal presi- care initiatives, high-income countries level of the country. dential republic with a population of still face the challenge of ensuring eq- The Institute of Medicine, the Global 323 million, as of 2016.7 The GDP is uitable distribution of resources among Task Force on Expanded Access to Can- $15 trillion, establishing it as a high-in- their population including minorities cer Care and Control in Developing come country. Health care accounts for and vulnerable groups. Additionally, Countries, WHO, and other groups have 17% of the GDP. Both public and pri- with the landscape of oncology shifting created frameworks detailing the most Ms. Hunt is an vate fi nancing contribute to the health toward targeted therapies and biologic important stepping stones in improving epidemiologist with care system, with up to 65% of funds agents, the cost of these agents must be the fi ght against cancer.7 Some of these Sinai Health System. sourced from the government. The life factored in when attempting to deliver include establishing universal health expectancy is 76 years for men and 81 equitable care. care coverage, creating national cancer years for women. The annual incidence Several strategies can be employed registries and data repositories on risk of cancer is just over 1.6 million cases, at every level to mitigate the dispari- factors and treatment outcomes, provid- with a mortality-to-incidence ratio of ties among countries of various income ing tobacco control programs, vaccinat- Dr. Asirwa is an assistant professor 0.36. classes7: ing against the most common viruses of clinical medi- A national cancer control plan has ■ Low-Income Countries—Preven- that cause cancer, creating reference cine with Indiana been implemented since 2010.7 Similar tion and risk reduction should be the cancer centers, ensuring access to essen- University School of to Brazil, smoking is banned in indoor primary focus via the establishment tial cancer medicines and palliative care, Medicine. public places, and policies are in place of a national cancer control plan and and other steps detailed throughout database to track trends in disease this review. That being said, economic Credit Neil Thomas patterns. Additionally, investment growth may be the ultimate remedy in Dr. Adebamowo is in basic health care infrastructure the long run. Middle-income countries the associate direc- and education, as well as efforts to have been at least partially successful tor for population expand coverage to remote areas, is through measures such as tax-funded science with the Greenebaum Com- paramount. health care; however, their low-income prehensive Cancer ■ Middle-Income Countries—In- counterparts may require international Center and profes- vestment in prevention and early support to achieve these targets. sor of epidemiology detection programs should be the The fi nancial impact of cancer across and public health objective. Access to basic pathology, all socioeconomic levels has been dem- with the University of Maryland School imaging, and other ancillary services, onstrated ad nauseam, particularly to of Medicine, Balti- as well as striving toward compliance those in low-income countries. Conse- more. He is presi- to prevent obesity and alcohol abuse. with the WHO Model List for Essen- quently, from both an economic and a dent of the Society Screening for preventable cancers, in- tial Medications, are also pivotal for pragmatic standpoint, it is pivotal to in- of Oncology and cluding cervical, breast, and colon, is progress. vest in measures to alleviate this burden. Cancer Research of Nigeria. widely available. Hepatitis B and HPV ■ High-Income Countries—Capital- This task would entail the consolidated vaccinations are ubiquitous, and there izing on advancing interventions and effort of governments, private stake- Dr. Lopes is a is increased public awareness regard- services should form the backbone holders, and nonprofi t organizations. medical oncologist, ing vaccinations, with 91% and 32% of care at this level. These include, Furthermore, from a humanistic stand- medical director of the target populations being vacci- for example, genomic assays, higher- point, all endeavors should be made to for international programs, and as- nated, respectively. Advanced imaging, resolution and nuclear studies, and curb this suffering. Following the United sociate director for surgical services, and pathology are also advanced radiation and surgical Nations summit on noncommunicable global oncology at available, as are radiation services, with techniques. Also, with the continuum disease in 2011, the worldwide plight of the Sylvester Com- more than 2,700 machines nationwide. extending to include more innovative cancer has come to the forefront in glob- prehensive Cancer Novel and inherently more expensive and consequently expensive medica- al public health.7 Indeed, it will take a Center. He is the Editor of the Journal chemotherapeutic agents are accessible tions, efforts should extend to make global initiative to have these ambitions of Global Oncology. through health care coverage. these available nationwide and to brought to fruition. Despite the high-income standing of all persons regardless of minority or Like Orpheus, son of Apollo and the the United States, socioeconomic sta- economic background. muse Calliope, we must venture into the tus, access to health care services, and underworld to rescue cancer control in cancer-prevention-and-control-reduce- individual behaviors continue to ad- Notwithstanding the obvious dispari- underserved areas, our Eurydice, from global-economic-burden. Published May versely affect health care equity. The ties highlighted here, basic challenges the reign of Hades. Let us not look back 5, 2015. Accessed January 25, 2018. highest cancer incidence rate among persist that are common among all stra- lest our dream vanishes in front of us be- 4. GLOBOCAN 2012: Estimated Cancer Inci- men is observed within the black com- ta of socioeconomic standing. Poverty fore we reach our goal. dence, Mortality and Prevalence World- munity.7 Overall rates are 15% higher has been a relentless obstacle to receiv- wide in 2012—All Cancers (Excluding ing cancer care.7 This prevents people References: Non-Melanoma Skin Cancer). Interna- from practicing good lifestyle habits 1. Disparities. Healthpeople.Gov. healthy tional Agency for Research on Cancer. ASCO INTERNATIONAL and accessing preventive and curative people.gov/2020/about/foundation- globocan.iarc.fr/Pages/fact_sheets_cancer. MEETINGS medical care promptly. Cancer care fi - health-measures/disparities. Accessed aspx. Accessed January 25, 2018. nancing is a global challenge. In high- January 25, 2018. 5. Cancer Fact Sheet. World Health Organiza- Host an ASCO educational event income countries, the high cost of new 2. National Cancer Control Planning (NCCP). tion. who.int/mediacentre/factsheets/ in your country. ASCO offers treatments is straining the system while Union for International Cancer Con- fs297/en. Published February 2017. Ac- training in multidisciplinary cancer LMICs struggle with the cost of provid- trol. uicc.org/national-cancer-control- cessed January 25, 2018. management, clinical research, ing the minimum set of cancer preven- planning-nccp. Published May 13, 2014. 6. The World Bank. The World Bank in Kenya: palliative care, and cancer control tion and treatment services for the ma- Accessed January 25, 2018. Overview. worldbank.org/en/country/ke- for primary care providers. Learn jority of their population. 3. Investing in Cancer Prevention and Con- nya/overview. Updated October 10, 2017. more at asco.org/international. Cancer treatment is often multifac- trol to Reduce Global Economic Burden. Accessed January 25, 2018. eted, including the need for readily ASCO Daily News. am.asco.org/investing- 7. Souza JA, et al. J Clin Oncol. 2016;34:6-13. am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 21 B CLINICAL CORNER Complete Resection for Second-Line Ovarian Cancer Treatment lizabeth L. Dickson Michelson, MD, ently than other metastatic solid tumor FACOG; Colleen Rivard Hunt, MD, types—even though ovarian cancer can FACOG; Melissa Geller, MD, MS, be chemosensitive, numerous studies FACOG; and Deanna Teoh, MD, have shown that surgical cytoreduction of EFACS, FACOG, answer a question posed tumor volume to no visible disease is sig- by an attendee during a Best of ASCO® nifi cantly correlated to improved patient Meeting. Dr. Dickson Michelson is a gy- outcomes.10 We continue to strive to fi nd necologic oncologist with Aurora Health the best combination modality treatment Care, and Dr. Rivard Hunt, Dr. Geller, for patients with ovarian cancer, and sur- and Dr. Teoh are gynecologic oncologists gical cytoreduction will continue to be with the University of Minnesota. the cornerstone of this therapy. Dr. Elizabeth L. Dickson Dr. Colleen Rivard Hunt Dr. Melissa Geller Michelson Question: Why is complete resection References: valuable in second-line ovarian 1. American Cancer Society. What Are the cancer treatment but not in fi rst-line no gross residual disease they have even cytoreductive surgery (204 patients) fol- Key Statistics About Ovarian Cancer? treatment? better survival.2 If a surgeon believes that lowed by chemotherapy versus standard cancer.org/cancer/ovarian-cancer/about/ Answer: Ovarian cancer, which will be optimal cytoreductive surgery will not be platinum-based chemotherapy alone key-statistics.html. Updated January 4, diagnosed in more than 21,000 women possible, neoadjuvant chemotherapy may (203 patients). Whereas the study was 2017. Accessed November 16, 2017. and be responsible for 14,000 deaths in be the next best step in order to reduce powered for overall survival (OS) analy- 2. Hoskins WJ, et al. Gynecol Oncol. 2017,1 continues to be the most deadly the burden of disease before attempting sis, the PFS data were promising, with 1992;47:159-66. gynecologic malignancy facing women cytoreductive surgery. There have been a PFS advantage of 19.6 months versus 3. Hoskins WJ, et al. AM J Obstet Gynecol. today. The mainstay of treatment com- mixed results from studies evaluating 14.0 months for the secondary cytore- 1994;170:974-9. bines aggressive surgical debulking with patients who had suboptimal debulking ductive surgery group. The most striking 4. Rose PG, et al. N Engl J Med. chemotherapy, and now targeted thera- surgery, then received chemotherapy, and fi nding, though, was that the cytoreduc- 2004;351:2489-97. pies are used as well. then a second attempt at debulking.4-10 tive surgery had to achieve complete re- 5. Van Der Burg ME, et al. N Engl J Med. Several studies have shown that pa- The DESKTOP III trial interim analy- section to obtain the benefi t of increased 1995;332:629-34. tients who undergo primary cytoreduc- sis was presented during the 2017 ASCO PFS (a median increase of 7.2 months). 6. Eisenkop SM, et al. Cancer. 2000;88:144-53. tive surgery, what is referred to as “opti- Annual Meeting.9 The data showed im- This study seems to confi rm what is al- 7. Kehoe S, et al. Lancet. 2015;386:249-57. mal debulking,” have the best survival proved progression-free survival (PFS) ready believed about primary debulking 8. Wright AA, et al. Gynecol Oncol. outcomes in ovarian cancer.2,3 The defi - with secondary cytoreduction. At the surgery: If a complete resection to no 2016;143:3-15. nition of optimal debulking has evolved time of a fi rst platinum-sensitive ovarian visible disease can be achieved, there is 9. Du Bois A, et al. J Clin Oncol. 2017;35 over time, from less than 3 cm of resid- cancer recurrence in which complete re- likely to be a survival advantage; how- (suppl; abstr 5501). ual disease to more recent studies show- section is deemed feasible, patients were ever, we must await the fi nal OS analysis. 10. Fader AN, et al. J Clin Oncol. 2007;25:2873- ing that if a patient can be debulked to randomly selected to receive secondary Overall, ovarian cancer acts differ- 83.

Assessing the Older Adult With Cancer ARTICLE decade of life (Fig. 1).1 Given changing How to Assess the Older Patient HIGHLIGHTS EXPERT demographics, approximately 70% of Chronologic age alone is insuffi cient all new cancer diagnoses will be in older in evaluating older adults given the sig- ■ Older adults with cancer vary EDITORIAL adults by 2030, yet the same treatment nifi cant variability in physiologic ability in health status irrespective of options are not appropriate for each indi- between individuals. Although the use age, and it is paramount to use Grant R. Williams, MD, and vidual patient.2 Older adults with cancer of performance status assessments may a comprehensive assessment to Ronald J. Maggiore, MD vary in health status irrespective of age, help in evaluating the overall level of adequately weigh the risks and and it is paramount to use a comprehen- physical functioning of our patients, it is benefi ts of treatment options. ancer is predominantly a disease of sive assessment to adequately weigh the subjective and may miss many important ■ Geriatric assessment evaluates older adults, with the majority of risks and benefi ts of treatment options. factors that are known to infl uence treat- a broad range of health domains new cancer diagnoses occurring in In this review, we highlight best practices ment outcomes.3 More systematic and including physical function, func- adults over age 65 and the cancer in evaluating older adults to better indi- comprehensive evaluations are needed tional status, nutrition, cognition, Cincidence rate peaking around the eighth vidualize cancer therapies. in order to appropriately individualize psychological health, comorbidity, therapies in older adults with cancer. and social support to develop a Fig. 1. Age-Specifi c Cancer Incidence Rates Geriatric assessment is a multidimen- coordinated and integrated plan sional and interdisciplinary assessment for treatment. 2,500 of an older person’s medical, function- ■ For busier oncology practices al, and psychosocial abilities.4 Geriatric or those with limited access to assessment evaluates a broad range of formal geriatrics specialty clinics 2,000 health domains including physical func- or resources, a geriatric screening tion, functional status, nutrition, cogni- tool may be able to help cancer tion, psychological health, comorbidity, therapy providers discern higher- 1,500 and social support to develop a coordi- risk patients for treatment-related nated and integrated plan for treatment toxicities, other complications, (Table 1, page 21B). Although these as- and/or worse prognosis. 1,000 sessments are traditionally performed by geriatricians and, ideally, as part of a mul- Rates per 100,000 Rates tidisciplinary evaluation, shortened ver- ferent clinical settings. A variety of well- 500 sions that are primarily patient-reported validated measures can be used to assess have been developed for ease of use in the domains of the geriatric assessment, oncology clinics.5 These abbreviated as- and deciding which measures to employ 0 sessments take about 20 to 30 minutes can be tailored to the provider and local 1-4 5-9 to complete and only about 5 minutes resources. The exact tools employed may <1 85+ 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 of health care provider time, and they vary, but should assess the following do- Age have been shown to be feasible in dif- See Assessing the Older Adult, Page 28B Avelumab (BAVENCIO®) RECOMMENDED BY THE NATIONAL COMPREHENSIVE CANCER NETWORK®b 1&&1®) AS AN OPTION • for patients with disseminated Merkel cell carcinoma (category 2A)1 • for patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (category 2A)2

The NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. REVEAL ANOTHER SIDE OF IMMUNITY BAVENCIO (avelumab) is an anti-PD-L1 immunotherapy that has been shown in preclinical models to engage both the adaptive and innate immune functions.3-7

The FIRST AND ONLY FDA-approved anti-PD-L1 immunotherapy for adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC)8

APPROVED for patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

INDICATIONS

BAVENCIO is indicated for the treatment of: • Adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC) • Patients with locally advanced or metastatic urothelial carcinoma (UC) who: – Have disease progression during or following platinum-containing chemotherapy – Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for WKHVHLQGLFDWLRQVPD\EHFRQWLQJHQWXSRQYHULͤFDWLRQDQGGHVFULSWLRQRIFOLQLFDOEHQHͤWLQFRQͤUPDWRU\WULDOV

Learn more at BAVENCIO.com

IMPORTANT SAFETY INFORMATION BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with *UDGHDQGͤYH ZLWK*UDGH BAVENCIO can cause immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune- mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3. BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis, and permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3. IMPORTANT SAFETY INFORMATION (continued)

BAVENCIO can cause immune-mediated endocrinopathiesLQFOXGLQJDGUHQDOLQVXͦFLHQF\WK\URLGGLVRUGHUVDQGW\SHGLDEHWHVPHOOLWXV Monitor patients for signs and symptoms of DGUHQDOLQVX̩FLHQF\during and after treatment, and administer corticosteroids as DSSURSULDWH:LWKKROG%$9(1&,2IRUVHYHUH *UDGH RUOLIHWKUHDWHQLQJ *UDGH DGUHQDOLQVXͦFLHQF\$GUHQDOLQVXͦFLHQF\ZDV reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3. 7K\URLGGLVRUGHUV can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3. 7\SHGLDEHWHVPHOOLWXVincluding diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of GLDEHWHV:LWKKROG%$9(1&,2DQGDGPLQLVWHUDQWLK\SHUJO\FHPLFVRULQVXOLQLQSDWLHQWVZLWKVHYHUHRUOLIHWKUHDWHQLQJ *UDGH͡ hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia. BAVENCIO can cause LPPXQHPHGLDWHGQHSKULWLVDQGUHQDOG\VIXQFWLRQ. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients. BAVENCIO can result in RWKHUVHYHUHDQGIDWDOLPPXQHPHGLDWHGDGYHUVHUHDFWLRQV involving any organ system during treatment or after WUHDWPHQWGLVFRQWLQXDWLRQ)RUVXVSHFWHGLPPXQHPHGLDWHGDGYHUVHUHDFWLRQVHYDOXDWHWRFRQͤUPRUUXOHRXWDQLPPXQHPHGLDWHG adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse UHDFWLRQ7KHIROORZLQJFOLQLFDOO\VLJQLͤFDQWLPPXQHPHGLDWHGDGYHUVHUHDFWLRQVRFFXUUHGLQOHVVWKDQRISDWLHQWVWUHDWHG with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, K\SRSLWXLWDULVPXYHLWLV*XLOODLQ%DUU«V\QGURPHDQGV\VWHPLFLQͥDPPDWRU\UHVSRQVH BAVENCIO can cause severe (Grade 3) or life-threatening (Grade 4) LQIXVLRQUHODWHGUHDFWLRQV. Patients should be premedicated with an DQWLKLVWDPLQHDQGDFHWDPLQRSKHQSULRUWRWKHͤUVWLQIXVLRQVDQGIRUVXEVHTXHQWGRVHVEDVHGXSRQFOLQLFDOMXGJPHQWDQGSUHVHQFH severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, ͥXVKLQJK\SRWHQVLRQG\VSQHDZKHH]LQJEDFNSDLQDEGRPLQDOSDLQDQGXUWLFDULD,QWHUUXSWRUVORZWKHUDWHRILQIXVLRQIRUPLOG *UDGH or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3. BAVENCIO can cause IHWDOKDUP when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman QRWWREUHDVWIHHG during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants. The most common adverse reactions DOOJUDGHV͡ LQSDWLHQWVZLWKmetastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%). 6HOHFWHGWUHDWPHQWHPHUJHQWODERUDWRU\DEQRUPDOLWLHV DOOJUDGHV͡ LQSDWLHQWVZLWKmetastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%). The most common adverse reactions DOOJUDGHV͡ LQSDWLHQWVZLWKORFDOO\DGYDQFHGRUPHWDVWDWLFXURWKHOLDOFDUFLQRPD 8& were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary tract infection (21%). 6HOHFWHGODERUDWRU\DEQRUPDOLWLHV *UDGHV͡ LQSDWLHQWVZLWKORFDOO\DGYDQFHGRUPHWDVWDWLF8& were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).

5HIHUHQFHVReferenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Merkel Cell Carcinoma. V.1.2018. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed October 19, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org.Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer V.5.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed October 19, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 2014;21(3):231-237. Kohrt HE, Houot R, Marabelle A, et al. Combination strategies to enhance antitumor ADCC. Immunotherapy. 2012;4(5):511-527. Dahan R, Sega E, Engelhardt J, Selby M, Korman AJ, 4CXGVEJ,8(E¸4UOQFWNCVGVJGCPVKVWOQTCEVKXKV[QHCPVKDQFKGUVCTIGVKPIVJG2&2&.CZKUCancer Cell. 2015;28(3):285-295. Hamilton G, Rath B. Avelumab: combining KOOWPGEJGEMRQKPVKPJKDKVKQPCPFCPVKDQF[FGRGPFGPVE[VQVQZKEKV[ Expert Opin Biol Ther. 2017;17(4):515-523. Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent EGNNWNCTE[VQVQZKEKV[CEVKXKV[QHCPQXGNCPVK2&.CPVKDQF[CXGNWOCD /5$% QPJWOCPVWOQTEGNNUCancer Immunol Res. 2015;3(10):1148-1157. U.S. National Library of Medicine. DailyMed: Advanced Search. +PFKECVKQP#PF7UCIG5GEVKQP JVVRUFCKN[OGFPNOPKJIQXFCKN[OGFCFXCPEGFUGCTEJEHO#EEGUUGF December 11, 2017.

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Copyright © 2017 EMD Serono, Inc. All rights reserved. December 2017 US/AVE/0317/0132d BAVENCIO® (avelumab) injection, for intravenous use Rx only PATIENTSRECEIVING"!6%.#)/INCLUDING 'RADEIMMUNE MEDIATEDTHYROIDDISORDERS BRIEF SUMMARY: Please see package insert for Full Prescribing Information )MMUNE MEDIATEDTHYROIDDISORDERSLEDTODISCONTINUATIONOF"!6%.#)/IN OFPATIENTS(YPOTHYROIDISMOCCURREDIN PATIENTSHYPERTHYROIDISMINSEVEN INDICATIONS AND USAGE PATIENTSANDTHYROIDITISINFOUR PATIENTSTREATEDWITH"!6%.#)/!MONGTHEPATIENTS s "!6%.#)/AVELUMAB ISINDICATEDFORTHETREATMENTOFADULTSANDPEDIATRICPATIENTS WITHIMMUNE MEDIATEDTHYROIDDISORDERS THEMEDIANTIMETOONSETWASMONTHSRANGE YEARSANDOLDERWITHMETASTATIC-ERKELCELLCARCINOMA-## WEEKSTOMONTHS ANDTHEMEDIANDURATIONWASNOTESTIMABLERANGEDAYSTOMORETHAN MONTHS )MMUNE MEDIATEDTHYROIDDISORDERSRESOLVEDINSEVEN OFTHEPATIENTS s "!6%.#)/ISINDICATEDFORTHETREATMENTOFPATIENTSWITHLOCALLYADVANCEDORMETASTATIC Type 1 Diabetes Mellitus:"!6%.#)/CANCAUSETYPEDIABETESMELLITUS INCLUDINGDIABETIC UROTHELIALCARCINOMA5# WHOHAVEDISEASEPROGRESSIONDURINGORFOLLOWINGPLATINUM KETOACIDOSIS-ONITORPATIENTSFORHYPERGLYCEMIAOROTHERSIGNSANDSYMPTOMSOFDIABETES CONTAININGCHEMOTHERAPYORHAVEDISEASEPROGRESSIONWITHINMONTHSOFNEOADJUVANTOR 7ITHHOLD"!6%.#)/ANDADMINISTERANTI HYPERGLYCEMICSORINSULININPATIENTSWITHSEVERE ADJUVANTTREATMENTWITHPLATINUM CONTAININGCHEMOTHERAPY ORLIFE THREATENING'RADEt HYPERGLYCEMIA2ESUMETREATMENTWITH"!6%.#)/WHEN 4HESEINDICATIONSAREAPPROVEDUNDERACCELERATEDAPPROVALBASEDONTUMORRESPONSERATE METABOLICCONTROLISACHIEVEDONINSULINREPLACEMENTORANTI HYPERGLYCEMICS4YPEDIABETES ANDDURATIONOFRESPONSE#ONTINUEDAPPROVALFORTHESEINDICATIONSMAYBECONTINGENTUPON MELLITUSWITHOUTANALTERNATIVEETIOLOGYOCCURREDIN OFPATIENTSINCLUDINGTWO VERIlCATIONANDDESCRIPTIONOFCLINICALBENElTINCONlRMATORYTRIALS CASESOF'RADEHYPERGLYCEMIATHATLEDTOPERMANENTDISCONTINUATIONOF"!6%.#)/ CONTRAINDICATIONS Immune-Mediated Nephritis and Renal Dysfunction: "!6%.#)/CANCAUSEIMMUNE MEDIATEDNEPHRITIS-ONITORPATIENTSFORELEVATEDSERUMCREATININEPRIORTOANDPERIODICALLY .ONE DURINGTREATMENT!DMINISTERCORTICOSTEROIDSINITIALDOSEOFTOMGKGDAYPREDNISONE WARNINGS AND PRECAUTIONS OREQUIVALENTFOLLOWEDBYACORTICOSTEROIDTAPER FOR'RADEORGREATERNEPHRITIS7ITHHOLD Immune-Mediated Pneumonitis:"!6%.#)/CANCAUSEIMMUNE MEDIATEDPNEUMONITIS "!6%.#)/FORMODERATE'RADE ORSEVERE'RADE NEPHRITISUNTILRESOLUTIONTOd'RADE INCLUDINGFATALCASES-ONITORPATIENTSFORSIGNSANDSYMPTOMSOFPNEUMONITISANDEVALUATE 0ERMANENTLYDISCONTINUE"!6%.#)/FORLIFE THREATENING'RADE NEPHRITIS)MMUNE PATIENTSWITHSUSPECTEDPNEUMONITISWITHRADIOGRAPHICIMAGING!DMINISTERCORTICOSTEROIDS MEDIATEDNEPHRITISOCCURREDIN OFPATIENTSRECEIVING"!6%.#)/"!6%.#)/ INITIALDOSEOFTOMGKGDAYPREDNISONEOREQUIVALENT FOLLOWEDBYACORTICOSTEROIDTAPER WASPERMANENTLYDISCONTINUEDINTHISPATIENT FOR'RADEORGREATERPNEUMONITIS7ITHHOLD"!6%.#)/FORMODERATE'RADE PNEUMONITIS Other Immune-Mediated Adverse Reactions: "!6%.#)/CANRESULTINSEVEREANDFATAL ANDPERMANENTLYDISCONTINUEFORSEVERE'RADE LIFE THREATENING'RADE ORRECURRENT IMMUNE MEDIATEDADVERSEREACTIONS4HESEIMMUNE MEDIATEDREACTIONSMAYINVOLVEANY MODERATE'RADE PNEUMONITIS0NEUMONITISOCCURREDIN OFPATIENTS ORGANSYSTEM-OSTIMMUNE MEDIATEDREACTIONSINITIALLYMANIFESTDURINGTREATMENTWITH RECEIVING"!6%.#)/INCLUDINGONEPATIENT WITH'RADE ONE WITH'RADE "!6%.#)/HOWEVER IMMUNE MEDIATEDADVERSEREACTIONSCANOCCURAFTERDISCONTINUATIONOF ANDlVE WITH'RADEPNEUMONITIS)MMUNE MEDIATEDPNEUMONITISLEDTOPERMANENT "!6%.#)/&ORSUSPECTEDIMMUNE MEDIATEDADVERSEREACTIONS EVALUATETOCONlRMORRULE DISCONTINUATIONOF"!6%.#)/IN PATIENTS!MONGTHEPATIENTSWITHIMMUNE OUTANIMMUNE MEDIATEDADVERSEREACTIONANDTOEXCLUDEOTHERCAUSES$EPENDINGUPONTHE MEDIATEDPNEUMONITIS THEMEDIANTIMETOONSETWASMONTHSRANGEDAYSTOMONTHS SEVERITYOFTHEADVERSEREACTION WITHHOLDORPERMANENTLYDISCONTINUE"!6%.#)/ ADMINISTER ANDTHEMEDIANDURATIONOFPNEUMONITISWASWEEKSRANGEDAYSTO MONTHS !LL HIGHDOSECORTICOSTEROIDS ANDIFAPPROPRIATE INITIATEHORMONEREPLACEMENTTHERAPY5PON PATIENTSWERETREATEDWITHSYSTEMICCORTICOSTEROIDS OFTHEPATIENTSRECEIVED IMPROVEMENTTO'RADEORLESS INITIATECORTICOSTEROIDTAPER2ESUME"!6%.#)/WHENTHE HIGH DOSECORTICOSTEROIDSFORAMEDIANOFDAYSRANGEDAYTOMONTHS 2ESOLUTIONOF IMMUNE MEDIATEDADVERSEREACTIONREMAINSAT'RADEORLESSFOLLOWINGCORTICOSTEROIDTAPER PNEUMONITISOCCURREDIN OFTHEPATIENTSATTHETIMEOFDATACUT OFF 0ERMANENTLYDISCONTINUE"!6%.#)/FORANYSEVERE'RADE IMMUNE MEDIATEDADVERSE Immune-Mediated Hepatitis:"!6%.#)/CANCAUSEIMMUNE MEDIATEDHEPATITISINCLUDING REACTIONTHATRECURSANDFORANYLIFE THREATENINGIMMUNE MEDIATEDADVERSEREACTION4HE FATALCASES-ONITORPATIENTSFORABNORMALLIVERTESTSPRIORTOANDPERIODICALLYDURINGTREATMENT FOLLOWINGCLINICALLYSIGNIlCANT IMMUNE MEDIATEDADVERSEREACTIONSOCCURREDINLESSTHAN !DMINISTERCORTICOSTEROIDSINITIALDOSEOF TOMGKGDAYPREDNISONEOREQUIVALENT FOLLOWED OFPATIENTSTREATEDWITH"!6%.#)/FOREACHOFTHEFOLLOWINGADVERSEREACTIONSIMMUNE BYACORTICOSTEROIDTAPER FOR'RADEORGREATERHEPATITIS7ITHHOLD"!6%.#)/FORMODERATE MEDIATEDMYOCARDITISINCLUDINGFATALCASES IMMUNE MEDIATEDMYOSITIS PSORIASIS ARTHRITIS 'RADE IMMUNE MEDIATEDHEPATITISUNTILRESOLUTIONANDPERMANENTLYDISCONTINUEFORSEVERE EXFOLIATIVEDERMATITIS ERYTHEMAMULTIFORME PEMPHIGOID HYPOPITUITARISM UVEITIS 'UILLAIN "ARRÏ 'RADE ORLIFE THREATENING'RADE IMMUNE MEDIATEDHEPATITIS)MMUNE MEDIATEDHEPATITIS SYNDROME ANDSYSTEMICINmAMMATORYRESPONSE4HEFOLLOWINGCLINICALLYSIGNIlCANT IMMUNE OCCURREDIN OFPATIENTSRECEIVING"!6%.#)/INCLUDINGTWOPATIENTS MEDIATEDADVERSEREACTIONSHAVEBEENREPORTEDWITHOTHERPRODUCTSINTHISCLASSBULLOUS WITH'RADEANDPATIENTS WITH'RADEIMMUNE MEDIATEDHEPATITIS)MMUNE DERMATITIS 3TEVENS*OHNSON3YNDROME3*3 TOXICEPIDERMALNECROLYSIS4%. PANCREATITIS MEDIATEDHEPATITISLEDTOPERMANENTDISCONTINUATIONOF"!6%.#)/IN OF RHABDOMYOLYSIS MYASTHENIAGRAVIS HISTIOCYTICNECROTIZINGLYMPHADENITIS DEMYELINATION PATIENTS!MONGTHEPATIENTSWITHIMMUNE MEDIATEDHEPATITIS THEMEDIANTIMETOONSET VASCULITIS HEMOLYTICANEMIA HYPOPHYSITIS IRITIS ANDENCEPHALITIS WASMONTHSRANGEWEEKTOMONTHS ANDTHEMEDIANDURATIONOFHEPATITISWAS Infusion-Related Reactions:"!6%.#)/CANCAUSESEVEREORLIFE THREATENINGINFUSION RELATED MONTHSRANGEDAYTO MONTHS !LLPATIENTSWERETREATEDWITHCORTICOSTEROIDS REACTIONS0REMEDICATEWITHANTIHISTAMINEANDACETAMINOPHENPRIORTOTHElRSTINFUSIONS OFTHEPATIENTSRECEIVEDHIGH DOSECORTICOSTEROIDSFORAMEDIANOFDAYSRANGE -ONITORPATIENTSFORSIGNSANDSYMPTOMSOFINFUSION RELATEDREACTIONSINCLUDINGPYREXIA CHILLS DAYTOMONTHS 2ESOLUTIONOFHEPATITISOCCURREDINNINE OFTHEPATIENTSATTHE mUSHING HYPOTENSION DYSPNEA WHEEZING BACKPAIN ABDOMINALPAIN ANDURTICARIA)NTERRUPT TIMEOFDATACUT OFF ORSLOWTHERATEOFINFUSIONFORMILDORMODERATEINFUSION RELATEDREACTIONS3TOPTHEINFUSION Immune-Mediated Colitis:"!6%.#)/CANCAUSEIMMUNE MEDIATEDCOLITIS-ONITORPATIENTS ANDPERMANENTLYDISCONTINUE"!6%.#)/FORSEVERE'RADE ORLIFE THREATENING'RADE FORSIGNSANDSYMPTOMSOFCOLITIS!DMINISTERCORTICOSTEROIDSINITIALDOSEOFTOMGKGDAY INFUSION RELATEDREACTIONS)NFUSION RELATEDREACTIONSOCCURREDIN OFPATIENTS PREDNISONEOREQUIVALENTFOLLOWEDBYACORTICOSTEROIDTAPER FOR'RADEORGREATERCOLITIS TREATEDWITH"!6%.#)/INCLUDINGTHREE 'RADEANDNINE 'RADEINFUSION 7ITHHOLD"!6%.#)/FORMODERATEORSEVERE'RADEOR COLITISUNTILRESOLUTION0ERMANENTLY RELATEDREACTIONS.INETY THREEPERCENT OFPATIENTSRECEIVEDPREMEDICATIONWITH DISCONTINUE"!6%.#)/FORLIFE THREATENING'RADE ORFORRECURRENT'RADE COLITISUPON ANTIHISTAMINEANDACETAMINOPHEN%LEVEN OFTHEPATIENTSWITH'RADEtREACTIONS RE INITIATIONOF"!6%.#)/)MMUNE MEDIATEDCOLITISOCCURREDIN OFPATIENTS WERETREATEDWITHINTRAVENOUSCORTICOSTEROIDS&OURTEENPERCENTOFPATIENTS HAD RECEIVING"!6%.#)/INCLUDINGSEVEN PATIENTSWITH'RADECOLITIS)MMUNE MEDIATED INFUSION RELATEDREACTIONSTHATOCCURREDAFTERTHE"!6%.#)/INFUSIONWASCOMPLETED COLITISLEDTOPERMANENTDISCONTINUATIONOF"!6%.#)/IN OFPATIENTS!MONG Embryo-Fetal Toxicity:"ASEDONITSMECHANISMOFACTION "!6%.#)/CANCAUSEFETALHARM THEPATIENTSWITHIMMUNE MEDIATEDCOLITIS THEMEDIANTIMETOONSETWASMONTHS WHENADMINISTEREDTOAPREGNANTWOMAN!NIMALSTUDIESHAVEDEMONSTRATEDTHATINHIBITIONOF RANGEDAYSTOMONTHS ANDTHEMEDIANDURATIONOFCOLITISWASWEEKSRANGEDAY THE0$ 0$ ,SIGNALINGPATHWAYCANLEADTOINCREASEDRISKOFIMMUNE MEDIATEDREJECTION TO MONTHS !LLPATIENTSWERETREATEDWITHCORTICOSTEROIDS OFTHEPATIENTS OFTHEDEVELOPINGFETUSRESULTINGINFETALDEATH)FTHISDRUGISUSEDDURINGPREGNANCY ORIFTHE RECEIVEDHIGH DOSECORTICOSTEROIDSFORAMEDIANOFDAYSRANGEDAYTOMONTHS PATIENTBECOMESPREGNANTWHILETAKING"!6%.#)/ INFORMTHEPATIENTOFTHEPOTENTIALRISKTOA 2ESOLUTIONOFCOLITISOCCURREDIN OFTHEPATIENTSATTHETIMEOFDATACUT OFF FETUS!DVISEFEMALESOFCHILDBEARINGPOTENTIALTOUSEEFFECTIVECONTRACEPTIONDURINGTREATMENT Immune-Mediated Endocrinopathies:"!6%.#)/CANCAUSEIMMUNE MEDIATED WITH"!6%.#)/ANDFORATLEASTONEMONTHAFTERTHELASTDOSEOF"!6%.#)/ Adrenal Insufﬁciency: ENDOCRINOPATHIES -ONITORPATIENTSFORSIGNSANDSYMPTOMSOFADRENAL ADVERSE REACTIONS INSUFlCIENCYDURINGANDAFTERTREATMENT!DMINISTERCORTICOSTEROIDSASAPPROPRIATEFORADRENAL 4HEFOLLOWINGADVERSEREACTIONSAREDISCUSSEDINGREATERDETAILINOTHERSECTIONSOFTHELABELING INSUFlCIENCY7ITHHOLD"!6%.#)/FORSEVERE'RADE ORLIFE THREATENING'RADE ADRENAL INSUFlCIENCY!DRENALINSUFlCIENCYOCCURREDIN OFPATIENTSRECEIVING"!6%.#)/ s )MMUNE MEDIATEDPNEUMONITIS INCLUDINGONEPATIENT WITH'RADEADRENALINSUFlCIENCY)MMUNE MEDIATEDADRENAL s )MMUNE MEDIATEDHEPATITIS INSUFlCIENCYLEDTOPERMANENTDISCONTINUATIONOF"!6%.#)/IN OFPATIENTS s )MMUNE MEDIATEDCOLITIS !MONGTHEPATIENTSWITHIMMUNE MEDIATEDADRENALINSUFlCIENCY THEMEDIANTIMETOONSET s )MMUNE MEDIATEDENDOCRINOPATHIES WASMONTHSRANGEDAYTOMONTHS !LLEIGHTPATIENTSWERETREATEDWITHCORTICOSTEROIDS s )MMUNE MEDIATEDNEPHRITISANDRENALDYSFUNCTION FOUR OFTHEEIGHTPATIENTSRECEIVEDHIGH DOSECORTICOSTEROIDSFORAMEDIANOFDAY s /THERIMMUNE MEDIATEDADVERSEREACTIONS RANGEDAYTODAYS Thyroid Disorders (Hypothyroidism/Hyperthyroidism): s )NFUSION RELATEDREACTIONS "!6%.#)/CANCAUSEIMMUNE MEDIATEDTHYROIDDISORDERS4HYROIDDISORDERSCANOCCUR ATANYTIMEDURINGTREATMENT-ONITORPATIENTSFORCHANGESINTHYROIDFUNCTIONATTHESTART Clinical Trials Experience:"ECAUSECLINICALTRIALSARECONDUCTEDUNDERWIDELYVARYING OFTREATMENT PERIODICALLYDURINGTREATMENT ANDASINDICATEDBASEDONCLINICALEVALUATION CONDITIONS ADVERSEREACTIONRATESOBSERVEDINTHECLINICALTRIALSOFADRUGCANNOTBEDIRECTLY -ANAGEHYPOTHYROIDISMWITHHORMONE REPLACEMENTTHERAPY)NITIATEMEDICALMANAGEMENT COMPAREDTORATESINTHECLINICALTRIALSOFANOTHERDRUGANDMAYNOTREmECTTHERATESOBSERVED FORCONTROLOFHYPERTHYROIDISM7ITHHOLD"!6%.#)/FORSEVERE'RADE ORLIFE THREATENING INPRACTICE4HEDATADESCRIBEDINTHE7!2.).'3!.$02%#!54)/.3SECTIONAREBASED 'RADE THYROIDDISORDERS)MMUNE MEDIATEDTHYROIDDISORDERSOCCURREDIN OF ONTWOTRIALS INWHICHPATIENTSRECEIVED"!6%.#)/ATDOSESOFMGKGINTRAVENOUSLY EVERYTWOWEEKS4HISINCLUDEDPATIENTSWITHMETASTATIC-##*!6%,).-ERKELTRIAL MACULO PAPULAR ERYTHEMA ANDDERMATITISBULLOUSG0RURITUSISACOMPOSITETERMTHATINCLUDES ANDPATIENTSWITHLOCALLYADVANCEDANDMETASTATIC5#WITHINTHE*!6%,).3OLID4UMOR PRURITUSANDPRURITUSGENERALIZEDH$YSPNEAISACOMPOSITETERMTHATINCLUDESDYSPNEAAND TRIAL)NTHE*!6%,).3OLID4UMORTRIAL PATIENTSWERETREATEDWITH"!6%.#)/ATDOSES DYSPNEAEXERTIONAL OFMGKG4HEFOLLOWINGCRITERIAWEREUSEDTOCLASSIFYANADVERSEREACTIONASIMMUNE MEDIATEDONSETWITHINDAYSAFTERLASTDOSEOF"!6%.#)/ NOSPONTANEOUSRESOLUTION Table 3 Selected Treatment-Emergent* Laboratory Abnormalities in Patients receiving WITHINDAYSOFONSET TREATMENTWITHCORTICOSTEROIDSOROTHERIMMUNOSUPPRESSANTORHORMONE BAVENCIO in the JAVELIN Merkel 200 Trial REPLACEMENTTHERAPY BIOPSYCONSISTENTWITHIMMUNE MEDIATEDREACTION ANDNOOTHERCLEAR Laboratory Tests Any Grade Grade 3-4 ETIOLOGY4HESTUDYPOPULATIONCHARACTERISTICSOFTHEPATIENTSWEREMEDIANAGEOF (N = 88) (N = 88) YEARSRANGETOYEARS MALE 7HITE !SIAN "LACKOR!FRICAN!MERICAN % % ANDOTHERETHNICGROUPS %#/'PERFORMANCESCOREOF IN AND Chemistry ANDTHEUNDERLYINGMALIGNANCIESWERENON SMALLCELLLUNGCANCER GASTRICAND 1 GASTROESOPHAGEALCANCER UROTHELIALCANCER OVARIANCANCER METASTATIC )NCREASEDASPARTATEAMINOTRANSFERASE!34 BREASTCANCER HEADANDNECKCANCER METASTATIC-## MESOTHELIOMA RENAL )NCREASEDALANINEAMINOTRANSFERASE!,4 CELLCARCINOMA MELANOMA ADRENOCORTICALCARCINOMAEACH COLORECTALCANCER CASTRATE )NCREASEDLIPASE )NCREASEDAMYLASE 1 RESISTANTPROSTATECANCER ANDUNKNOWNEACH )NTHISPOPULATION OFPATIENTSWERE 1 EXPOSEDTO"!6%.#)/FORtMONTHSANDWEREEXPOSEDTO"!6%.#)/FORtMONTHS )NCREASEDBILIRUBIN (YPERGLYCEMIA -ETASTATIC-ERKEL#ELL#ARCINOMA Hematology 4HEDATADESCRIBEDBELOWREmECTEXPOSURETO"!6%.#)/MGKGINTRAVENOUSLYEVERY !NEMIA WEEKSINPATIENTSWITHMETASTATIC-##ENROLLEDINTHE*!6%,).-ERKELTRIAL ,YMPHOPENIA 0ATIENTSWITHANYOFTHEFOLLOWINGWEREEXCLUDEDAUTOIMMUNEDISEASEMEDICALCONDITIONS 4HROMBOCYTOPENIA 1 REQUIRINGSYSTEMICIMMUNOSUPPRESSIONPRIORORGANORALLOGENEICSTEMCELLTRANSPLANTATION .EUTROPENIA 1 PRIORTREATMENTWITHANTI 0$ ANTI 0$ ,ORANTI #4,! ANTIBODIESCENTRALNERVOUSSYSTEM 4REATMENTEMERGENTCONSISTSOFNEWONSETOFLABORATORYABNORMALITYORWORSENINGOF #.3 METASTASESINFECTIONWITH()6 HEPATITIS"ORHEPATITIS#OR%#/'PERFORMANCESCORE BASELINELABORATORYABNORMALITY t4HEMEDIANDURATIONOFEXPOSURETO"!6%.#)/WASMONTHSRANGEWEEKSTO (YPERGLYCEMIALIMITEDTO'RADEtEVENTSSINCEFASTINGMEASUREMENTSWERENOTOBTAINED MONTHS &ORTYPERCENTOFPATIENTSRECEIVED"!6%.#)/FORMORETHANMONTHSAND ROUTINELY WERETREATEDFORMORETHANONEYEAR4HESTUDYPOPULATIONCHARACTERISTICSWEREMEDIANAGE OFYEARSRANGETO MALE 7HITE %#/'PERFORMANCESCOREOF ,OCALLY!DVANCEDOR-ETASTATIC5ROTHELIAL#ANCER OR ANDOFPATIENTSHADONEPRIORANTI CANCERTHERAPYFORMETASTATIC-##AND 4ABLEDESCRIBESADVERSEREACTIONSREPORTEDINPATIENTSWITHLOCALLYADVANCEDOR HADTWO ORMOREPRIORTHERAPIES"!6%.#)/WASPERMANENTLYDISCONTINUEDFORADVERSE METASTATIC5#RECEIVING"!6%.#)/ATMGKGEVERYWEEKSINTHE5#COHORTSOFTHE REACTIONSINSIX PATIENTSADVERSEREACTIONSRESULTINGINPERMANENTDISCONTINUATIONWERE *!6%,).3OLID4UMORTRIAL0ATIENTSRECEIVEDPRE MEDICATIONWITHANANTI HISTAMINEAND ILEUS 'RADETRANSAMINITIS 'RADECREATINEKINASEELEVATION TUBULOINTERSTITIALNEPHRITIS ACETAMINOPHENPRIORTOEACHINFUSION4HEMEDIANDURATIONOFEXPOSURETO"!6%.#)/WAS AND'RADEPERICARDIALEFFUSION"!6%.#)/WASTEMPORARILYDISCONTINUEDIN WEEKSRANGEWEEKSTOWEEKS &OURTEENPATIENTS WHOWERETREATEDWITH PATIENTSFORADVERSEEVENTS EXCLUDINGTEMPORARYDOSEINTERRUPTIONFORINFUSION RELATED "!6%.#)/EXPERIENCEDPNEUMONITIS RESPIRATORYFAILURE SEPSISUROSEPSIS CEREBROVASCULAR REACTIONSWHEREINFUSIONWASRESTARTEDTHESAMEDAY4HEMOSTCOMMONADVERSEREACTION ACCIDENT ORGASTROINTESTINALADVERSEEVENTS WHICHLEDTODEATH"!6%.#)/WASPERMANENTLY REQUIRINGDOSEINTERRUPTIONWASANEMIA3ERIOUSADVERSEREACTIONSTHATOCCURREDINMORE DISCONTINUEDFOR'RADE ADVERSEREACTIONSIN PATIENTS4HEADVERSEREACTION THANONEPATIENTWEREACUTEKIDNEYINJURY ANEMIA ABDOMINALPAIN ILEUS ASTHENIA AND THATRESULTEDINPERMANENTDISCONTINUATIONINOFPATIENTSWASFATIGUE"!6%.#)/WAS CELLULITIS4HEMOSTCOMMONADVERSEREACTIONSt WEREFATIGUE MUSCULOSKELETALPAIN TEMPORARILYDISCONTINUEDINOFPATIENTSFORADVERSEREACTIONS EXCLUDINGTEMPORARYDOSE DIARRHEA NAUSEA INFUSION RELATEDREACTION RASH DECREASEDAPPETITE ANDPERIPHERALEDEMA INTERRUPTIONFORINFUSION RELATEDREACTIONSWHEREINFUSIONWASRESTARTEDONTHESAMEDAY4HE ADVERSEREACTIONSTHATRESULTEDINTEMPORARYDISCONTINUATIONINOFPATIENTSWEREDIARRHEA Table 2: Adverse Reactions in t 10% of Patients Receiving BAVENCIO in the JAVELIN FATIGUE DYSPNEA URINARYTRACTINFECTION ANDRASH Merkel 200 Trial 'RADE SERIOUSADVERSEREACTIONSWEREREPORTEDINOFPATIENTS4HEMOSTFREQUENT Adverse Reactions BAVENCIO SERIOUSADVERSEREACTIONSREPORTEDINtOFPATIENTSWEREURINARYTRACTINFECTIONUROSEPSIS (N = 88) ABDOMINALPAIN MUSCULOSKELETALPAIN CREATININEINCREASEDRENALFAILURE DEHYDRATION All Grades (%) Grade 3-4 (%) HEMATURIAURINARYTRACTHEMORRHAGE INTESTINALOBSTRUCTIONSMALLINTESTINEOBSTRUCTION AND General Disorders PYREXIA4HEMOSTCOMMON'RADEANDADVERSEREACTIONSt WEREANEMIA FATIGUE &ATIGUEA 2 HYPONATREMIA HYPERTENSION URINARYTRACTINFECTION ANDMUSCULOSKELETALPAIN )NFUSION RELATEDREACTIONB 22 4HEMOSTCOMMONADVERSEREACTIONSt WEREFATIGUE INFUSION RELATEDREACTION 0ERIPHERALEDEMAC MUSCULOSKELETALPAIN NAUSEA DECREASEDAPPETITE ANDURINARYTRACTINFECTION%LEVEN Musculoskeletal and Connective Tissue Disorders PATIENTSRECEIVEDANORALPREDNISONEDOSEEQUIVALENTTOtMGDAILYFORANIMMUNE -USCULOSKELETALPAIND 2 MEDIATEDADVERSEREACTION !RTHRALGIA 1 Table 4: All Grade Adverse Reactions in t 10% of Patients with Locally Advanced or Gastrointestinal Disorders Metastatic UC in the JAVELIN Solid Tumor Trial $IARRHEA .AUSEA 22 Adverse Reactions BAVENCIO #ONSTIPATION 1 (N = 242) E 2 !BDOMINALPAIN All grades Grade 3-4 6OMITING (%) (%) Skin and Subcutaneous Tissue Disorders Any 2ASHF 22 Gastrointestinal Disorders 0RURITUSG .AUSEA 1 Metabolism and Nutrition Disorders !BDOMINALPAINA 2 $ECREASEDAPPETITE 2 $IARRHEA 2 $ECREASEDWEIGHT #ONSTIPATION 1 Respiratory, Thoracic and Mediastinal Disorders 6OMITING2ETCHING 1 #OUGH General Disorders and Administration Site Conditions $YSPNEAH 11 1 &ATIGUEB Nervous System Disorders )NFUSION RELATEDREACTIONC $IZZINESS 0ERIPHERALEDEMAD (EADACHE 0YREXIA4EMPERATUREINCREASED 1 Vascular Disorders Infections (YPERTENSION 5RINARYTRACTINFECTIONE 21 A B &ATIGUEISACOMPOSITETERMTHATINCLUDESFATIGUEANDASTHENIA )NFUSION RELATEDREACTION Investigations ISACOMPOSITETERMTHATINCLUDESDRUGHYPERSENSITIVITY HYPERSENSITIVITY CHILLS PYREXIA BACK 7EIGHDECREASED PAIN ANDHYPOTENSIONC0ERIPHERALEDEMAISACOMPOSITETERMTHATINCLUDESPERIPHERALEDEMA D Metabolism and Nutrition Disorders ANDPERIPHERALSWELLING -USCULOSKELETALPAINISACOMPOSITETERMTHATINCLUDESBACKPAIN $ECREASEDAPPETITE(YPOPHAGIA 21 2 MYALGIA NECKPAIN PAININEXTREMITYE!BDOMINALPAINISACOMPOSITETERMTHATINCLUDES F Musculoskeletal and Connective Tissue Disorders ABDOMINALPAINANDABDOMINALPAINUPPER 2ASHISACOMPOSITETERMTHATINCLUDESRASH -USCULOSKELETALPAINF Adverse Reactions BAVENCIO 0$ 0$ ,SIGNALINGINTHEOFFSPRINGOFTHESEANIMALSHOWEVER IMMUNE MEDIATEDDISORDERS (N = 242) OCCURREDIN0$ AND0$ ,KNOCKOUTMICE"ASEDONITSMECHANISMOFACTION FETALEXPOSURE TO"!6%.#)/MAYINCREASETHERISKOFDEVELOPINGIMMUNERELATEDDISORDERSORALTERINGTHE All grades Grade 3-4 NORMALIMMUNERESPONSE (%) (%) Renal Disorders Lactation,2ISK3UMMARY4HEREISNOINFORMATIONREGARDINGTHEPRESENCEOFAVELUMAB #REATININEINCREASED2ENALFAILUREG INHUMANMILK THEEFFECTSONTHEBREASTFEDINFANT ORTHEEFFECTSONMILKPRODUCTION3INCE Respiratory, Thoracic and Mediastinal Disorders MANYDRUGSINCLUDINGANTIBODIESAREEXCRETEDINHUMANMILK ADVISEALACTATINGWOMANNOTTO $YSPNEA%XERTIONALDYSPNEA 2 BREASTFEEDDURINGTREATMENTANDFORATLEASTONEMONTHAFTERTHELASTDOSEOF"!6%.#)/DUE #OUGH0RODUCTIVECOUGH TOTHEPOTENTIALFORSERIOUSADVERSEREACTIONSINBREASTFEDINFANTS Skin and Subcutaneous Tissue Disorders Females and Males of Reproductive Potential,#ONTRACEPTION"ASEDONITSMECHANISM 2ASHH OFACTION "!6%.#)/CANCAUSEFETALHARMWHENADMINISTEREDTOAPREGNANTWOMAN 0RURITUS'ENERALIZEDPRURITUS !DVISEFEMALESOFREPRODUCTIVEPOTENTIALTOUSEEFFECTIVECONTRACEPTIONDURINGTREATMENTWITH Vascular Disorders "!6%.#)/ANDFORATLEASTMONTHAFTERTHELASTDOSEOF"!6%.#)/ (YPERTENSION(YPERTENSIVECRISIS Pediatric Use:3AFETYANDEFFECTIVENESSOF"!6%.#)/HAVEBEENESTABLISHEDINPEDIATRIC A)NCLUDESABDOMINALDISCOMFORT ABDOMINALPAINUPPERANDLOWER ANDGASTROINTESTINALPAIN PATIENTSAGEDYEARSANDOLDERFORMETASTATIC-##5SEOF"!6%.#)/INTHISAGEGROUPIS B)NCLUDESASTHENIAANDMALAISEC)NFUSION RELATEDREACTIONISACOMPOSITETERMTHATINCLUDES SUPPORTEDBYEVIDENCEFROMADEQUATEANDWELL CONTROLLEDSTUDIESOF"!6%.#)/INADULTSWITH CHILLS PYREXIA BACKPAIN mUSHING DYSPNEA ANDHYPOTENSIOND)NCLUDESEDEMA GENERALIZED ADDITIONALPOPULATIONPHARMACOKINETICDATADEMONSTRATINGTHATAGEANDBODYWEIGHTHADNO EDEMA ANDPERIPHERALSWELLINGE)NCLUDESUROSEPSIS CYSTITIS KIDNEYINFECTION PYURIA AND CLINICALLYMEANINGFULEFFECTONTHESTEADYSTATEEXPOSUREOFAVELUMAB THATDRUGEXPOSUREIS URINARYTRACTINFECTIONDUETOFUNGUS BACTERIAL ANDENTEROCOCCUSF)NCLUDESBACKPAIN GENERALLYSIMILARBETWEENADULTSANDPEDIATRICPATIENTSAGEYEARSANDOLDERFORMONOCLONAL MYALGIA NECKPAIN ANDPAININEXTREMITYG)NCLUDESACUTEKIDNEYINJURYANDGLOMERULAR ANTIBODIES ANDTHATTHECOURSEOF-##ISSUFlCIENTLYSIMILARINADULTANDPEDIATRICPATIENTSTO lLTRATIONRATEDECREASEDH)NCLUDESDERMATITISACNEIFORM ECZEMA ERYTHEMA ERYTHEMA ALLOWEXTRAPOLATIONOFDATAINADULTSTOPEDIATRICPATIENTS4HERECOMMENDEDDOSEINPEDIATRIC MULTIFORME ERYTHEMATOUS MACULAR MACULOPAPULAR PAPULAR ANDPRURITICRASH PATIENTSYEARSOFAGEORGREATERISTHESAMEASTHATINADULTS3AFETYANDEFFECTIVENESSOF "!6%.#)/HAVENOTBEENESTABLISHEDINPEDIATRICPATIENTSLESSTHANYEARSOFAGE Table 5: Selected Laboratory Abnormalities* (Grade 3-4) in t1% of Patients with Locally Advanced or Metastatic UC Receiving BAVENCIO in the JAVELIN Solid Tumor Trial Geriatric Use -ETASTATIC-ERKEL#ELL#ARCINOMA#LINICALSTUDIESOF"!6%.#)/IN-##DIDNOTINCLUDE Laboratory Tests Grade 3-4 SUFlCIENTNUMBERSOFPATIENTSAGEDANDOVERTODETERMINEWHETHERTHEYRESPONDDIFFERENTLY (N = 242)** FROMYOUNGERPATIENTS % ,OCALLY!DVANCEDOR-ETASTATIC5ROTHELIAL#ANCER/FTHEPATIENTSWITHLOCALLYADVANCED Chemistry 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At Immunomedics, we are working with the oncology community to delve deeper into ways to address this signiˡ cant unmet need.

Visit Booth #17011 to participate in today’s living mural. You can help create ©2018 Immunomedics, Inc. All rights reserved. June 2018. a unique artistic expression of your promise to patients with TNBC, and ours. Printed in the U.S.A. UNBR-0013

Y48268_BRICI_DailyNews_Promise_1025x14_v2.indd 1 4/27/18 9:47 AM B 28 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Assessing the Older Adult assessment in all older adults with can- Table 1. Domains Assessed in a Typical Geriatric Assessment Continued from page 21B cer can be time- and resource-consum- Domain What Is Measured? ing, since this includes nearly half of all Functional Status Activities of daily living and instrumental activities of daily living mains: functional status, physical per- new cancer diagnoses. formance, comorbidity/polypharmacy, Screening tools have been developed Physical Function Ability to ambulate, walk stairs, and history of falls cognition, nutrition, psychological sta- to aid in identifying which patients Comorbidity Number of any coexisting conditions in addition to cancer, hearing/vision 6 tus, and social support. may benefi t the most from undergoing Psychological State Assessment of anxiety and depression a full geriatric assessment. Using screen- Why Perform a Geriatric Assessment? ing tools such as the Geriatric 8 (G8) or Social Support Availability of social support There are several benefi ts to perform- the Vulnerable Elders Survey takes only Nutritional Status History of weight loss, BMI ing a geriatric assessment in older adults a few minutes to complete and provides Cognition Measure of cognitive function with cancer. First, a geriatric assessment useful and prognostic information.9 For Medications Number and type of medications including potential interactions can reveal areas of vulnerability that patients who test positive on a screening often go unnoticed during a routine tool, a full geriatric assessment should be Abbreviation: BMI, body mass index. oncologic evaluation. For example, the pursued. In settings with available spe- Table 2. Selected Online Resources for Geriatric Oncology presence of falls and/or impairments in cialty care for older adults with cancer, Instrumental Activities of Daily Living referral and consultation is preferred; Site What It Contains URL (IADL) are frequently overlooked by tra- however, as most areas lack this special- International Society • Links to numerous published guidelines on siog.org ditional evaluations, yet are important ized care, using a patient-reported geri- of Geriatric Oncology management of older adults with cancer health indicators. In one study of older atric assessment survey is recommended, • Further information on screening tools and geriatric patients with cancer and normal perfor- such as the Cancer and Aging Research assessment measures • Information regarding more advanced educational mance status, more than two-thirds of Group (CARG)’s geriatric assessment. courses on geriatric oncology patients had a geriatric assessment–iden- Table 2 highlights some selected online tifi ed impairment, and one-quarter of resources for geriatric oncology that in- Cancer & Aging • Access to geriatric assessments (in a variety of mycarg.org different languages) and an online chemotherapy older patients had three or more impair- clude access to the CARG geriatric assess- Research Group 3 toxicity calculator ments. Second, these identifi ed areas of ment in a variety of different languages, • Updates on grant and job opportunities related to vulnerability and impairments can aid as well as further educational resources. cancer and aging research in prediction of several important out- ASCO: Geriatric • Geriatric oncology resources and updates with links asco.org comes such as prognosis, risk of surgical Case Examples Oncology Website on a variety of different aging-related topics including complications, and tolerability of sys- To demonstrate how geriatric assess- cancer-specifi c information temic chemotherapy.7 Using falls and ments can aid in patient care, we present Portal of Geriatric • Free public repository of a growing collection of geriatric pogoe.org IADL impairments as examples, both are two cases of stage III colon cancer. Mr. Online Education educational materials in various e-learning formats independently predictive of grade 3-5 Jones and Mr. Smith are 74-year-old men chemotherapy toxicity.8 Better under- who presented to urgent care with bright toxicity score is calculated at 94% risk ics or resources, a geriatric screening tool standing the likelihood of severe chemo- red blood in their stool, and on subse- of developing a grade 3-5 toxicity. After (e.g., G8 and Vulnerable Elders Survey) therapy toxicities, complications, and quent colonoscopy were found to have discussion of the risks/benefi ts of adju- may help cancer therapy providers dis- survival can help in the decision-making invasive adenocarcinoma of the sigmoid vant therapy, Mr. Smith decides to forgo cern higher-risk patients for treatment- process when weighing the risks and colon. Both patients undergo CT staging adjuvant therapy and instead is referred related toxicities, other complications, benefi ts of certain cancer treatments. without any identifi cation of metastatic for physical and occupational therapy and/or worse prognosis. Lastly, geriatric assessment can identify disease and undergo laparoscopic colecto- (for his IADL and mobility limitations) impairments that are amenable to inter- my with pathology later revealing pT3N1 and to see a nutritionist (for weight loss). About the Authors: Dr. Williams is a ventions, such as physical and occupa- (stage IIIb) disease and microsatellite sta- geriatrician and medical oncologist at the tional therapy, nutritional guidance, and bility. Both patients were referred for con- Conclusion University of Alabama at Birmingham. improved management of comorbid consultation with their medical oncologist to Performing a geriatric assessment can Dr. Maggiore is a geriatrician and medical ditions. How these interventions impact discuss possible adjuvant therapy. not only provide useful prognostic infor- oncologist at the University of Rochester. long-term outcomes in older adults with Upon consultation with their medical mation to aid decision-making, but also cancer is an area of active investigation, oncologist to discuss adjuvant therapy, guide intervention strategies for patients References: but promising results in noncancer popu- Mr. Jones undergoes a G8 screening tool with identifi ed impairments. It’s impor- 1. National Cancer Institute: Surveillance lations suggest improved health-related and scores a 16 out of 17 (notable only tant to note, however, that chronologic Epidemiology and End Results (SEER) quality of life and, potentially, survival. for more than three daily medications), age and physiologic age are distinct enti- Program. Fast Stats: An interactive tool for indicating a negative screen for vulner- ties, and there is signifi cant heterogene- access to SEER cancer statistics. seer.cancer. Incorporating Geriatric Assessment Into ability (total score ≤ 14 = vulnerable). He ity in aging between individuals of the gov/faststats. Accessed February 20, 2018. Routine Oncologic Practice has minimal comorbid conditions and same age; therefore, the determination of 2. Smith BD, et al. J Clin Oncol. As chronological age does not always remains active with no functional status fi tness for more versus less intense can- 2009;27:2758-65. correlate with physiologic age, defi n- limitations, and is recommended to un- cer treatment strategies requires a com- 3. Jolly TA, et al. Oncologist. 2015;20:379-85. ing a threshold age for performing a dergo adjuvant therapy with capecitabine. prehensive evaluation of an individual’s 4. Wildiers H, et al. J Clin Oncol. geriatric assessment is challenging. Ex- On the other hand, Mr. Smith un- health status. A geriatric assessment may 2014;32:2595-603. perts recommend performing a geriat- dergoes the same screening assessment benefi t cancer care providers in assessing 5. Hurria A, et al. Cancer. 2005;104:1998- ric assessment in all patients age 75 or but scores a 9 out of 17 (below the ≤ 14 fi tness of older adults and/or those with 2005. older or in younger patients with spe- cutoff), and therefore has a full geriat- geriatric syndromes such as functional 6. Mohile SG, et al. J Natl Compr Canc Netw. cifi c age-related concerns (“geriatric syn- ric assessment performed that reveals and cognitive impairments for cancer 2015;13:1120-30. dromes”), such as cognitive impairment signifi cant weight loss, history of falls, treatments and facilitate their treatment 7. Puts MTE, et al. Ann Oncol. 2014;25:307-15. or a history of falls.6 Although many of limitations in ability to walk one block, decision-making with older adults with 8. Hurria A, et al. J Clin Oncol. 2011;29:3457- these assessments have been streamlined impairments in IADL, and polyphar- cancer and their caregivers. For busier 65. and designed specifi cally for use in busy macy related to the ongoing care of his oncology practices or those with limited 9. Decoster L, et al. Ann Oncol. 2015;26:288- oncology clinics, performing a geriatric heart failure. His CARG chemotherapy access to formal geriatrics specialty clin- 300.

Patient-Reported Outcomes Clinical Practice, Version: January 2015. Management of Symptoms During and 13. European Medicines Agency. Refl ection Continued from page 15B isoqol.org/UserFiles/2015UsersGuide- Following Cancer Treatment. Published paper on the regulatory guidance for the Version2.pdf. Accessed February 21, 2018. October 18, 2017. grants.nih.gov/grants/ use of HRQL measures in the evaluation of 5. Kotronoulas G, et al. J Clin Oncol. 10. Patient-Centered Outcomes Research guide/rfa-fi les/RFA-CA-17-042.html. medicinal products. ema.europa.eu/docs/ 2014;32:1480-501. Institute. User’s Guide to Integrating Accessed February 21, 2018. en_GB/document_library/Scientifi c_ 6. Velikova G, et al. J Clin Oncol. Patient-Reported Outcomes in Electronic 12. U.S. Food and Drug Administration. guideline/2009/09/WC500003637.pdf. 2004;22:714-24. Health Records, Version: May 2017. pcori. Guidance for Industry Patient-Reported Accessed February 21, 2018. 7. Denis F, et al. J Clin Oncol. 2016;34 (suppl; org/sites/default/fi les/PCORI-JHU-Users- Outcome Measures: Use in Medical 14. Kluetz PG, et al. Clin Cancer Res. abstr LBA9006). Guide-To-Integrating-Patient-Reported- Product Development to Support Label- 2016;22:1553-8. 8. Basch E, et al. JAMA. 2017;318:197-8. Outcomes-in-Electronic-Health-Records. ling Claims. Published 2009. http://www. 15. Basch E, et al. J Natl Cancer Inst. 2014;106. 9. International Society for Quality of Life pdf. Accessed February 21, 2018. fda.gov/downloads/Drugs/Guidances/ pii: dju244. Research. User’s Guide to Implementing 11. Department of Health and Human UCM193282.pdf. Accessed February 21, Patient-Reported Outcomes Assessment in Services. Research Centers for Improving 2018.

B 30 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

our results suggest important opportuni- In the Journals ties for improving care across scientifi c evidence that could be translated to the Real-World Treatment of mRCC in Low-Resource Settings reality of a low-resource setting. The challenges faced in Brazil are simi- “Assessment of Treatment Patterns (79%) received fi rst-line therapy, only countries that were previously pub- lar to those experienced in other low- for Metastatic Renal Cell Carcinoma 641 (20%) and 152 (5%) received sec- lished.1,2 resource settings, such as lack of access in Brazil” ond- and third-line therapy, respective- Our dataset included 4,379 patients, to certain types of treatment. We hope ly. In the fi rst-line setting, vascular en- 3,990 of whom presented with meta- that our fi ndings can inform and guide Journal: Journal of Global Oncology dothelial growth factor–directed agents static disease. We identifi ed that pa- the improvement of quality cancer care DOI: 10.1200/JGO.17.00113 represented the most commonly used tients with mRCC in Brazil have some in these countries. therapy, whereas in the second-line set- overlap in treatment with patients in Abstract ting, vascular endothelial growth fac- high-income countries, especially in the Q: Have you seen any signifi cant Purpose: Although multiple therapies tor–directed and mammalian target of fi rst-line setting. Nevertheless, there was changes in treatment decisions in the have emerged for the treatment of meta- rapamycin–directed agents were used marked attrition from fi rst- to second- wake of your study? static renal cell carcinoma (mRCC), it with similar frequency. Marked differ- line therapy and also from second- to Dr. Bergerot: Our fi ndings are thought- is unclear whether application of these ences were seen in receipt of systemic third-line therapy. There was also a sig- provoking. Although it is too early to see agents is consistent in high-income and therapy on the basis of treatment in pri- nifi cant disparity between public and changes in treatment decisions, we have developing countries. We sought to de- vate or public hospitals. private institutions in that patients who received interesting feedback, which termine patterns of care for mRCC in Conclusion: Relative to high-income were treated in private settings received has opened a dialogue with physicians Brazil as a representative developing countries, marked attrition is noted be- systemic therapy in the fi rst- and second- across many different countries. This, country. tween each subsequent line of therapy in line setting more frequently than those we believe, is the fi rst step in a long and Methods: A commercial database was used Brazil. Patterns of care also vary greatly treated within a public setting. Finally, important journey that was previously to acquire infor- in private and public settings, pointing we found a substantial difference in the unexplored. This constructive conversa- mation pertain- to fi nancial constraints as a potential type of treatment given to patients with tion, without doubt, is the greatest out- ing to patients cause for discordances in treatment. mRCC in Brazil, as many received quite come from our study. with mRCC unconventional therapies. Some notable receiving treat- Author Perspective examples of these included imatinib or Q: What about these data surprised ment at private Paulo G. Bergerot, MD, City of Hope erlotinib, as well as older cytotoxic drugs you? or public hos- Comprehensive Cancer Center such as dacarbazine, doxorubicin, and Dr. Bergerot: We were pleasantly sur- pitals in Brazil other cytotoxic regimens that have little prised to fi nd that some treatment pat- between March Q: Technically, Brazil is a higher- evidence base in mRCC. terns in Brazil were similar to those used 2013 and Octo- middle income country, but its public in high-income countries. However, the ber 2016. Basic health system is equivalent to that Q: How does your study seek to discrepancies seen in second- and third- clinical and de- Dr. Paulo G. Bergerot of a low-income country. Within this improve mRCC treatment in Brazil, line therapies between low-resource set- mographic crite- context, what did your study reveal and possibly other low-resource tings and high-income countries was a ria were available, as well as information about mRCC in Brazil? settings, going forward? concerning observation. Although sur- to ascertain the International Metastatic Dr. Bergerot: Our study brings real- Dr. Bergerot: Our study refl ects the prising, these fi ndings are encouraging Renal Cell Carcinoma Database Consor- world evidence about treatment patterns largest experience related to treatment and will hopefully convince providers tium risk. Treatment-related data across for patients with mRCC in Brazil. Our patterns for patients with mRCC in Bra- to access biosimilars, participate in clin- multiple lines of therapy were collected. fi ndings show a large dichotomy between zil and fi lls an incredible gap that exists ical trials, and prioritize training oppor- Results: Of 4,379 patients assessed, public and private practices that sug- in the literature about kidney cancer tunities they may not have considered 3,990 (91%) had metastatic disease, gests a strong limitation on resources in epidemiology there. These fi ndings are previously. and 26%, 48%, and 26% of patients the public system—maybe refl ecting the crucial for proper public health manage- had good, intermediate, and poor In- socioeconomic disparity of a country in ment and can be applied to daily prac- References: ternational Metastatic Renal Cell Carci- a low-resource setting. Furthermore, we tice. Although it is encouraging to see 1. Pal SK, et al. Int J Urol. 2017;24:272-8. noma Database Consortium risk disease, compared our data from a low-resource many practitioners adhering to treat- 2. Heng DYC, et al. J Clin Oncol. 2015;33 respectively. Although 3,149 patients setting with fi ndings from high-income ment guidelines in the fi rst-line setting, (suppl, abstr e15578).

Guideline Addresses Palliative Care “There is increasing stratifi ed guidelines in her teaching and Bone-Modifying Agents Continued from page 16B advocacy work, she said, and will now in- Continued from page 4B evidence that supports the clude this guideline’s recommendations. 28 million people with serious health- view that palliative care is an “I don’t think I’ve given a single presen- Management of Complications related suffering are in low- and middle- tation without the ASCO statement about Guidelines note that the risk for osteo- income countries, and they suffer inad- essential part of cancer care.” providing palliative care concurrent necrosis of the jaw appears to increase equate pain management,” Dr. Osman –DR. JAMES F. CLEARY with treatment since the guideline came with the use of more potent bisphos- said. “So unlike in the U.S. guideline, out in 2016,” she said. “The resource- phonates and is also observed with we felt it was very important to address ers should be sensitive to the religious stratifi ed guidelines will help us approach denosumab. Patients should undergo the opioid issue in the resource-stratifi ed norms of patients and families. Dr. policymakers to lobby for change that is a comprehensive dental examination guideline.” Cleary noted some religious sects do not realistic and feasible in our setting.” with appropriate preventive measures Spirituality is another “very important allow the use of intoxicants or alcohol, “The clinical offi cer, the nursing com- before starting bone-modifying therapy. dimension of palliative care, but when we but allow use for pain relief. munity—these are the people who can Active oral infections should be treated are concerned about resources, it often be- “It’s the intention of the medicine,” start providing this type of care,” Dr. and high-risk sites should be eliminat- comes the fi rst element of palliative care he said. “This becomes critical as we look Cleary said. “Palliative care is truly speed. Clinicians should talk with patients to be cut,” Dr. Osman said. “The panel and address many African and Asian cialized care. We’re really coming back to about the importance of oral hygiene wanted to ensure that the spiritual di- countries. There is increasing evidence the importance of primary palliative care and avoiding invasive dental procedures mension retained some importance even that supports the view that palliative and the benefi ts it provides to patients if possible. in areas with low resources.” Very little care is an essential part of cancer care.” and their caretakers and/or families.” –Melinda Tanzola, PhD published literature exists on the topic, –Michelle Dalton, ELS she added, making the panel “feel more Integrating the Guideline References: strongly about highlighting spiritual care Dr. Cleary said integrating palliative References: 1. Anderson K, et al. J Clin Oncol. 2018;Jan as an important part of palliative care.” care on the level of some resource-con- 1. Osman H, et al. J Global Oncol. 2018 [In 17:JCO2017766402. [Epub ahead of ASCO’s guideline notes that in ad- strained communities “is going to be Press]. print]. dition to providing direct patient care, very tough” in situations where there 2. World Health Organization. Palliative 2. Broderick J. OncLive. FDA Approves De- “spiritual care providers may advise and may only be four social workers in the Care. who.int/ncds/management/ nosumab for Multiple Myeloma. onclive. support the care team to support the entire country or when local health cen- palliative-care/en. Accessed March 5, com/web-exclusives/fda-approves- patients and their families,” and sug- ters may not have someone dedicated to 2018. denosumab-for-multiple-myeloma. gests nurses or counselors can be trained palliative care. 3. Knaul FM, et al. Lancet. 2017:Oct 11 [Epub Published January 5, 2018. Accessed Feb- to provide this support. These provid- Dr. Osman uses the nonresource- ahead of print]. ruary 7, 2018. Being a teaching hospital makes us stronger. Being a teaching hospital for two great medical schools makes us NewYork-Presbyterian Hosptial.

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Reference: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; February 2018.

© 2018 Bayer. All rights reserved. BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer. radium Ra 223 dichloride PP-600-US-3474 04/18 Printed in USA INJECTION SUNDAY · JUNE 3, 2018 C Dr. Gabriel Hortobagyi Receives 2018 Gianni Bonadonna Breast Cancer Award abriel N. Hortobagyi, MD, FACP, their example of standing up after adver- treatment of breast cancer, to the devel- FASCO, is the recipient of the sity was very inspirational through emi- opment of new drugs—especially pacli- 2018 Gianni Bonadonna Breast gration and political discrimination,” he taxel and docetaxel—in the neoadjuvant Cancer Award for his leadership said, referring to his family’s emigration setting, to his work with gene therapy, Gand contribution in the fi eld of trans- from Hungary and eventually to Colom- to the control of bone metastases with lational medicine in breast cancer, with bia, where Dr. Hortobagyi earned his bisphosphonates and strategies to pre- an exceptional record of mentorship. A medical degree. vent resistance to endocrine treatment past ASCO president, Dr. Hortobagyi is In kind, Dr. Hortobagyi has been an of breast cancer, he has become an inter- professor and chair emeritus of the De- active mentor to younger colleagues in national leader in developing new breast partment of Breast Medical Oncology at the fi eld of oncology, beginning with his cancer treatments. The University of Texas MD Anderson time as director of residency training at He is widely acknowledged as a leader Cancer Center. He will deliver a lecture MD Anderson in 1978. “I enjoy interact- in the fi eld of neoadjuvant chemother- accepting his award on June 4. ing with younger people,” he said, com- apy. “I did much of the early work of Dr. Gabriel Hortobagyi menting that he must have trained more neoadjuvant chemotherapy, but by the A Lifetime of Mentoring than 500 to 600 fellows over the years. “I time I came to MD Anderson, one of my cancer that spread to bone. That frustra- Dr. Hortobagyi has been affi liated with have always been surrounded by restless predecessors had been administering tion led to conducting some of the piv- MD Anderson since the completion of young minds. Working with them not chemotherapy before surgery to some otal trials with bisphosphonates, which his fellowship training in 1976. He has only expands your own, but also provides [patients with] locally advanced breast ultimately resulted in the availability of enjoyed a lifetime of mentorships and you the opportunity to distribute the cancers,” Dr. Hortobagyi said. pamidronate, zoledronate, and deno- professional associations from a long list work and train your younger colleagues.” It was not intended as a research strat- sumab for prevention of bone-related of achievers and colleagues in the oncol- egy but was done out of desperation, complications in that setting. He is par- ogy fi eld, including Gianni Bonadonna, Research Contributions because the disease was responding so ticularly satisfi ed that this approach later MD, after whom the award was named. Dr. Hortobagyi has personally led poorly to standard treatment. went through the hands of his trainees “My parents were my fi rst mentors,” or helped guide dozens of clinical tri- In the early 1980s, he remembers be- into adjuvant bisphosphonate therapy in Dr. Hortobagyi said. “We lived in a very als. Starting from his work optimizing coming frustrated with the lack of thera- early-stage breast cancer. tumultuous era of the 21st century, and doxorubicin hydrochloride into the pies for patients with metastatic breast See Gianni Bonadonna Award, Page 8C SESSION PREVIEW Medical Marijuana: Incorporating Immunotherapy in Frail Effi cacy, Toxicity, and Legality Adults With Common Malignancies The modern trend toward state-level lthough immunotherapy drugs may now provide a treatment option for EXPERT legalization of medical marijuana started older patients with cancer who are ineligible for, or whose disease fails, with California in 1996.1 Despite grow- chemotherapy, there are many unanswered questions about the effi cacy EDITORIAL ing nationwide support for marijuana and adverse effects of immunotherapy in this patient population. High- legalization, it remains classifi ed as a Alighting these knowledge gaps, as well as discussing ways to reconcile those gaps in Wesley M. Durand, ScB, and Schedule I substance: one with high clinical practice, will be the focus of an Education Session on June 4 titled “Treating Tina Rizack, MD, MPH See Medical Marijuana, Page 3C Frail Adults With Common Malignancies: Best Evidence to Personalize Therapy.”* “People should come to the session to get a deep dive into the current exist- annabis use in Western medi- ing evidence base for older or more vulnerable adults who are receiving immu- cine was initially popularized notherapy,” said ses- by Irish physician William B. ARTICLE sion Chair Ronald J. O’Shaughnessy in 1840.1-3 It was Maggiore, MD, of the Cincluded in the U.S. Pharmacopeia short- HIGHLIGHTS University of Roch- ly afterward and was often prescribed for ■ A wide variety of formulations ester Medical Center. rheumatism, cholera, tetanus, rabies, exist for medical marijuana use, Older adults are often and labor pain.1,4 In the early 20th cen- including dried cannabis fl owers, not candidates for tury, however, cannabis was outlawed resins, extracts, and oils. standard chemother- in several states.5 Access was further re- ■ apeutic treatments duced with the passage of the Harrison The legalization and use of can- because of comor- Narcotics Tax Act in 1914, defi ning drug nabis for medical purposes is an bidities and poor per- use as a crime de facto.1,6 The Marijuana evolving issue, and physician formance status, Dr. Tax Act was passed in 1936, declaring perspectives are likely evolving in Maggiore said. nonmedical cannabis illegal.1,5 It was re- tandem. The session will fo- moved from the U.S. Pharmacopeia in ■ At present, there is limited but cus on non–small cell 1942, justifi ed by a lack of recognized evolving support for the use of lung cancer (NSCLC), medical value.4,5 The 1950s saw passage cannabinoids as anticancer thera- which Dr. Maggiore will discuss, as well as bladder cancer and lymphoma. The of the Boggs Control Act and Narcot- pies; the largest evidence base session will also cover immunotherapy recently approved by the U.S. Food and ics Control Acts codifying mandatory exists in gliomas. Drug Administration (FDA) for these cancer types, including pembrolizumab for penalties for those caught possessing or ■ A growing proportion of state 1 1 patients with bladder cancer, Hodgkin lymphoma, and NSCLC. distributing marijuana. Although laws legislatures have voted in favor of However, the clinical trials that led to many of the immunotherapy drug ap- were temporarily eased in the 1970s, medical marijuana use, although provals included younger patients than oncologists typically see, Dr. Maggiore the Reagan administration’s Anti-Drug tension between state and federal See Immunotherapy in Frail Adults, Page 3C Abuse Act (1986) reestablished a tough laws persists. federal stance on marijuana use.1,7 Ipatasertib (GDC-0068, RG7440): An investigational, ATP-competitive AKT inhibitor Currently Enrolling in Breast Cancer

IPATunity130 Ipatasertib

Phase III • NCT03337724 A Study of Ipatasertib in Combination With Paclitaxel as a Treatment for Participants With PIK3CA/AKT1/PTEN-Altered, Locally Advanced or Metastatic, Triple-Negative Breast Cancer or Hormone Receptor–Positive, HER2-Negative Breast Cancer

A randomized, double-blind, placebo-controlled study of patients with Ipatasertib + paclitaxel Post-treatment follow-up • Locally advanced or metastatic TNBC or HR+/ HER2– breast cancer R • Survival

• No prior chemotherapy for LA/MBC Disease • GHS/HRQoL scores*

Placebo + paclitaxel progression • PIK3CA/AKT1/PTEN-altered tumor N=450

Study Endpoints Selected Eligibility Criteria Primary Outcome Measure: Histologically documented TNBC or HR+/HER2– adenocarcinoma of the breast that is locally advanced or metastatic and is not Progression-free survival, defi ned as the time amenable to resection with curative intent from randomization to the fi rst occurrence of disease progression or death from any cause† Measurable disease according to RECIST v1.1 Valid results confi rming PIK3CA/AKT1/PTEN-altered status Selected Secondary Outcome Measures: in tumor tissue Objective response rate, defi ned as a complete No prior treatment with chemotherapy for inoperable LA/MBC response or partial response on 2 consecutive No history of diabetes requiring insulin occasions ≥4 weeks apart† ECOG performance status of 0 or 1 Duration of response, defi ned as the time from the fi rst occurrence of a documented objective response to disease progression or death from any cause Overall survival, defi ned as the time from randomization to death from any cause GHS/HRQoL scores*

*As assessed using selected questions from EORTC QLQ-C30. † As determined by the investigator through the use of RECIST v1.1.

Find out if your patients are eligible for enrollment. For more information:

Visit: IPATunity130.com

Call: Genentech Trial Information Support Line: 1-888-662-6728 (US and Canada only)

Email: [email protected]

www.ClinicalTrials.gov Identifi er: NCT03337724; Sponsor Study Identifi er: CO40016. ATP=adenosine triphosphate; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS=global health status; HER=human epidermal growth factor receptor; HR=hormone receptor; HRQoL=health-related quality of life; LA=locally advanced; MBC=metastatic breast cancer; PIK3CA=phosphoinositide-3-kinase, catalytic, alpha polypeptide; PTEN=phosphatase and tensin homolog; RECIST=Response Evaluation Criteria In Solid Tumors; TNBC=triple-negative breast cancer. This compound and the combination of agents and their uses are investigational and have not been approved by the US Food and Drug Administration. Effi cacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of fi ndings in preclinical studies to humans is currently being evaluated. Information is consistent with www.ClinicalTrials.gov as of February 1, 2018.

Medical Marijuana 1).12 Finally, although the National Insti- generally considered responsible for the FDA-approved cannabinoid products Continued from page 1C tutes of Health provided $111 million for psychoactive effects of cannabis, whereas At present, the U.S. Food and Drug Ad- research on cannabinoid compounds in CBD lacks such activity. This discrepancy ministration (FDA) has approved three potential for abuse and lacking a current- 2016, others have charged that the pace may be attributable to differential bind- cannabinoid products for medical use.13 ly accepted medical use.8 Perhaps in re- of cannabis research is hampered by re- ing affi nity of CBD versus THC for the Dronabinol is a synthetic THC isomer 13,16,17 sponse to this trend, in 2009 the Obama strictions on scientifi c marijuana acquisi- CB1 and CB2 cannabinoid receptors. available in both oral capsular and liq- administration recommended against tion and distribution.13,14 Online purchasing is possible, and a uid formulations. Both are indicated for prosecution of marijuana for medical recent JAMA research letter purchased anorexia associated with weight loss in purposes.9,10 In 2013, the U.S. Depart- Cannabis Pharmacology and examined 84 cannabinoid products adult patients with AIDS and treatment ment of Justice clarifi ed that, although Formulation online and found that with respect to of chemotherapy-associated nausea and marijuana remained illegal on a federal A wide variety of formulations exist for CBD, only 31% (+10%) were labeled ac- vomiting (CINV) in nonresponders to level, it would presently refrain from medical marijuana use, including dried curately: 43% had more cannabinoids conventional antiemetic therapies.20 challenging state-level legalization.11 As cannabis fl owers, resins, extracts, and than labeled, whereas 26% had less or Nabilone is a synthetic cannabinoid de- of January 2018, 29 states, the District of oils.13 Cannabis oils may be particularly no active ingredient. THC was found in rivative also available in an oral capsu- Columbia, and Puerto Rico permit medi- potent; evidence supports that oils may 21%. Oils were the most likely to be la- lar formulation.21 Nabilone is indicated cal marijuana use; an additional 18 states contain up to 75% THC, as compared to beled accurately (45%), whereas vapor- for second-line treatment of CINV, and permit use of “low delta 9-tetrahydrocan- 20% in other formulations.15 Important- ization liquids were the least likely.18 its prescribing information indicates nabinol (THC), high cannabidiol (CBD)” ly, cannabis products may be composed that the product is limited to refractory products in medical circumstances (Fig. of either THC, CBD, or both. THC is Route of administration CINV due to “psychotomimetic reac- Cannabis products can be inhaled, tions not observed with other antiemet- ingested, or administered topically, ic agents.”21 12 Fig. 1. Map of State Medical Marijuana Laws (2017) vaginally, or rectally.13,19 These diverse Several additional cannabinoid routes of administration are associated products may also be on the horizon. with distinct pharmacologic profi les. Ajulemic acid is an nonpsychoactive Evidence suggests that inhaled cannabis synthetic endocannabinoid analog that (typically smoked or vaporized) is asso- is being developed in a range of indi- ciated with more rapid and predictable cations related to infl ammation and effects, although ingestion of cannabis fi brosis.13,21 Cannabidiol (an oral solu- yields more variable results.13 Smoke or tion of CBD extract) was submitted for inhaled cannabis act quickly, with usual consideration by the FDA in late 2017.13 onset in minutes, and lasts 2 to 4 hours. Nabiximol is an oromucosal spray with Pills and edible forms of cannabis take THC/CBD extracts; although it is cur- longer to achieve a therapeutic effect rently marked ex-U.S., the company has and last longer (4 to 12 hours). They can yet to fi le for approval with the FDA.13,22 be perceived as not working and lead to These latter two are notable in that they increased doses and potential cumula- are composed of cannabis extracts rather tive overdose. Novel, synthetic canna- than synthetic cannabinoids. The FDA’s binoid products are generally adminis- response to these products will likely Abbreviations: THC, tetrahydrocannabinol; CBD, cannabidiol. tered orally via capsules.13 See Medical Marijuana, Page 14C

Immunotherapy in Frail Adults relationship between baseline immune Continued from page 1C function, as evaluated through a comprehensive immune assessment, and said. Most of the patients enrolled in outcomes of immunotherapy in older the seminal studies of immunotherapy patients, he said. for NSCLC were in their early to mid- Dr. Cordoba will also discuss early 60s, yet 50% of patients diagnosed with clinical studies testing combination lung cancer in the United States are old- nivolumab and brentuximab vedotin er than 70.2 These trials also excluded as fi rst-line treatment of patients with patients with poor performance status advanced Hodgkin lymphoma. “This from participation a priori,3,4 although strategy seems to be attractive in older Dr. Ravindran post-marketing and FDA safety analyses Dr. Ronald J. Maggiore Dr. Raul Cordoba patients with Hodgkin lymphoma who have been somewhat encouraging for Kanesvaran are not candidates for conventional che- single-agent checkpoint inhibitors in motherapy because of frailty or comor- older adults or those with poorer perfor- Patients who are frail or who have apply to older patients with advanced bidities,” Dr. Cordoba said. mance status, Dr. Maggiore added. poor renal function are ineligible for bladder cancer. In general, clinical trial –Carina Storrs, PhD It can be challenging to apply data cisplatin-based chemotherapy, which is enrollments are biased toward younger from these trials to clinical decision- the standard of care for advanced blad- populations, and it is a challenge to de- References: making for older patients, particularly if der cancer. “Thanks to immunotherapy, cide how to extrapolate those data to the 1. National Cancer Institute. FDA Expands they have other comorbidities, Dr. Mag- patients who may not have received the older patient,” Dr. Kanesvaran said. Approval of Pembrolizumab for First-Line giore said. One of the issues is that, as current standard of care can potentially Treatment of Non-Small Cell Lung Cancer. patients age and develop comorbidities, get some treatment that can prolong Immunotherapy for Older Patients cancer.gov/news-events/cancer-currents- immune function may decline and there their life and give them good quality of With Lymphoma in the First-Line blog/2017/fda-pembrolizumab-lung- may be changes in the tumor microen- life,” Dr. Kanesvaran said. and Relapsed Settings expanded. Published June 6, 2017. vironment, all of which could affect the The recent approvals of pembroli- As is the case with most cancer types, Accessed February 21, 2018. effi cacy of immunotherapy drugs. zumab and atezolizumab in the fi rst-line clinical trials of immunotherapy drugs 2. Ferrara R, et al. Cancer Treat Rev. The session will feature a clinical vi- treatment of patients with advanced for Hodgkin and non-Hodgkin lym- 2017;60:60-8. gnette to illustrate some of the key chal- bladder cancer who were cisplatin-inel- phoma have included few patients older 3. Reck M, et al. N Engl J Med. lenges in deciding how to treat older igible were based on single-arm phase II than 65. Raul Cordoba, MD, PhD, MS, of 2016;375:1823-33. patients with immunotherapy, Dr. Mag- clinical trials that reported good toler- the Fundacion Jimenez Diaz University 4. Brahmer J, et al, N Engl J Med. giore said. ability and antitumor activity. 5,6 More- Hospital, in Madrid, Spain, will review 2015;373:123-35. over, because trial participants were inel- data on PD-1 inhibitors and CAR T-cell 5. Balar AV, et al. Lancet Oncol. 2017;18:1483- Older Patients in Advanced igible for cisplatin treatment because of therapy for patients with aggressive re- 92. Bladder Cancer Trials poor performance status or comorbidi- lapsed lymphoma. 6. Balar AV, et al. Lancet. 2017;389:67-76. During his presentation, Ravindran ties such as kidney dysfunction, neurop- “So far, clinical data on effi cacy and Kanesvaran, MD, of the National Can- athy, or hearing loss, they tended to be safety of immunotherapy in older pa- *Program information updated as of cer Centre Singapore, will discuss the elderly (median age: 74 and 73 years for tients with lymphoma seem to be similar February 22. For session time and location characteristics of older patients with ad- the pembrolizumab and atezolizumab to younger patients, but we need longer information, please refer to the ASCO vanced bladder cancer who could ben- studies, respectively). follow-up,” Dr. Cordoba said. Research iPlanner on the Attendee Resource Center efi t from immunotherapy drugs. “Now we know these data specifi cally should be conducted to understand the (am.asco.org/arc). CAR T IS HERE

YESCARTA®, THE FIRST CAR T THERAPY FOR CERTAIN TYPES OF RELAPSED OR REFRACTORY LARGE B-CELL LYMPHOMA The following data reflect results from the ZUMA-1 pivotal trial*1

// PROVEN // CYTOKINE RELEASE // RAPID & RELIABLE 51%EFFICACY 13%SYNDROME94% 17MANUFACTURING DAYS

Patients achieved a best Grade Ɛ3 incidence Overall incidence Median turnaround time† response of complete remission (CR) (52/101) // NEUROLOGIC NR 31%TOXICITIES87% 99% Response duration was not Manufacturing success reached at a median follow-up of CAR T cells engineered of 7.9 months in patients who Grade Ɛ3 incidence Overall incidence and expanded ex vivo achieved CR

VISIT YESCARTAHCP.COM/CENTERS TO FIND A LIST OF AUTHORIZED TREATMENT CENTERS

* ZUMA-1 was an open-label, single-arm study in 101 adult patients who received YESCARTA® therapy. Patients received lymphodepleting chemotherapy prior to a single infusion of YESCARTA® at a target dose of 2 x 106 viable CAR T cells/kg body weight (maximum of 2 x 108 viable CAR T cells). Patients had refractory disease to their most recent therapy, or had relapsed within 1 year after autologous hematopoietic stem cell transplantation. †The median time from leukapheresis to product delivery. INDICATION IMPORTANT SAFETY INFORMATION YESCARTA® is a CD19-directed genetically modified BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES autologous T cell immunotherapy indicated for • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in the treatment of adult patients with relapsed or patients receiving YESCARTA®. Do not administer YESCARTA® to patients with active infection refractory large B-cell lymphoma after two or more or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab lines of systemic therapy, including diffuse large or tocilizumab and corticosteroids. B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high • Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients grade B-cell lymphoma, and DLBCL arising from receiving YESCARTA®, including concurrently with CRS or after CRS resolution. Monitor follicular lymphoma. for neurologic toxicities after treatment with YESCARTA®. Provide supportive care and/or corticosteroids as needed. Limitation of Use: YESCARTA® is not indicated for the treatment of patients with primary central nervous • YESCARTA ® is available only through a restricted program under a Risk Evaluation system lymphoma. and Mitigation Strategy (REMS) called the YESCARTA® REMS. Important Safety Information continued on adjacent page.

YESCARTA, the YESCARTA Logo, KITE, and the KITE Logo are trademarks of Kite Pharma, Inc. GILEAD is a trademark of Gilead Sciences, Inc. © 2018 Kite Pharma | PRC-00413 03/2018 VISIT US AT THE GILEAD BOOTH #18063

IMPORTANT SAFETY INFORMATION YESCARTA® REMS: Because of the risk of CRS PROLONGED CYTOPENIAS: Patients may and neurologic toxicities, YESCARTA® is available exhibit cytopenias for several weeks following (continued) only through a restricted program under a Risk lymphodepleting chemotherapy and YESCARTA® Evaluation and Mitigation Strategy (REMS) called infusion. Grade 3 or higher cytopenias not resolved CYTOKINE RELEASE SYNDROME (CRS): CRS the YESCARTA® REMS. The required components by Day 30 following YESCARTA® infusion occurred occurred in 94% of patients, including 13% with of the YESCARTA® REMS are: Healthcare facilities in 28% of patients and included thrombocytopenia Ɛ Grade 3. Among patients who died after receiving that dispense and administer YESCARTA® must be (18%), neutropenia (15%), and anemia (3%). ® YESCARTA , 4 had ongoing CRS at death. enrolled and comply with the REMS requirements. Monitor blood counts after YESCARTA® infusion. The median time to onset was 2 days (range: Certified healthcare facilities must have on-site, 1-12 days) and median duration was 7 days (range: HYPOGAMMAGLOBULINEMIA: B-cell aplasia immediate access to tocilizumab, and ensure that and hypogammaglobulinemia can occur. 2-58 days). Key manifestations include fever (78%), a minimum of 2 doses of tocilizumab are available hypotension (41%), tachycardia (28%), hypoxia Hypogammaglobulinemia occurred in 15% for each patient for infusion within 2 hours after of patients. Monitor immunoglobulin levels (22%), and chills (20%). Serious events that may be ® infusion, if needed for treatment of YESCARTA after treatment and manage using infection associated with CRS include cardiac arrhythmias CRS. Certified healthcare facilities must ensure precautions, antibiotic prophylaxis and (including atrial fibrillation and ventricular that healthcare providers who prescribe, dispense immunoglobulin replacement. The safety of tachycardia), cardiac arrest, cardiac failure, or administer YESCARTA® are trained about the immunization with live viral vaccines during or renal insufficiency, capillary leak syndrome, management of CRS and neurologic toxicities. following YESCARTA® treatment has not been hypotension, hypoxia, and hemophagocytic Further information is available at lymphohistiocytosis/macrophage activation studied. Vaccination with live virus vaccines is not www.YESCARTAREMS.com or recommended for at least 6 weeks prior to the syndrome. Ensure that 2 doses of tocilizumab are 1-844-454-KITE (5483). available prior to infusion of YESCARTA®. Monitor start of lymphodepleting chemotherapy, during ® patients at least daily for 7 days at the certified HYPERSENSITIVITY REACTIONS: Allergic YESCARTA treatment, and until immune recovery healthcare facility following infusion for signs reactions may occur. Serious hypersensitivity following treatment. and symptoms of CRS. Monitor patients for signs reactions including anaphylaxis may be due to SECONDARY MALIGNANCIES: Patients may or symptoms of CRS for 4 weeks after infusion. dimethyl sulfoxide (DMSO) or residual gentamicin develop secondary malignancies. Monitor life- ®. Counsel patients to seek immediate medical in YESCARTA long for secondary malignancies. In the event that attention should signs or symptoms of CRS occur SERIOUS INFECTIONS: Severe or life-threatening a secondary malignancy occurs, contact Kite at at any time. At the first sign of CRS, institute infections occurred. Infections (all grades) 1-844-454-KITE (5483) to obtain instructions on treatment with supportive care, tocilizumab or occurred in 38% of patients, and in 23% with patient samples to collect for testing. tocilizumab and corticosteroids as indicated. Grade 3. Grade 3 or higher infections with an Ɛ EFFECTS ON ABILITY TO DRIVE AND USE unspecified pathogen occurred in 16% of patients, NEUROLOGIC TOXICITIES: Neurologic toxicities MACHINES: Due to the potential for neurologic bacterial infections in 9%, and viral infections occurred in 87% of patients. Ninety-eight percent events, including altered mental status or in 4%. YESCARTA® should not be administered of all neurologic toxicities occurred within the first seizures, patients are at risk for altered or to patients with clinically significant active 8 weeks, with a median time to onset of 4 days decreased consciousness or coordination in the systemic infections. Monitor patients for signs (range: 1-43 days) and a median duration of 8 weeks following YESCARTA® infusion. Advise 17 days. Grade 3 or higher occurred in 31% of and symptoms of infection before and after patients to refrain from driving and engaging ® infusion and treat appropriately. patients. The most common neurologic toxicities YESCARTA in hazardous occupations or activities, such Administer prophylactic anti-microbials included encephalopathy (57%), headache as operating heavy or potentially dangerous according to local guidelines. Febrile neutropenia (44%), tremor (31%), dizziness (21%), aphasia machinery, during this initial period. (18%), delirium (17%), insomnia (9%) and anxiety was observed in 36% of patients and may be ADVERSE REACTIONS: The most common (9%). Prolonged encephalopathy lasting up to concurrent with CRS. In the event of febrile adverse reactions (incidence Ɛ 20%) include CRS, 173 days was noted. Serious events including neutropenia, evaluate for infection and manage fever, hypotension, encephalopathy, tachycardia, leukoencephalopathy and seizures occurred with with broad spectrum antibiotics, fluids and other fatigue, headache, decreased appetite, chills, YESCARTA®. Fatal and serious cases of cerebral supportive care as medically indicated. Hepatitis B diarrhea, febrile neutropenia, infections-pathogen edema have occurred in patients treated with virus (HBV) reactivation, in some cases resulting unspecified, nausea, hypoxia, tremor, cough, YESCARTA®. Monitor patients at least daily for in fulminant hepatitis, hepatic failure and death, vomiting, dizziness, constipation, and cardiac 7 days at the certified healthcare facility following can occur in patients treated with drugs directed infusion for signs and symptoms of neurologic against B cells. Perform screening for HBV, HCV, arrhythmias. toxicities. Monitor patients for signs or symptoms and HIV in accordance with clinical guidelines Please see Brief Summary of Prescribing of neurologic toxicities for 4 weeks after infusion before collection of cells for manufacturing. Information, including BOXED WARNING, and treat promptly. on the following pages.

Reference: 1. YESCARTA™ [package insert]. Santa Monica, CA: Kite Pharma; 2017. Santa Monica, CA ® BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR YESCARTA Table 1. CRS Grading and Management Guidance (continued) (axicabtagene ciloleucel) suspension for intravenous infusion SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION CRS Grade (a) Tocilizumab Corticosteroids Grade 3 Per Grade 2 Administer methylprednisolone WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES Symptoms require and respond 1 mg/kg intravenously to aggressive intervention. twice daily or equivalent • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients dexamethasone (e.g., receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory Oxygen requirement greater 10 mg intravenously every disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids than or equal to 40% FiO2 or 6 hours). [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)]. hypotension requiring high-dose or multiple vasopressors or Continue corticosteroids use • Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving until the event is Grade 1 or less, YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic Grade 3 organ toxicity or Grade 4 then taper over 3 days. toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids, as transaminitis. needed [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.2)]. • YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Grade 4 Per Grade 2 Administer methylprednisolone Strategy (REMS) called the YESCARTA REMS [see Warnings and Precautions (5.3)]. Life-threatening symptoms. 1000 mg intravenously per day for 3 days; if improves, then Requirements for ventilator manage as above. 1 INDICATIONS AND USAGE support, continuous veno-venous YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the hemodialysis (CVVHD) or treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines Grade 4 organ toxicity (excluding of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary transaminitis). mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. (a) Lee et al 2014, (b) Refer to Table 2 for management of neurologic toxicity, (c) Refer to tocilizumab Prescribing Information for details Limitation of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma. Neurologic Toxicity: Monitor patients for signs and symptoms of neurologic toxicities (Table 2). Rule out other causes of neurologic symptoms. Patients who experience Grade 2 or higher neurologic toxicities should be 2 DOSAGE AND ADMINISTRATION monitored with continuous cardiac telemetry and pulse oximetry. Provide intensive care supportive therapy for 2.2 Administration: YESCARTA is for autologous use only. The patient’s identity must match the patient severe or life threatening neurologic toxicities. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) identifiers on the YESCARTA cassette and infusion bag. Do not infuse YESCARTA if the information on the for seizure prophylaxis for any Grade 2 or higher neurologic toxicities. patient-specific label does not match the intended patient [see Dosage and Administration(2.2.3)]. Table 2. Neurologic Toxicity Grading and Management Guidance Preparing Patient for YESCARTA Infusion: Confirm availability of YESCARTA prior to starting the Grading lymphodepleting regimen. Pre-treatment: Administer a lymphodepleting chemotherapy regimen of Concurrent CRS No Concurrent CRS cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 intravenously on the fifth, fourth, Assessment and third day before infusion of YESCARTA. Premedication: Administer acetaminophen 650 mg PO and Grade 2 Administer tocilizumab per Table 1 for Administer dexamethasone 10 mg diphenhydramine 12.5 mg intravenously or PO approximately 1 hour before YESCARTA infusion. Avoid management of Grade 2 CRS. intravenously every 6 hours. prophylactic use of systemic corticosteroids, as it may interfere with the activity of YESCARTA. If no improvement within 24 hours after starting Continue dexamethasone Preparation of YESCARTA for Infusion: Coordinate the timing of YESCARTA thaw and infusion. Confirm the tocilizumab, administer dexamethasone 10 mg use until the event is Grade 1 or infusion time in advance, and adjust the start time of YESCARTA thaw such that it will be available for infusion intravenously every 6 hours if not already taking less, then taper over 3 days. when the patient is ready. Confirm patient identity: Prior to YESCARTA preparation, match the patient’s identity other corticosteroids. Continue dexamethasone with the patient identifiers on the YESCARTA cassette. Do not remove the YESCARTA product bag from the use until the event is Grade 1 or less, then taper cassette if the information on the patient-specific label does not match the intended patient. Once patient over 3 days. identification is confirmed, remove the YESCARTA product bag from the cassette and check that the patient information on the cassette label matches the bag label. Inspect the product bag for any breaches of container Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure integrity such as breaks or cracks before thawing. If the bag is compromised, follow the local guidelines (or prophylaxis. call Kite at 1-844-454-KITE). Place the infusion bag inside a second sterile bag per local guidelines. Thaw YESCARTA at approximately 37°C using either a water bath or dry thaw method until there is no visible ice in Grade 3 Administer tocilizumab per Table 1 for Administer dexamethasone 10 mg the infusion bag. Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps management of Grade 2 CRS. intravenously every 6 hours. remain continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not wash, spin down, and/or re-suspend YESCARTA in new media prior to infusion. In addition, administer dexamethasone 10 mg Continue dexamethasone use until Once thawed, YESCARTA may be stored at room temperature (20°C to 25°C) for up to 3 hours. intravenously with the first dose of tocilizumab the event is Grade 1 or less, then and repeat dose every taper over 3 days. Administration: For autologous use only. Ensure that tocilizumab and emergency equipment are available 6 hours. Continue dexamethasone use until the prior to infusion and during the recovery period. Do NOT use a leukodepleting filter. Central venous access is event is Grade 1 or less, then taper over 3 days. recommended for the infusion of YESCARTA. Confirm the patient’s identity matches the patient identifiers on the YESCARTA product bag. Prime the tubing with normal saline prior to infusion. Infuse the entire contents Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure of the YESCARTA bag within 30 minutes by either gravity or a peristaltic pump. YESCARTA is stable at prophylaxis. room temperature for up to 3 hours after thaw. Gently agitate the product bag during YESCARTA infusion to prevent cell clumping. After the entire content of the product bag is infused, rinse the tubing with Grade 4 Administer tocilizumab per Table 1 for Administer methylprednisolone normal saline at the same infusion rate to ensure all product is delivered. YESCARTA contains human management of Grade 2 CRS. 1000 mg intravenously per day for blood cells that are genetically modified with replication incompetent retroviral vector. Follow universal Administer methylprednisolone 3 days; if improves, then manage precautions and local biosafety guidelines for handling and disposal to avoid potential transmission of 1000 mg intravenously per day with first dose of as above. infectious diseases. tocilizumab and continue methylprednisolone Monitoring: Administer YESCARTA at a certified healthcare facility. Monitor patients at least daily for 7 days 1000 mg intravenously per day for 2 more days; at the certified healthcare facility following infusion for signs and symptoms of CRS and neurologic toxicities. if improves, then manage as above. Instruct patients to remain within proximity of the certified healthcare facility for at least 4 weeks following infusion. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. 2.3 Management of Severe Adverse Reactions Cytokine Release Syndrome (CRS): Identify CRS based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is 4 CONTRAINDICATIONS: None. suspected, manage according to the recommendations in Table 1. Patients who experience Grade 2 or higher 5 WARNINGS AND PRECAUTIONS CRS (e.g., hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For patients experiencing severe CRS, 5.1 Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following consider performing an echocardiogram to assess cardiac function. For severe or life-threatening CRS, treatment with YESCARTA. In Study 1, CRS occurred in 94% (101/108) of patients receiving YESCARTA, consider intensive care supportive therapy. including ≥ Grade 3 (Lee grading system) CRS in 13% (14/108) of patients. Among patients who died after receiving YESCARTA, four had ongoing CRS events at the time of death. The median time to onset Table 1. CRS Grading and Management Guidance was 2 days (range: 1 to 12 days) and the median duration of CRS was 7 days (range: 2 to 58 days). Key CRS Grade (a) Tocilizumab Corticosteroids manifestations of CRS include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial Grade 1 N/A N/A fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak Symptoms require symptomatic syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome treatment only (e.g., fever, (HLH/MAS) [see Adverse Reactions (6)]. Ensure that 2 doses of tocilizumab are available prior to infusion nausea, fatigue, headache, of YESCARTA. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion myalgia, malaise). for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time Grade 2 Administer tocilizumab (c) Manage per Grade 3 if no [see Patient Counseling Information (17)]. At the first sign of CRS, institute treatment with supportive care, Symptoms require and respond 8 mg/kg intravenously over improvement within 24 hours tocilizumab or tocilizumab and corticosteroids as indicated [See Dosage and Administration (2.3)]. 1 hour (not to exceed 800 mg). after starting tocilizumab. to moderate intervention. 5.2 Neurologic Toxicities: Neurologic toxicities, that were fatal or life-threatening, occurred following Oxygen requirement less than Repeat tocilizumab every treatment with YESCARTA. Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all 8 hours as needed if not neurologic toxicities occurred within the first 8 weeks of YESCARTA infusion, with a median time to onset 40% FiO2 or hypotension responsive to fluids or low-dose responsive to intravenous fluids of 4 days (range: 1 to 43 days). The median duration of neurologic toxicities was 17 days. Grade 3 or of one vasopressor or or increasing supplemental higher neurologic toxicities occurred in 31% of patients. The most common neurologic toxicities included oxygen. encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), Grade 2 organ toxicity (b). Limit to a maximum of 3 doses insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events in a 24-hour period; maximum including leukoencephalopathy and seizures occurred with YESCARTA. Fatal and serious cases of cerebral total of 4 doses. edema have occurred in patients treated with YESCARTA. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly [see Summary of Adverse Reactions Observed in at Least 10% of the Patients Treated with YESCARTA Management of Severe Adverse Reactions (2.3); Neurologic Toxicities]. in Study 1 (continued) 5.3 YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a Adverse Reaction Any Grade Grades 3 or restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA REMS [see Boxed (%) Higher (%) Warning and Warnings and Precautions (5.1 and 5.2)]. The required components of the YESCARTA REMS are: • Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS Musculoskeletal and connective Motor dysfunction 19 1 requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and tissue disorders Pain in extremity 17 2 ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within Back pain 15 1 2 hours after YESCARTA infusion, if needed for treatment of CRS. Muscle pain 14 1 • Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Arthralgia 10 0 YESCARTA are trained about the management of CRS and neurologic toxicities. Nervous system disorders Encephalopathy 57 29 Further information is available at www.YescartaREMS.com or 1-844-454-KITE (5483). Headache 45 1 Tremor 31 2 5.4 Hypersensitivity Reactions: Allergic reactions may occur with the infusion of YESCARTA. Serious Dizziness 21 1 hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) or residual Aphasia 18 6 gentamicin in YESCARTA. Psychiatric disorders Delirium 17 6 5.5 Serious Infections: Severe or life-threatening infections occurred in patients after YESCARTA infusion. In Study 1, infections (all grades) occurred in 38% of patients. Grade 3 or higher infections occurred in Respiratory, thoracic and Hypoxia 32 11 23% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, mediastinal disorders Cough 30 0 bacterial infections in 9%, and viral infections in 4%. YESCARTA should not be administered to patients with Dyspnea 19 3 clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before Pleural effusion 13 2 and after YESCARTA infusion and treat appropriately. Administer prophylactic anti-microbials according to Renal and urinary disorders Renal insufficiency 12 5 local guidelines. Febrile neutropenia was observed in 36% of patients after YESCARTA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad Vascular disorders Hypotension 57 15 spectrum antibiotics, fluids and other supportive care as medically indicated. Viral Reactivation: Hepatitis Hypertension 15 6 B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can Thrombosis 10 1 occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. The following events were also counted in the incidence of CRS: tachycardia, arrhythmia, fever, chills, hypoxemia, renal insufficiency, 5.6 Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting and hypotension. For a complete list of events that contributed to the incidence of certain adverse reactions, please see footnote below Table 3 in Section 6.1 of the Full Prescribing Information. chemotherapy and YESCARTA infusion. In Study 1, Grade 3 or higher cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia Other clinically important adverse reactions that occurred in less than 10% of patients treated with (15%), and anemia (3%). Monitor blood counts after YESCARTA infusion. YESCARTA include the following: blood and lymphatic system disorders: coagulopathy (2%); cardiac 5.7 Hypogammaglobulinemia: B-cell aplasia and hypogammaglobulinemia can occur in patients disorders: cardiac failure (6%) and cardiac arrest (4%); immune system disorders: hemophagocytic receiving treatment with YESCARTA. In Study 1, hypogammaglobulinemia occurred in 15% of patients. lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) (1%), hypersensitivity (1%); infections Monitor immunoglobulin levels after treatment with YESCARTA and manage using infection precautions, and infestations disorders: fungal infections (5%); nervous system disorders: ataxia (6%), seizure (4%), antibiotic prophylaxis and immunoglobulin replacement. The safety of immunization with live viral vaccines dyscalculia (2%), and myoclonus (2%); respiratory, thoracic and mediastinal disorders: pulmonary edema during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not (9%); skin and subcutaneous tissue disorders: rash (9%); vascular disorders: capillary leak syndrome (3%). recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in Study 1 treatment, and until immune recovery following treatment with YESCARTA. Following Treatment with YESCARTA based on CTCAE (N=108) 5.8 Secondary Malignancies: Patients treated with YESCARTA may develop secondary malignancies. Monitor Lymphopenia 100%, Leukopenia 96%, Neutropenia 93%, Anemia 66%, Thrombocytopenia 58%, life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at Hypophosphatemia 50%, Hyponatremia 19%, Uric acid increased 13%, Direct Bilirubin increased 13%, 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing. Hypokalemia 10%, Alanine Aminotransferase increased 10%. 5.9 Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including 6.2 Immunogenicity: YESCARTA has the potential to induce anti-product antibodies. The immunogenicity altered mental status or seizures, patients receiving YESCARTA are at risk for altered or decreased of YESCARTA has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain binding antibodies against FMC63, the originating antibody of the anti-CD19 CAR. Three patients tested positive from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially for pre-dose anti-FMC63 antibodies at baseline and Months 1, 3, or 6 in Study 1. There is no evidence that dangerous machinery, during this initial period. the kinetics of initial expansion and persistence of YESCARTA, or the safety or effectiveness of YESCARTA, was altered in these patients. 6 ADVERSE REACTIONS: The following adverse reactions are described in Warnings and Precautions: Cytokine Release Syndrome, Neurologic Toxicities, Hypersensitivity Reactions, Serious Infections, Prolonged 8 USE IN SPECIFIC POPULATIONS Cytopenias, Hypogammaglobulinemia. 8.1 Pregnancy: Risk Summary: There are no available data with YESCARTA use in pregnant women. No 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, animal reproductive and developmental toxicity studies have been conducted with YESCARTA to assess adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the whether it can cause fetal harm when administered to a pregnant woman. It is not known if YESCARTA has clinical trials of another drug and may not reflect the rates observed in practice. The safety data described the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross in this section reflect exposure to YESCARTA in the clinical trial (Study 1) in which 108 patients with relapsed/ the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia. Therefore, YESCARTA is not refractory B-cell NHL received CAR-positive T cells based on a recommended dose which was weight-based recommended for women who are pregnant, and pregnancy after YESCARTA infusion should be discussed [see Clinical Trials (14)] . Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) with the treating physician. In the U.S. general population, the estimated background risk of major birth or autoimmune disease requiring systemic immunosuppression were ineligible. The median duration of defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. follow up was 8.7 months. The median age of the study population was 58 years (range: 23 to 76 years); 68% 8.2 Lactation: Risk Summary: There is no information regarding the presence of YESCARTA in human milk, were men. The baseline ECOG performance status was 43% with ECOG 0, and 57% with ECOG 1. The most the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, of breastfeeding should be considered along with the mother’s clinical need for YESCARTA and any potential fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, adverse effects on the breastfed infant from YESCARTA or from the underlying maternal condition. nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. Serious adverse reactions occurred in 52% of patients. The most common serious adverse reactions (> 2%) include 8.3 Females and Males of Reproductive Potential: Pregnancy Testing: Pregnancy status of females with encephalopathy, fever, lung infection, febrile neutropenia, cardiac arrhythmia, cardiac failure, urinary tract reproductive potential should be verified. Sexually-active females of reproductive potential should have a infection, renal insufficiency, aphasia, cardiac arrest, Clostridium difficile infection, delirium, hypotension, pregnancy test prior to starting treatment with YESCARTA. Contraception: See the prescribing information and hypoxia. The most common (≥ 10%) Grade 3 or higher reactions include febrile neutropenia, fever, for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia, and lung infections. Forty-five receive the lymphodepleting chemotherapy. There are insufficient exposure data to provide a recommendation percent (49/108) of patients received tocilizumab after infusion of YESCARTA. concerning duration of contraception following treatment with YESCARTA. Infertility: There are no data on the effect of YESCARTA on fertility. Summary of Adverse Reactions Observed in at Least 10% of the Patients Treated with YESCARTA in Study 1 8.4 Pediatric Use: The safety and efficacy of YESCARTA have not been established in pediatric patients. Any Grade Grades 3 or 8.5 Geriatric Use: Clinical trials of YESCARTA did not include sufficient numbers of patients aged 65 years Adverse Reaction (%) Higher (%) and older to determine whether they respond differently or have different safety outcomes as compared to younger patients. Cardiac disorders Tachycardia 57 2 Arrhythmia 23 7 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Ensure that patients Gastrointestinal disorders Diarrhea 38 4 understand the risk of manufacturing failure (1% in clinical trial). In case of a manufacturing failure, a Nausea 34 0 second manufacturing of YESCARTA may be attempted. In addition, while the patient awaits the product, Vomiting 26 1 additional chemotherapy (not the lymphodepletion) may be necessary and may increase the risk of Constipation 23 0 adverse events during the pre-infusion period. Advise patients to seek immediate attention for any of the Abdominal pain 14 1 following: Cytokine Release Syndrome, Neurologic Toxicities, Serious Infections, Prolonged Cytopenia [see Dry mouth 11 0 Warnings and Precautions (5.1, 5.2, 5.3, 5.5) and Adverse Reactions (6) for more information and signs and symptoms]. Advise patients for the need to: Refrain from driving or operating heavy or potentially General disorders and Fever 86 16 dangerous machinery after YESCARTA infusion until at least 8 weeks after infusion [see Warnings and administration site conditions Fatigue 46 3 Precautions (5.2)], Have periodic monitoring of blood counts. Contact Kite at 1-844-454-KITE (5483) if Chills 40 0 they are diagnosed with a secondary malignancy [see Warnings and Precautions (5.8)]. Edema 19 1 Immune system disorders Cytokine release syndrome 94 13 Manufactured by, Packed by, Distributed by: Kite Pharma, Inc., Santa Monica, CA 90404 Hypogammaglobulinemia 15 0 US License No 2064 Infections and infestations Infections-pathogen unspecified 26 16 YESCARTA and KITE are trademarks of Kite Pharma, Inc. Viral infections 16 4 Bacterial infections 13 9 © 2018 Kite Pharma | PRC-00428 03/2018 Investigations Decreased appetite 44 2 Weight decreased 16 0 Dehydration 11 3 C 8 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

been practice-changing in the metastatic Looking Back: First Antibody-Drug Conjugate setting,” she said. “It’s wonderful to have a drug that is well tolerated and does not Changed Practice in Breast Cancer Treatment have the traditional toxicity we saw with the previous chemotherapy regimen. It’s uring the 2012 ASCO Annual Meet- practice of breast cancer treatment in the very important accomplishment.” a demonstration of what we all strive for ing Plenary Session, Kimberly L. 6 years since that presentation, the ASCO Contacted in 2018 for this retrospec- in the treatment of patients facing cancer, Blackwell, MD, of Duke University Daily News recently spoke to Dr. Blackwell tive article, Dr. Weiner told the ASCO which is to not hurt the patient as much Medical Center, presented the pri- and Louis M. Weiner, MD, of Georgetown Daily News, “I fi nd my opinions remark- as we hurt their cancer.” Dmary results of the EMILIA trial.1 In that Lombardi Comprehensive Cancer Center. ably unchanged from back then. The Based primarily on the strength of the phase III clinical trial, in patients with In 2012, Dr. Weiner—who was the drug lived up to its promise. It adds to EMILIA fi ndings, T-DM1, also known previously treated HER2-positive locally discussant for the abstract during the the therapeutic armamentarium, as ado-trastuzumab emtansine, was ap- advanced or metastatic breast cancer, Plenary Session—called T-DM1 “an im- predicted. It’s being widely employed. proved by the U.S. Food and Drug Ad- investigators demonstrated that trastu- portant new weapon in the therapeutic Breast cancer oncologists have learned ministration (FDA) in 2013.2,3 T-DM1 is zumab emtansine (T-DM1) conferred a armamentarium for breast cancer.” He how and when to use it.” an antibody-drug conjugate comprising signifi cant and clinically meaningful im- said the results of the trial served as jus- Dr. Blackwell agreed that T-DM1 met trastuzumab, a linker, and the cytotox- provement in progression-free survival tifi cation to explore other antibody-drug expectations. “This was the fi rst antibody- ic agent derivative emtansine, or DM1. (PFS) over its comparator regimen. conjugates, and he congratulated the drug conjugate approved for the treat- It combines the antitumor activities of To assess the effect of the study on the study authors for their “excellent and ment of solid tumors, and it has defi nitely trastuzumab and the HER2-targeted delivery of DM1, a microtubule inhibitor. The drug is indicated for the treatment of patients with HER2-positive metastatic breast cancer who have previously received trastuzumab and a taxane. CDK9 regulation of MCL-1 1-5 Last June, 5 years after the Plenary inhibits apoptosis, enabling presentation, the fi nal overall survival CDK9 (OS) results of EMILIA were published in See First Antibody-Drug Conjugate, Page 9C

Gianni Bonadonna Award Continued from page 1C

Working with long-time MD Ander- MCL-1 mRNA son collaborator Mien-Chie Hung, PhD, Dr. Hortobagyi started some of the initial clinical trials on gene modiﬁ cation in the early 1990s. “At the time the tools were very primitive, but now it is so MCL-1 dependence may CDK9 is a key regulator of Inhibition of CDK9 as a satisfying for me to see how, indirectly from earlier trials, we have the ability drive progression of AML 3,6 MCL-1 function1,2,5 rational therapeutic strategy to harvest CAR T cells and implement MCL-1 in MCL-1–dependent AML1,5,7 Disease progression and treatment mRNA transcription in newer gene therapy programs that are resistance in a subset of acute AML blasts is regulated by cyclin- Because MCL-1 has a short half-life actually working,” he said. myeloid leukemia (AML) have dependent kinase 9 (CDK9),1,2 a of 2-4 hours, the effects of targeting been associated with a key anti- protein that plays a critical role in its upstream regulators are Current Research Efforts apoptotic protein, myeloid cell transcription regulation without expected to reduce MCL-1 levels For the past 5 to 6 years, Dr. Horto- leukemia 1 (MCL-1).3,6 MCL-1 directly affecting cell-cycle control.5,10 11 rapidly. CDK9 inhibition has been bagyi has been working on developing is a member of the apoptosis- MCL-1 shown to block transcription, improved endocrine therapy in breast regulating BCL-2 family of proteins.7 resulting in rapid depletion of cancer. Having earlier discovered a num- CDK9-mediated transcriptional MCL-1 protein, which may restore In MCL-1–dependent AML,* the ber of genomic abnormalities that were apoptosis in MCL-1–dependent AML blasts depend primarily regulation of anti-apoptotic commonly associated with breast cancer, AML blasts.1,5,7 on the function of MCL-1 for the proteins, including MCL-1, among them activation or abnormalities anti-apoptotic mechanism of Understanding the role of CDK9 of the AKT/mTOR pathway, he developed survival.8,9 MCL-1 inhibits apoptosis is critical for the survival of in regulating MCL-1 may inform the idea that some of those abnormalities and sustains the survival of AML MCL-1–dependent AML blasts.5 therapeutic targeting strategies might be involved in the development of blasts, allowing them to proliferate, in AML. resistance to endocrine therapy. which may lead to relapse.3 MCL-1 The next step was to look for drugs dependence is also associated that were far enough in development to with resistance to agents that otherwise have activity against test the hypothesis. Working with José leukemic blasts.7 Baselga, MD, PhD, on the BOLERO-2 *The prevalence of MCL-1–dependent trial, everolimus, one of the ﬁ rst mTOR AML is under investigation. inhibitors, emerged. From that trial, two adjuvant trials are now ongoing with BOOTH If you have patients with AML, learn more everolimus. #10135 about available clinical trials at the 2018 Dr. Hortobagyi has been deeply in- ASCO Annual Meeting volved in development of the cyclin A matter of cell life and cell death CDK4/6 inhibitors, such as ribociclib, which represent another pathway for Tolero Pharmaceuticals, Inc. is a leading developer of novel therapeutics to inhibit preventing endocrine therapy resistance Learn more at www.toleropharma.com biological drivers of hematologic and oncologic diseases. in breast cancer. He designed the suc-

References: 1. Chen R, Keating MJ, Gandhi V, Plunkett W. Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood. 2005;106(7):2513-2519. 2. Ocana A, Pandiella A. cessful MONALEESA-2 clinical study Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies. Oncotarget. 2017;8(13):22218-22234. 3. Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl- with ribociclib and is now conducting 1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012;26(2):120-125. 4. Perciavalle RM, Opferman JT. Delving deeper: MCL-1’s contributions to normal and cancer biology. Trends Cell Biol. 2013;23(1):22-29. 5. Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A. Cyclin dependent kinase 9 inhibitors for cancer therapy. J Med Chem. 2016;59(19):8667- adjuvant ribociclib trials. 8684. 6. Xiang Z, Luo H, Payton JE, et al. Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia. J Clin Invest. 2010;120(6):2109-2118. 7. Thomas D, Powell JA, Vergez F, et al. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013;122(5):738-748. 8. Yoshimoto G, Miyamoto T, Jabbarzadeh-Tabrizi S, et al. FLT3-ITD “Progress in any fi eld, including breast up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD–specific STAT5 activation. Blood. 2009;114(24):5034-5043. 9. Butterworth M, Pettitt A, Varadarajan S, Cohen GM. BH3 cancer, is a process of who builds on profiling and a toolkit of BH3-mimetic drugs predict anti-apoptotic dependence of cancer cells. Br J Cancer. 2016;114(6):638-641. 10. Morales F, Giordano A. Overview of CDK9 as a target in cancer research. Cell Cycle. 2016;15(4):519-527. 11. Gores GJ, Kaufmann SH. Selectively targeting Mcl-1 for the treatment of acute myelogenous leukemia and solid tumors. Genes Dev. 2012;26(4):305-311. what and how to take advantage of ex- Tolero Pharmaceuticals is a registered trademark of Sumitomo Dainippon Pharma Co., Ltd. ©2018 Boston Biomedical, Inc. All rights reserved. PM-NPS-0009 4/2018 isting knowledge, whether positive or negative, and move forward,” Dr. Horto- bagyi said. –Alice McCarthy am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 9 C

Medical Center, in Manila, and a 2014 Oncologists in the Philippines Determined recipient of ASCO’s International Devel- opment and Education Award in Pallia- tive Care (IDEA-PC), said. “But then in to Make Palliative Care the Norm government hospitals, cancer care is less developed due to a lack of government s one of the world’s largest ar- funding.” chipelago nations—comprising The comprehensive care offered at pri- more than 7,100 individual is- vate hospitals comes at a much higher lands—the Philippines is dispa- expense than the care offered at govern- Arate by nature. Among its population ment hospitals. Coupled with the fact of 100.9 million people, demographics, that there are 98,200 new cases of cancer economic standing, and living condi- diagnosed in the Philippines each year, tions vary considerably. Although the this expense results in a signifi cant fi - country’s rich natural resources and en- nancial burden nationwide.3 vironmental assets secured a 6.6% eco- “Here in the Philippines, families nomic growth rate in 2012, 26.5% of the and loved ones often pay for treatment population still lives below the poverty themselves,” said Maria Diana Aileen line, and with a gross national income Bautista, MD, a medical oncologist at per capita of $3,580 in 2016, the Phil- the University of Santo Tomas Hospi- ippines is classifi ed as a low- to middle- system—and, accordingly, its cancer care. comprehensive cancer hospitals in the tal, in Manila, and a 2017 International income nation.1,2 “In the private hospitals—which are United States and other high-resource Development and Education Award Nowhere is this disparity so clearly re- mostly concentrated in major cities— settings,” Marie Belle Francia, MD, (IDEA) recipient. fl ected as in the Philippines’ health care the level of cancer care is on par with MSc, a medical oncologist at St. Luke’s See Oncologists in the Philippines, Page 20C

First Antibody-Drug Conjugate HR for death from any cause 0.68, 95% more than 100 patients with T-DM1 out- Dr. Weiner noted that, during his dis- Continued from page 8C CI [0.55, 0.85]; p < 0.001).2 side the clinical trial setting, and the re- cussion of the abstract, he “ruminated T-DM1 was well tolerated in the study, sults mirror what the investigators saw about the possibility that T-DM1 might The Lancet Oncology.4 That publication with no unexpected safety signals. during the EMILIA trial. “The toxicities be acting, at least in part, by stimulating confi rmed that T-DM1 “improved OS in Thrombocytopenia and increased se- are things that patients don’t even know host immune responses.” Subsequent patients with previously treated HER2- rum aminotransferase levels were more about, unlike traditional chemother- to that Plenary discussion, “it’s become positive metastatic breast cancer even common in those receiving T-DM1, but apy where they get diarrhea, lose their quite clear that checkpoint-focused anti- in the presence of crossover treatment.” diarrhea, nausea, vomiting, and palmar- hair, and throw up,” Dr. Blackwell said. bodies have a very powerful role to play The safety profi le was similar to that plantar erythrodysesthesia were higher “These toxicities are lab fi ndings.” in the treatment of human cancers,” seen in previous reports. with lapatinib plus capecitabine.1 he said. “I’ve been gratifi ed to hear of a The authors concluded that T-DM1 The Legacy number of different strategies to explore Recapping the Trial conferred a signifi cant and clinically Several antibody-drug conjugates are the induction of host immunity by im- EMILIA was a meaningful improvement in PFS com- now available for the treatment of he- munoconjugates. I think it’s too soon to phase III clini- pared with lapatinib plus capecitabine, matologic malignancies, but T-DM1 re- know if these studies will turn out to be cal trial com- and that the drug was an active and mains the only such agent approved for as potentially transformational as the paring T-DM1 well-tolerated novel therapy for HER2- treatment of solid tumors.5 That status development of an effective immuno- with the che- positive breast cancer.1 may not last long, however. Blackwell conjugate was, but I think they point to motherapy noted that two antibody-drug conjugates a direction for future investigation that regimen of Changing Mindset in advanced stages of development for appears to be extremely promising.” lapatinib plus Dr. Blackwell said she sees the fi ndings TDM1-refractory breast cancer have been –Tim Donald, ELS capecitabine in of the EMILIA trial as a pivotal point in granted accelerated approval status by patients with her career. the FDA. “They both have a trastuzumab- References: HER2-positive “The reason EMILIA was accepted as a antibody component, but different cyto- 1. Blackwell K, et al. J Clin Oncol. 2012;30 Dr. Kimberly L. locally ad- Plenary abstract, in my opinion, was not toxins,” she said. “This lays the ground- (suppl; abstr LBA1). Blackwell vanced or met- so much the trial itself, but the demon- work for other very promising drugs.” 2. Verma S, et al. N Engl J Med. astatic breast stration of the power of antibody-drug One of these compounds, DS-8201, is a 2012;367:1783-91. cancer previ- conjugates and, for that matter, of target- humanized HER2 antibody attached to a 3. Cancer Network. FDA Approves T-DM1 ously treated ed drug delivery,” she said. “It was a dem- novel topoisomerase I inhibitor payload (Kadcyla) for HER2-Positive Breast Cancer. with trastuzum- onstration that we had reached a point in by a tetrapeptide linker. It was granted cancernetwork.com/her2-positive-breast- ab and a taxane. oncology where we were no longer going accelerated review based on prelimi- cancer/fda-approves-t-dm1-kadcyla-her2- Lapatinib plus to accept giving nontargeted poisons for nary clinical evidence of potential clini- positive-breast-cancer. Published February capecitabine the treatment of patients facing cancer. cal benefi t for the treatment of patients 23, 2013. Accessed March 8, 2018. was, at that “Look what doors have opened since with HER2-positive locally advanced or 4. Diéras V, et al. Lancet Oncol. 2017;18:732- time, the only then,” Dr. Blackwell continued. “Now metastatic breast cancer who have been 42. approved che- we have all these immuno-oncology treated with trastuzumab and pertuzum- 5. Miller ML, et al. Mol Cancer Ther. 2018:Feb motherapy Dr. Louis M. Weiner agents that represent a similar paradigm. ab and have disease progression after 13 [Epub ahead of print]. combination I think it was that moment in 2012 when T-DM1, according to the manufacturer.6 6. Daiichi-Sankyo. FDA grants breakthrough for trastuzumab-refractory HER2-posi- people realized that this might actually The other, [vic-]trastuzumab duocarma- therapy designation to Daiichi Sankyo’s tive metastatic breast cancer.1 happen during our lifetimes.” zine (SYD985), received the Fast Track DS-8201 for HER2-positive metastatic Patients in the trial were random- She spoke about the investigators’ designation based on promising data breast cancer. daiichisankyo.com/media_ ly assigned to receive lapatinib plus misgivings during the trial—wondering from heavily pretreated patients with investors/media_relations/press_releases/ capecitabine or T-DM1. The primary whether the drug was working because HER2-positive metastatic breast cancer detail/006699.html. Published August 30, endpoints were PFS, OS, and safety. In patients were not exhibiting toxicities. in a phase I clinical trial.7,8 2017. Accessed March 7, 2018. 991 patients, there was a signifi cant im- “We were giving these patients drugs In addition to these, multiple other 7. Synthon. Synthon’s [vic-]trastuzumab provement in PFS favoring T-DM1 (me- every 3 weeks, and they weren’t getting antibody-drug conjugates are in devel- duocarmazine (SYD985) granted FDA Fast dian 9.6 vs. 6.4 months; HR for death sick,” Dr. Blackwell said. “Our mind- opment. It has been only 6 years since Track designation for pre-treated HER2- from any cause 0.65, 95% CI [0.55, set up to that point was, if the patient the presentation of the EMILIA Plenary positive metastatic breast cancer. synthon. 0.77]; p < 0.001).2 doesn’t have some toxicity, maybe it abstract demonstrated the promise of com/press-releases/synthons-vic- At the time of the Plenary Session, wasn’t working. Looking at the practice this type of drug targeting system. As trastuzumab-duocarmazine-granted- the median OS for T-DM1 had not been of oncology today, I think EMILIA al- Dr. Weiner pointed out, 6 years “would fda-fast-track-designation-pre-treated- reached.1 When the study results were lowed us to say that there can be drugs be an awfully quick turnaround to a use- her2-positive-metastatic-breast-cancer. published later in 2012, the authors re- that work but that don’t cause harm to ful drug if one was only getting started” Published January 25, 2018. Accessed ported that median OS crossed the stop- patients. That was the practice-changing at the time of the abstract presentation, March 8, 2018. ping boundary for effi cacy at the second component of EMILIA.” based on the promising results demon- 8. Aftimos PG, et al. San Antonio Breast interim analysis (30.9 vs. 25.1 months; Dr. Blackwell said she has now treated strated by T-DM1 in EMILIA. Cancer Symposium. 2016 (abstr P6-12-02). Investigating multiple mechanisms of immune escape in cancer

Genentech is exploring new possibilities by researching pathway combinations with PD-L1

PD-L1=programmed death-ligand 1. Reference: US National Institutes of Health. ClinicalTrials.gov. https://www.clinicaltrials.gov. Accessed January 28, 2018. C 12 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

reporting. The ability of patients to use Patient-Reported Outcomes in Oncology Practices computerized PRO systems varies widely, and introductory material and hands-on tution. Findings from focus groups, in- include PROs, to Basch and Snyder’s training should be available. Patients, or EXPERT dividual interviews, and cognitive and commentary on how to tackle PRO in- those assisting patients—whether family usability testing all suggest common tegration in clinical practice and elec- members or staff—need to be supported EDITORIAL desired features for PRO systems: track- tronic medical records (EMRs).18,19 The when using PRO tools. ing symptoms on custom calendars International Society for Quality of Life Limited options for PRO reporting Donna L. Berry, RN, PhD, and that incorporate medications (both Research produced the “User’s Guide to increases patient effort, complicates William B. Lober, MD, MS self- and clinic-administered) and Implementing Patient-Reported Out- scheduling, and decreases engagement. tracked laboratory values; information comes Assessment in Clinical Practice,” Although clinic-based reporting may vidence from multiple positive tri- regarding how to manage symptoms at including practical steps for planning seem easier to support than home use, als, support from literature reviews home; and timely electronic commu- PRO assessments.20 Subsequently, the patients may need to arrive earlier for and editorials, and the endorse- nication between patients, caregivers, Patient-Centered Outcomes Research appointments or schedule the use of ments of professional societies and and clinicians. Perhaps most impor- Institute developed the “Users’ Guide to limited tablets or kiosks. PROs should be Efunding agencies all promote the use tantly, patients and caregivers want to Integrating Patient-Reported Outcomes offered to the patient on their own com- of patient-reported outcomes (PROs) in know when and who to call for help, in Electronic Health Records.”21 ASCO puter or device, meeting them in the clinical cancer care. And yet, relatively for which symptom, and what to ex- and the Oncology Nursing Society have times and places most convenient. Some few cancer care settings have imple- pect in terms of a response. also featured columns highlighting the will need device access or additional sup- mented consistent methods of PRO as- importance of clinically integrated PRO port, and in-clinic access should also be sessment and integrated interventions. Evidence systems.22,23 Subsequent to the Beau available. In one clinic with both home What are the reasons for the lack of Various strategies to enhance patient- Biden Cancer Moonshot Initiative, the and clinic access, unpublished data widespread adoption? In other words, clinician communication have been National Cancer Institute released a show half of patients with chronic pain why is this easier said than done? The studied. Trials in the United States, UM1 opportunity for funding (RFA- will complete their PROs on their own pros and cons of a comprehensive PRO Canada, Australia, and Northern Europe CA-17-042) to test PRO implementation device, before return visits, and half re- supportive program are complex, and have shown symptom management and and use. quire clinic devices and/or support. PRO solutions to address the barriers are quality-of-life clinical screening to be systems should be available to the pa- largely unkno wn. feasible and clinically benefi cial with Barriers and Recommendations tient in both settings. regard to communication and, most Many of the barriers to effective PRO Diverse health, computer, and reading Why PROs? importantly, patient outcomes. Several implementation and use relate either to literacy present challenges for those who Communication large trial interventions included sub- value perceived by specifi c stakeholders need support. For savvy computer users, Patient-clinician communication is stantial in-person contact by research (patients, clinic staff, clinicians, health simplistic navigation may be frustrating, required for adequate symptom manage- personnel, limiting applicability to care organizations, etc.) or to the in- arguing for a customized interface based ment. Assessment and monitoring of an many clinical settings.8-11 In more au- tegration of PROs with existing work- on previous technology use. PROs should individual’s health status and delivery tomated trial interventions, evidence fl ows. For instance, low PRO response be designed to ensure that patients are of cutting-edge interventions require suggests clinicians can readily use PRO by patients may result from their belief engaged at an appropriate literacy level engagement of patients and direct care summaries in practice to signifi cantly that the data aren’t used in clinical care and in the language most appropriate to clinicians, as well as technology experts, enhance communication and improve or from inadequate support for PRO them. We use a fourth-grade reading lev- innovators, and support staff. However, patient experience.8,12-14 Howell et al completion. el for survey items and responses, with our current health system is character- conducted a scoping review of the use, Technical capabilities of PRO systems medical terms at a higher reading level ized by limited face-to-face patient-cli- impact on health outcomes, and imple- may substantially impact barriers. For accompanied by defi nitions. Computer nician contact. Time constraints during mentation factors related to PRO use instance, access to a standalone com- adaptive surveys offer the opportunity clinic visits and patients’ hesitancy to in practice, concluding that PRO use puterized PRO system may require the for personalization to support those pa- verbally report certain symptoms can re- is likely acceptable to patients, enables administration of patient usernames tients with higher literacy levels and is sult in missed or under-communicated, earlier assessment and identifi cation of and passwords. Using PRO tools within an area that should be explored. but signifi cant, symptoms.1,2 Unreported symptoms, and may improve patient- patient portals lessens those barriers, No access to data may decrease the adverse outcomes may have even led to clinician communication.15 Basch and but low adoption of an organization’s value perceived by patients. Patients chemotherapy overdose.3 Medical on- colleagues established that PROs extend patient portal or underdeveloped or value longitudinal summaries of their cologists value patient-reported toxici- life in patients with advanced disease.16 infl exible questionnaire software cre- PRO data, which they can use for shared ties for planning safe and effective doses Given the longer survival, coupled with ates new problems. Emerging technolo- symptom management strategies during of chemotherapy, notably self-adminis- the effi cacy of other systems to reduce gies address these problems by allow- a clinical visit and view outside the visit tered oral agents.4 symptom distress and depression during ing tighter, more seamless integration as a reminder of progress or associations treatment in patients of all stages of can- of PRO apps into EMR software, using with treatment days and peak symp- What patients want cer, there is no question that PRO collec- the same standards and strategies across tomatology.7 The potential value of PRO Qualitative work has described pa- tion and intervention is benefi cial.17 multiple vendors.24,25 data as a “health diary” should be inves- tients’ and caregivers’ experiences with Barriers and recommendations below tigated further. cancer symptoms, reporting, and man- Professional opinions and funding are organized by the primary stakehold- High patient burden from frequent or agement.5-7 Study participants identi- Thought leaders and investigators ers they impact. We have referenced long assessments can occur when PROs fi ed their own methods of tracking have called for the implementation of evidence where we are aware of it; ad- satisfy research interests in longitudinal symptoms, as they lacked the proper PROs, ranging from Bruner’s 2007 sug- ditional discussion is based on our ex- outcomes data or regulatory require- tools from the cancer treatment insti- gestion that every cancer clinical trial perience with approximately 40 PRO ments for the health care organization. implementations in research and usual PRO assessments may encompass the care settings, cancer, HIV/AIDS, chronic union of all stakeholder requirements, pain, orthopedics, general surgery, and resulting in long assessments that pa- primary care/behavioral health integra- tients perceive as tangential to their ARTICLE HIGHLIGHTS tion. care and burdensome. PRO assessments should be relevant to the patient’s care ■ Assessment and monitoring of an individual’s health status and delivery of The patient and easily perceived as such. cutting-edge interventions require engagement of patients, direct care clini- The lack of consistent endorsement cians, technology experts, innovators, and support staff. by clinicians or clinic staff undermines The clinician patients’ perceptions of PRO value. En- Information overload may be con- ■ Thought leaders and investigators have called for the implementation of patient-reported outcomes (PROs), ranging from suggestions that every cancer dorsement by the physician and report- cerning to clinicians who are faced with ing reminders were shown to be the two a new route for unmoderated feedback clinical trial include PROs, to commentary on how to tackle PRO integration in 27 clinical practice. factors most associated with high PRO from patients. This can take several response rates in one study.26 Clinicians forms: increased patient access to clini- ■ PRO data should support clinical decision-making and be presented to empha- should ensure patients know that PRO cians, poorly summarized data, and data size longitudinal changes. data supports their care and remind pa- that are not clinically actionable. PRO ■ PROs are desired by patients, enable clinicians to effi ciently address the tients to report their experiences and data should support clinical decision- whole patient, and impact clinical outcomes and patients’ experience of outcomes. making and be presented to emphasize disease. Inadequate support for using PRO tools longitudinal changes. may limit patients’ abilities to complete See Patient-Reported Outcomes, Page 24C Visit us at Booth #7036

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Medical Marijuana reapplication for use. The median age A separate meta-analysis by Andreae About the Authors Continued from page 3C was 51 years, and patients reported a et al studied inhaled cannabis specifi - 64% average relative decrease in pain cally, pooling data from fi ve randomized signal its receptivity to further, nonsyn- (7.8 out of 10 at baseline, 2.8 post- controlled trials in chronic neuropathic thetic cannabis derivatives. treatment). Additional reported benefi ts pain.41 Using a hierarchical Bayesian Mr. Durand is a included reduction in stress and insom- model, they aggregated data from trials medical student at Toxicity and adverse reactions nia, and the vast majority of patients with differing designs and outcomes. Brown University. Medical cannabis exhibits a very favor- (71%) reported no adverse reactions. The results indicated a statistically sig- able toxicity profi le. The lethal dose of Reinarman et al reviewed data from nifi cant benefi t of inhaled cannabis in THC has been estimated to be far greater 1,746 consecutive admissions to a net- the reduction of chronic neuropathic than amounts consumed in either medi- work of California medical cannabis as- pain, with a number-needed-to-treat of Dr. Rizack is a cal or recreational use.3,23-25 The same is sessment clinics from July to September 5.6 (95% CI [3.4,14]). Nevertheless, the medical oncologist 35 at South County true for synthetic cannabinoids; mon- of 2006. A relative underrepresenta- authors caution that further long-term Hospital and a keys administered nabilone at 2 mg/kg/ tion of Latino patients was also observed studies are required to evaluate the long- clinical assistant day experienced no signifi cant adverse (14% of the cohort, compared to 32% term effi cacy and safety profi le of in- professor of medi- effects.26 in California overall as of 2000 Census haled medical marijuana. cine of obstetrics Nevertheless, cannabis use is associ- data). The authors hypothesized that this Cannabinoids are known to enhance and gynecology at the Alpert Medical ated with a variety of side effects. In the may be due to the “undocumented sta- the potency of opioids, and when used School of Brown acute phase, these may include eupho- tus of many Latinos in California.” The synergistically they can allow for re- University. ria, altered judgment, paranoia, amnesia, majority of patients reported that medi- duced doses of opioids and better pain diffi culty concentrating, hallucinations, cal marijuana relieved pain (83%) and control. When used alone, cannabinoids panic attacks, sedation, unsteadiness, improved sleep (71%). Many patients re- have shown effi cacy in neuropathic pain nabilone as compared to both placebo dizziness, dry mucous membranes, and ported substituting marijuana for anoth- but appear to be less effective when used and amitriptyline.13,32 A more recent trial headache.27-29 There is also substantial ever prescription medication (51%) or al- alone for other types of pain. The 2017 by Carley et al compared dronabinol to idence of an association between chronic cohol (13%). Importantly, most patients National Academies of Sciences, Engineer- placebo in the treatment of moderate-to- cannabis use and the development of reported using medical cannabis daily ing, and Medicine report concluded that severe obstructive sleep apnea.44 Treat- schizophrenia in a dose-dependent man- (67%), and the vast majority reported adults with chronic pain treated with ment with dronabinol (10 mg/day) was ner.30 Evidence of a link between mari- administration via smoke inhalation at cannabis or cannabinoids are more like- associated with signifi cantly improved juana use and other mental health dis- least some of the time (86%). ly to experience a clinically signifi cant apnea/hypopnea index and Epworth orders exists, but is less understood.13 reduction in pain symptoms, adding Sleepiness Scale as compared to placebo. Although many cannabinoids are used in Physician opinions that the effect is modest.13 Additional studies suggest that these treatment of nausea and vomiting, select The legalization and use of cannabis results may be generalizable to improved patients may experience cannabinoid for medical purposes is an evolving is- Chemotherapy-induced nausea sleep among patients without sleep dis- hyperemesis syndrome, characterized sue, and physician perspectives are likely and vomiting (CINV) orders. Whiting et al analyzed 19 chronic by persistent nausea, vomiting, and ab- evolving in tandem. A 2005 study by A large number of studies have as- pain and multiple sclerosis trials that in- dominal pain, and frequent hot bathing Charuvastra et al found that 36% of a na- sessed the effi cacy of cannabinoids in the cluded sleep-related outcomes.32 In total, to relieve symptoms.31-33 tional sample of physicians believed that treatment of CINV. Whiting et al’s recent patients treated with cannabinoids (in- The risk of substance dependence may medically prescribed marijuana should meta-analysis analyzed 28 studies with cluding nabiximols, nabilone, dronabi- also be considered a potential side ef- be legal.39 In 2013, Adler et al published 1,772 total patients, ultimately fi nd- nol, THC/CBD capsules, and smoked fect of medical cannabis use. The risk of results from a poll of New England Journal ing that patients receiving dronabinol THC) exhibited superior sleep quality as addiction among those experimenting of Medicine readers; in total, 76% of re- or nabiximols had signifi cantly greater compared to placebo. with marijuana has been cited as 9%, spondents favored use of medical canna- odds of exhibiting a complete nausea and although the vast majority of medi- bis.40 Among U.S. respondents, however, and vomiting response, as compared to Anticancer agent cal cannabis patients may use marijuana the results differed strongly by state. For placebo (OR 3.82, 95% CI [1.55, 9.42]). A At present, there is limited but evolv- daily, this statistic may be less relevant example, whereas 96% (103 of 107) re- recent Cochrane review similarly found ing support for the use of cannabinoids to these patients.29,34,35 Coffey et al’s spondents from Pennsylvania had favor- substantial evidence supporting effi cacy as anticancer therapies; the largest ev- 2002 study of Australian young adults able views of medical marijuana, only of cannabinoids over placebo in CINV idence-base exists in gliomas. A wide observed DSM-IV cannabis dependence about 1% of those from Utah (1 of 76) (complete absence of nausea and vomit- range of preclinical in vivo and in vitro rates of 53% among those using can- responded favorably. Notably, neither ing RR 2.9, 95% CI [1.8, 4.7]).42 studies have observed that cannabinoids nabis “weekly or more often”; the pro- Pennsylvania nor Utah had legalized A 2001 meta-analysis by Tramèr et exhibit substantial antitumoral activity portion increased to 72% among those marijuana for medical use at the time al found that cannabinoids (including through a wide range of mechanisms, in- using cannabis “almost daily.”36 The of this survey.12 If accurate, these results nabilone, dronabinol, and levonantra- cluding necrosis, apoptosis, cytotoxicity, most common dependence symptoms suggest that federal-level efforts to legis- dol) were more effective as fi rst-line anti- antiproliferation, and oxidative stress- included persistent desire, unintentional late medical marijuana use will need to emetics as compared to prochlorperazine, induced cellular damage.45 At present, use, and withdrawal. Further research on reconcile diverse regional perspectives. metoclopramide, chlorpromazine, thieth- clinical evidence is limited to a single the long-term safety profi le of medical ylperazine, haloperidol, domperidone, or phase I trial conducted on surgery- and cannabis use is warranted; such stud- Therapeutic Uses alizapride (complete control of nausea and radiotherapy-refractory glioblastoma ies should ideally be conducted among Chronic pain vomiting RR 1.38, 95% CI [1.18, 1.62]).43 multiforme patients; Guzman et al ad- both patients with intended long-term There is a large body of evidence sup- These effects, however, were not observed ministered intracranial THC to nine pa- versus limited-term use (e.g., chronic porting the effi cacy of cannabinoids in among patients receiving chemotherapy tients, observing minimal adverse ef- pain vs. CINV, respectively). the treatment of chronic pain. In 2015, with very low or very high emetogenic fects.46 A reduction in tumor growth was Whiting et al published a meta-analysis potential. Further, evidence from cross- observed in two patients. Medical Cannabis: Patients and Providers of trials evaluating cannabinoids for a over trials suggested that patients strongly Who is using medical cannabis? wide range of indications; chronic pain preferred cannabinoids. However, Smith Conclusions Several surveys have sought to under- and CINV were among those with the et al’s recent Cochrane review found dif- Medical cannabis is an evolving and stand demographics among patients us- greatest number of included studies.32 ferently; although they observed a trend potentially divisive issue. A growing ing medical cannabis. In 2006, Reiman Studied cannabinoid modalities includ- toward superior effi cacy of cannabinoids proportion of state legislatures have et al surveyed 130 patients from medical ed nabiximols, smoked and vaporized over prochlorperazine, the results were voted in favor of medical marijuana marijuana facilities in the San Francisco THC, nabilone, THC oromucosal spray, not statistically signifi cant.42 Additionally, use, although tension between state and Bay Area.37 They observed a mean age of dronabinol, and oral THC capsules, and the authors noted the lack of studies com- federal laws persists. Cannabis is associ-

40 years and male predominance (74%) almost all studies used a placebo comparing cannabinoids to 5-HT3 antagonists ated with a number of potential adverse among their sample. Medi-Cal (38%) was parator. Diagnoses included neuropathic and NK-1 inhibitors, indicating the need reactions and risk of dependence; ad- the most represented insurance type, fol- pain, cancer pain, and diabetic periph- for additional studies of cannabinoid ef- dressing these issues may be crucial for lowed by no insurance (24%), and 59% eral neuropathy, among others. In aggre- fi cacy against modern antiemetic agents. those seeking broader cannabinoid uti- of those surveyed indicated an annual gate, cannabinoids exhibited superior re- lization. Nevertheless, medical cannabis income of less than $20,000. duction in pain as compared to placebo. Sleep disorders has demonstrated effi cacy as a treatment A 2014 study by Webb et al surveyed Although no differences were observed Whiting et al’s meta-analysis identifi ed for a wide range of conditions, including 100 patients in Hawaii, 97% of whom between diagnosis types or cannabinoid two large-scale randomized controlled chronic pain, CINV, and sleep disorders. were prescribed cannabis for chronic modalities, the ability to adequately trials studying cannabinoids in sleep dis- It may also have potential as an antican- pain.38 All patients had been certifi ed for detect differences may have been ham- orders specifi cally, reporting signifi cant cer agent, although the evidence for this 1 year or less and were surveyed upon pered by limited statistical power. improvement in the sleep quality with See Medical Marijuana, Page 22C am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 15 C Examining Smoking Cessation in Current Practice

patients to stop using tobacco (84%). is crucial, but we cannot be the only to- However, only 44% routinely discuss bacco cessation resource for the patient. EXPERT medication options with patients, and Just as we involve respiratory therapists, ASCO Daily News The Offi cial Newspaper of the only 39% provide cessation support.2 physical therapists, and other medical EDITORIAL 2018 ASCO Annual Meeting As this is self-reported data of survey re- specialists in a multidisciplinary fashion, Vol. 21, No. 3 Carolyn M. Dresler, MD, MPA, and spondents, the actual, real-world imple- we need to recognize that tobacco cessa- Sunday, June 3 Matthew A. Steliga, MD mentation is likely even less. We must tion is an area with specialized resources be better at identifying persistent tobac- and experts who can help our patients, ASCO Daily News, the offi cial newspaper of the 2018 ASCO Annual Meeting, is published by hen we were asked to write co users when they come to us for treat- and we need to integrate these resources the American Society of Clinical Oncology as a an Expert Editorial about ment and at intervening to help them into patient care. service to all who attend. smoking cessation in pa- stop tobacco use. The National Cancer Institute (NCI) American Society of Clinical Oncology tients with cancer, our fi rst launched the Cancer Center Cessation 2017–2018 Offi cers Wthought was, isn’t this topic settled and Addressing Addiction Initiative as part of the NCI Cancer Bruce E. Johnson, MD, FASCO already well understood? But, then, that Tobacco use, particularly by inhalation Moonshot program to help cancer cen- President is what our “expert” thinking is—versus of combusted tobacco, is the most dead- ters build and implement sustainable Monica M. Bertagnolli, MD, FACS, FASCO what actually exists in the fi eld. There ly—and, the most addictive—drug we tobacco cessation programs to target President-Elect are a few interesting updates in the are- have in our societies. Big tobacco en- patients with cancer.7 Twenty-two lead- Daniel F. Hayes, MD, FACP, FASCO na for smoking cessation, but let’s fi rst gages in massive marketing campaigns ing cancer centers received funding, and Immediate Past President make sure that everyone is on the same targeting youth to initiate and become this initiative demonstrates NCI’s under- Craig R. Nichols, MD page. addicted.3,4 It is not a “choice” to be ad- standing of the necessity for this type of Treasurer First, we all know that using tobacco dicted. Many people who use tobacco program in cancer treatment. Perhaps ASCO Meeting and Member causes many cancers, as well as other want to quit, and have probably tried there will be more funding for expanded Publications Editorial Board diseases, and that there is no safe use at least several times. It is terrifi cally dif- programs at non–NCI-designated cancer Susana Campos, MD, MPH George Demetri, MD, FASCO of tobacco products. Second, as on- fi cult to quit, so there should never be centers in the future. Steven Finkelstein, MD cologists, we should all know that con- “blame” or “shame” to anyone who uses If your cancer center or clinic partici- Sabha Ganai, MD, PhD tinued smoking after cancer diagnosis or is addicted to tobacco. No one “de- pates in a lung cancer screening pro- Timothy Gilligan, MD, MSc, FASCO signifi cantly affects cancer treatment serves” to get cancer. gram, does it already have a smoking Roy Herbst, MD, PhD, FACP outcomes and survival. In the 2014 Sur- Thus, when implementing a tobacco cessation program within it? It should. Stephen Leong, MD Gregory Masters, MD, FACP, FASCO geon General Report, the evidence base cessation program in your practice, be Is there a way to access that tobacco ces- Bruno Medeiros, MD was assessed regarding continued tobac- very sensitive to this blame or shame sation program? (We assume that if you Travis Osterman, DO co use by people with cancer, with the that our patients might feel when ad- have a lung cancer screening program, Caroline Robert, MD, PhD following key outcomes in patients with dressing their need for cessation. We you also address smoking cessation.) We Hope Rugo, MD, FASCO 1 cancer and survivors: need to make it very clear that the rea- believe that cancer centers or large clini- ASCO Daily News 1. The evidence is suffi cient to infer a son for addressing cessation is because it cal oncology clinics should design and John Sweetenham, MD, FACP, FRCP, FASCO causal relationship between cigarette really matters for their health and treat- implement their own program that com- Editor in Chief smoking and adverse health out- ment outcome. We choose the best treat- prehensively addresses tobacco cessation Nicholas J. Petrelli, MD, FACS comes. Quitting smoking improves ment protocol or regimen with the least and integrates cessation into the clinical Associate Editor the prognosis of patients with cancer. side effects while maximizing the out- care of all patients. The National Com- David Sampson 2. The evidence is suffi cient to infer a come and survival, and tobacco cessa- prehensive Cancer Network (NCCN) has Publisher causal relationship between cigarette tion is a critical piece of this effort. Also, published one example of smoking ces- Faith A. Hayden smoking and increased all-cause and quitting tobacco is a process. Tobacco sation guidelines in cancer care,8 and the Managing Editor cancer-specifi c mortality. addiction is a chronic disease, and any most recent updates are always available Renee Simpson 3. The evidence is suffi cient to infer blame goes to the tobacco industry that at NCCN.org. Associate Managing Editor a causal relationship between ciga- promulgates these products without any Content Staff rette smoking and increased risk for shame on their part. Telephone-Based Resources Jennifer Giblin A. Kate MacDougall second primary cancers known to be For practices without tobacco cessa- Amy Hindman Lindsay Pickell caused by cigarette smoking, such as Program Implementation tion programs, there are outside avail- Andrea Primeau, PhD lung cancer. To implement a program that address- able resources, often at low cost or free Nicole Van Hoey, PharmD 4. The evidence is suggestive but not es tobacco use and cessation, visit ASCO’s to patients. Many oncologists are un- Contributing Writers suffi cient to infer a causal relation- webpage on Tobacco Cessation Tools aware of tobacco cessation programs Michelle Dalton, ELS Emily Kuhl, PhD ship between cigarette smoking and and Resources, which lays out the data that all U.S. states have in the form of Tim Donald, ELS Leah Lawrence the risk of recurrence, poorer re- and process.5 Look for resources that can telephone-based quitlines. These quit- Marilyn Fenichel David Levitan sponse to treatment, and increased help you implement such a program in lines provide evidence-based strategies Debra Gordon Alice McCarthy Kathy Holliman, MEd Kara Nyberg, PhD treatment-related toxicity. your setting. We found from surveys that including free telephone counseling Caroline Hopkins Carina Storrs most oncologists are not trained and/or and often free or reduced-cost nicotine Melinda Tanzola, PhD Third, oncologists need to do better do not feel comfortable or competent in replacement therapy to support quit Jasenka Piljac Žegarac, PhD 2,6 at addressing tobacco cessation. In an addressing tobacco cessation. Tobacco attempts. Quitlines are cost-effective Design ASCO membership survey several years cessation is an integral part of a patient’s programs and typically have acceptable Kelli Schmidt, KSchmidt Designs, LLC ago, respondents indicated that at ini- treatment, and there are experts who are cessation rates. However, they are fund- Production tial visit, most physicians routinely knowledgeable and trained in this prac- ed by state departments of health with Donna Dottellis and Julie Blum ask patients about tobacco use (90%), tice. As physicians, we are dedicated and assistance from the Centers for Disease ask patients to quit (80%), and advise caring, and our message to the patient Control and Prevention. These programs Advertising Representative may be in a challenging funding status, Joe Frank, National Sales Manager The Walchli Tauber Group, Inc. which impacts what a particular state 443-512-8899 Ext. 114 quitline can actually provide. The best [email protected] ARTICLE HIGHLIGHTS way to know what your state offers is to call your state department of health and Disclaimer: The information contained in ASCO Daily News is provided for educational purposes ■ When implementing a tobacco cessation program in your practice, be sensi- ask to speak with the person in their to- only. The ideas and opinions expressed, including in tive to the blame or shame that our patients might feel when addressing their bacco control program who works with the editorials, do not necessarily refl ect the views of the state quitline and who can share the American Society of Clinical Oncology (“ASCO”) need for cessation. or institutions affi liated with the author(s). The their tools to access and successfully ■ For practices without tobacco cessation programs, there are outside available reference to any product, service, or therapy in any use the quitline. Many quitlines accept article or advertisement does not, either expressly resources, often at a low cost or free to patients. referrals from physicians in the form of or by implication, indicate that the Society endorses the product, service, or therapy or its manufacturer ■ We likely have a few more years of assessment of intensive research on the fax or online referrals, and integration or distributor. ASCO specifi cally disclaims any and topic of electronic cigarettes. of quitline resources through electronic all responsibility for the contents, advertisements, health records should be explored. and any other material submitted to and contained ■ At each visit with your patient, discuss their tobacco use status just like you in ASCO Daily News. Other countries address tobacco check for adverse events or other symptoms. ©2018, American Society of Clinical Oncology See Smoking Cessation, Page 21C FDA approved for metastatic CRPC since 2012

Upon progression on GnRH therapy* in mCRPC1 In the US alone, 106,000 patients have been prescribed XTANDI—and counting†2

†Estimate based on US sales and use data from September 2012 to December 2017. Reference: Astellas. XTANDI. Data on File. Source: Symphony Health.2

Indication and Important Safety Information Indication Adverse Reactions XTANDI (enzalutamide) capsules is indicated for the The most common adverse reactions (≥ 10%) that occurred treatment of patients with metastatic castration-resistant more commonly (≥ 2% over placebo) in the XTANDI patients prostate cancer (CRPC). from the two placebo-controlled clinical trials were asthenia/ fatigue, back pain, decreased appetite, constipation, Important Safety Information arthralgia, diarrhea, hot fl ush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal Contraindications pain, weight decreased, headache, hypertension, and XTANDI is not indicated for women. XTANDI can cause fetal dizziness/vertigo. In the bicalutamide-controlled study of harm and potential loss of pregnancy. chemotherapy-naïve patients, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot fl ush, Warnings and Precautions hypertension, nausea, constipation, upper respiratory tract Seizure occurred in 0.5% of patients receiving XTANDI infection, diarrhea, and weight loss. in clinical studies. In a study of patients with predisposing In the placebo-controlled study of patients taking XTANDI factors, seizures were reported in 2.2% of patients. See who previously received docetaxel, Grade 3 and higher section 5.1 of the Prescribing Information for the list of adverse reactions were reported among 47% of XTANDI predisposing factors. It is unknown whether anti-epileptic patients and 53% of placebo patients. Discontinuations medications will prevent seizures with XTANDI. Permanently due to adverse events were reported for 16% of XTANDI discontinue XTANDI in patients who develop a seizure patients and 18% of placebo patients. In the placebo- during treatment. controlled study of chemotherapy-naïve patients, Grade 3-4 Posterior Reversible Encephalopathy Syndrome (PRES) adverse reactions were reported in 44% of XTANDI patients In post approval use, there have been reports of PRES and 37% of placebo patients. Discontinuations due to in patients receiving XTANDI. PRES is a neurological disorder adverse events were reported for 6% of both study groups. which can present with rapidly evolving symptoms including In the bicalutamide-controlled study of chemotherapy- seizure, headache, lethargy, confusion, blindness, and other naïve patients, Grade 3-4 adverse reactions were reported visual and neurological disturbances, with or without in 38.8% of XTANDI patients and 37.6% of bicalutamide associated hypertension. A diagnosis of PRES requires patients. Discontinuations due to adverse events were confi rmation by brain imaging, preferably MRI. Discontinue reported for 7.6% of XTANDI patients and 6.3% of XTANDI in patients who develop PRES. bicalutamide patients. Supported by 3 randomized, controlled trials

AFFIRM TRIAL PREVAIL TRIAL TERRAIN TRIAL

1199 patients with metastatic 1717 patients with metastatic 375 patients with metastatic CRPC who were previously on CRPC who were asymptomatic or CRPC who were asymptomatic or docetaxel therapy were randomized mildly symptomatic were randomized mildly symptomatic were randomized to XTANDI + GnRH therapy* to XTANDI + GnRH therapy* to XTANDI + GnRH therapy* (n = 800) or placebo (n = 872) or placebo (n = 184) or bicalutamide + GnRH therapy* (n = 399).1 + GnRH therapy* (n = 845).1,3 + GnRH therapy* (n = 191).1,4

GnRH therapy, gonadotropin-releasing hormone therapy; mCRPC, metastatic castration-resistant prostate cancer. *Or after bilateral orchiectomy.1

Visit XtandiHCP.com to learn more about XTANDI in metastatic CRPC patients

Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients Drug Interactions (1% Grade 3-4) and 6% of placebo patients (0.5% Grade Effect of Other Drugs on XTANDI Avoid strong CYP2C8 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI inhibitors, as they can increase the plasma exposure to XTANDI. patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% If co-administration is necessary, reduce the dose of XTANDI. Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% Avoid strong CYP3A4 inducers as they can decrease of XTANDI patients (0.2% Grade 3-4) and 16% of placebo the plasma exposure to XTANDI. If co-administration is patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin necessary, increase the dose of XTANDI. occurred in 3% of XTANDI patients (0.1% Grade 3-4) and Effect of XTANDI on Other Drugs 2% of placebo patients (no Grade 3-4). Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as Infections: In the study of patients taking XTANDI who previously XTANDI may decrease the plasma exposures of these drugs. If received docetaxel, 1% of XTANDI patients compared to 0.3% XTANDI is co-administered with warfarin (CYP2C9 substrate), of placebo patients died from infections or sepsis. In the study conduct additional INR monitoring. of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death. Please see adjacent pages for Brief Summary of Full Prescribing Information. Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebo- References: 1. XTANDI [package insert]. Northbrook, IL: Astellas, Inc. 2. 3. controlled trials. Falls were not associated with loss of Astellas. XTANDI. Data on File. Beer TM, Armstrong AJ, Rathkopf DE, et al; for the PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before consciousness or seizure. Fall-related injuries were more severe chemotherapy. N Engl J Med 2014;371(5):424-33. 4. Shore ND, Chowdhury S, in XTANDI patients, and included non-pathologic fractures, Villers A, et al. Efﬁ cacy and safety of enzalutamide versus bicalutamide for patients joint injuries, and hematomas. with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 Hypertension occurred in 11% of XTANDI patients and 4% study. Lancet Oncol 2016;17(2):153-63. of placebo patients in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

© 2018 Astellas Pharma US, Inc. and Pﬁ zer Inc. All rights reserved. Printed in USA. 076-3221-PM 3/18 XTANDI, Astellas, and the ﬂ ying star logo are registered trademarks of Astellas Pharma Inc. Study 1: XTANDI versus Placebo in Metastatic CRPC Study 2: XTANDI versus Placebo in Chemotherapy- Following Chemotherapy naïve Metastatic CRPC Study 1 enrolled 1199 patients with metastatic CRPC Study 2 enrolled 1717 patients with metastatic CRPC who who had previously received docetaxel. The median had not received prior cytotoxic chemotherapy, of whom duration of treatment was 8.3 months with XTANDI 1715 received at least one dose of study drug. The median

® and 3.0 months with placebo. During the trial, 48% of duration of treatment was 17.5 months with XTANDI and XTANDI (enzalutamide) capsules for oral use patients on the XTANDI arm and 46% of patients on the 4.6 months with placebo. Grade 3-4 adverse reactions Initial U.S. Approval: 2012 placebo arm received glucocorticoids. were reported in 44% of XTANDI-treated patients and BRIEF SUMMARY OF PRESCRIBING INFORMATION Grade 3 and higher adverse reactions were reported 37% of placebo-treated patients. Discontinuations due to The following is a brief summary. Please see the package among 47% of XTANDI-treated patients and 53% of adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The insert for full prescribing information. placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients most common adverse reaction leading to treatment INDICATIONS AND USAGE and 18% of placebo-treated patients. The most common discontinuation was fatigue/asthenia, which occurred in XTANDI is indicated for the treatment of patients with adverse reaction leading to treatment discontinuation was 1% of patients on each treatment arm. Table 2 includes metastatic castration-resistant prostate cancer (CRPC). seizure, which occurred in 0.9% of the XTANDI-treated adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to CONTRAINDICATIONS patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the placebo arm. Pregnancy Study 1 that occurred at a ≥ 2% higher frequency in the Table 2. Adverse Reactions in Study 2 XTANDI can cause fetal harm and potential loss of pregnancy. XTANDI arm compared to the placebo arm. XTANDI Placebo WARNINGS AND PRECAUTIONS Table 1. Adverse Reactions in Study 1 N = 871 N = 844 Seizure Grade Grade Grade Grade XTANDI Placebo a Seizure occurred in 0.5% of patients receiving XTANDI in N = 800 N = 399 1-4 3-4 1-4 3-4 clinical studies. In these trials patients with predisposing Grade Grade Grade Grade (%) (%) (%) (%) factors for seizure were generally excluded. Seizure 1-4a 3-4 1-4 3-4 General Disorders occurred from 31 to 603 days after initiation of XTANDI. (%) (%) (%) (%) Asthenic 46.9 3.4 33.0 2.8 Patients experiencing seizures were permanently General Disorders Conditionsb discontinued from therapy and all seizure events resolved. Peripheral Asthenic 50.6 9.0 44.4 9.3 11.5 0.2 8.2 0.4 In a single-arm trial designed to assess the risk of Conditionsb Edema seizure in patients with pre-disposing factors for seizure, Musculoskeletal And Connective Tissue Disorders Peripheral 15.4 1.0 13.3 0.8 8 of 366 (2.2%) XTANDI-treated patients experienced Edema Back Pain 28.6 2.5 22.4 3.0 a seizure. Three of the 8 patients experienced a second Musculoskeletal And Connective Tissue Disorders Arthralgia 21.4 1.6 16.1 1.1 seizure during continued treatment with XTANDI after Back Pain 26.4 5.3 24.3 4.0 their first seizure resolved. It is unknown whether Gastrointestinal Disorders anti-epileptic medications will prevent seizures with Arthralgia 20.5 2.5 17.3 1.8 Constipation 23.2 0.7 17.3 0.4 XTANDI. Patients in the study had one or more of the Musculoskeletal Diarrhea 16.8 0.3 14.3 0.4 Pain 15.0 1.3 11.5 0.3 following pre-disposing factors: the use of medications Vascular Disorders that may lower the seizure threshold (~ 54%), history Muscular 9.8 1.5 6.8 1.8 of traumatic brain or head injury (~ 28%), history of Weakness Hot Flush 18.0 0.1 7.8 0.0 cerebrovascular accident or transient ischemic attack Musculoskeletal Hypertension 14.2 7.2 4.1 2.3 Stiffness 2.6 0.3 0.3 0.0 (~ 24%), and Alzheimer’s disease, meningioma, or Nervous System Disorders leptomeningeal disease from prostate cancer, unexplained Gastrointestinal Disorders Dizzinessc 11.3 0.3 7.1 0.0 loss of consciousness within the last 12 months, past Diarrhea 21.8 1.1 17.5 0.3 history of seizure, presence of a space occupying lesion Vascular Disorders Headache 11.0 0.2 7.0 0.4 of the brain, history of arteriovenous malformation, or Hot Flush 20.3 0.0 10.3 0.0 Dysgeusia 7.6 0.1 3.7 0.0 history of brain infection (all < 5%). Approximately 17% Mental of patients had more than one risk factor. Hypertension 6.4 2.1 2.8 1.3 Impairment 5.7 0.0 1.3 0.1 d Advise patients of the risk of developing a seizure while Nervous System Disorders Disorders receiving XTANDI and of engaging in any activity where Headache 12.1 0.9 5.5 0.0 Restless Legs Syndrome 2.1 0.1 0.4 0.0 sudden loss of consciousness could cause serious harm Dizzinessc 9.5 0.5 7.5 0.5 to themselves or others. Spinal Cord Respiratory Disorders Permanently discontinue XTANDI in patients who develop Compression Dyspneae 11.0 0.6 8.5 0.6 a seizure during treatment. and Cauda 7.4 6.6 4.5 3.8 Infections And Infestations Posterior Reversible Encephalopathy Syndrome (PRES) Equina Syndrome Upper There have been reports of posterior reversible Respiratory 16.4 0.0 10.5 0.0 encephalopathy syndrome (PRES) in patients receiving Paresthesia 6.6 0.0 4.5 0.0 Tract Infectionf XTANDI. PRES is a neurological disorder which can present Mental Lower with rapidly evolving symptoms including seizure, Impairment 4.3 0.3 1.8 0.0 Respiratory Disordersd Tract And Lung 7.9 1.5 4.7 1.1 headache, lethargy, confusion, blindness, and other g visual and neurological disturbances, with or without Hypoesthesia 4.0 0.3 1.8 0.0 Infection associated hypertension. A diagnosis of PRES requires Infections And Infestations Psychiatric Disorders confirmation by brain imaging, preferably magnetic Upper Insomnia 8.2 0.1 5.7 0.0 resonance imaging (MRI). Discontinue XTANDI in Respiratory 10.9 0.0 6.5 0.3 Renal And Urinary Disorders patients who develop PRES. Tract Infectione Lower Hematuria 8.8 1.3 5.8 1.3 ADVERSE REACTIONS Injury, Poisoning And Procedural Complications Respiratory 8.5 2.4 4.8 1.3 Clinical Trial Experience Tract And Lung Fall 12.7 1.6 5.3 0.7 f Because clinical trials are conducted under widely varying Infection Non-Pathological conditions, adverse reaction rates observed in the clinical Psychiatric Disorders Fracture 8.8 2.1 3.0 1.1 trials of a drug cannot be directly compared to rates in the Insomnia 8.8 0.0 6.0 0.5 Metabolism and Nutrition Disorders clinical trials of another drug and may not reflect the rates observed in practice. Anxiety 6.5 0.3 4.0 0.0 Decreased Appetite 18.9 0.3 16.4 0.7 Three randomized clinical trials enrolled patients with Renal And Urinary Disorders Investigations metastatic prostate cancer that has progressed on Hematuria 6.9 1.8 4.5 1.0 androgen deprivation therapy (GnRH therapy or bilateral Weight Pollakiuria 4.8 0.0 2.5 0.0 Decreased 12.4 0.8 8.5 0.2 orchiectomy), a disease setting that is also defined as Injury, Poisoning And Procedural Complications metastatic CRPC. Two trials were placebo-controlled Reproductive System and Breast Disorders (Studies 1 and 2), and one trial was bicalutamide- Fall 4.6 0.3 1.3 0.0 Gynecomastia 3.4 0.0 1.4 0.0 controlled (Study 3). In Studies 1 and 2, patients received Non-pathologic 4.0 1.4 0.8 0.3 a CTCAE v4. XTANDI 160 mg or placebo orally once daily. In Study 3, Fractures b Includes asthenia and fatigue. patients received XTANDI 160 mg or bicalutamide Skin And Subcutaneous Tissue Disorders c Includes dizziness and vertigo. d Includes amnesia, memory impairment, cognitive disorder, 50 mg orally once daily. All patients continued androgen Pruritus 3.8 0.0 1.3 0.0 and disturbance in attention. deprivation therapy. Patients were allowed, but not Dry Skin 3.5 0.0 1.3 0.0 e Includes dyspnea, exertional dyspnea, and dyspnea at rest. required, to take glucocorticoids. f Includes nasopharyngitis, upper respiratory tract infection, Respiratory Disorders sinusitis, rhinitis, pharyngitis, and laryngitis. The most common adverse reactions (≥ 10%) that g Includes pneumonia, lower respiratory tract infection, occurred more commonly (≥ 2% over placebo) in the Epistaxis 3.3 0.1 1.3 0.3 bronchitis, and lung infection. XTANDI-treated patients from the two randomized a CTCAE v4. placebo-controlled clinical trials were asthenia/fatigue, b Includes asthenia and fatigue. Study 3: XTANDI versus Bicalutamide in Chemotherapy- c Includes dizziness and vertigo. naïve Metastatic CRPC back pain, decreased appetite, constipation, arthralgia, d Includes amnesia, memory impairment, cognitive disorder, diarrhea, hot flush, upper respiratory tract infection, and disturbance in attention. Study 3 enrolled 375 patients with metastatic CRPC who peripheral edema, dyspnea, musculoskeletal pain, e Includes nasopharyngitis, upper respiratory tract infection, had not received prior cytotoxic chemotherapy, of whom weight decreased, headache, hypertension, and sinusitis, rhinitis, pharyngitis, and laryngitis. 372 received at least one dose of study drug. The median f Includes pneumonia, lower respiratory tract infection, dizziness/vertigo. bronchitis, and lung infection. duration of treatment was 11.6 months with XTANDI and 5.8 months with bicalutamide. Discontinuations with Gastrointestinal Disorders: vomiting Geriatric Use an adverse event as the primary reason were reported for Neurological Disorders: posterior reversible encephalopathy Of 1671 patients who received XTANDI in the two 7.6% of XTANDI-treated patients and 6.3% of bicalutamide- syndrome (PRES) randomized placebo-controlled clinical trials, 75% were treated patients. The most common adverse reactions Skin and Subcutaneous Tissue Disorders: rash 65 and over, while 31% were 75 and over. No overall leading to treatment discontinuation were back pain and DRUG INTERACTIONS differences in safety or effectiveness were observed pathological fracture, which occurred in 3.8% of XTANDI- Drugs that Inhibit CYP2C8 between these patients and younger patients. Other treated patients for each event and in 2.1% and 1.6% of reported clinical experience has not identified differences bicalutamide-treated patients, respectively. Table 3 shows Co-administration of a strong CYP2C8 inhibitor in responses between the elderly and younger patients, overall and common adverse reactions (≥ 10%) in XTANDI- (gemfibrozil) increased the composite area under but greater sensitivity of some older individuals cannot treated patients. the plasma concentration-time curve (AUC) of be ruled out. enzalutamide plus N-desmethyl enzalutamide by Table 3. Adverse Reactions in Study 3 2.2-fold. Co-administration of XTANDI with strong Patients with Renal Impairment XTANDI Bicalutamide CYP2C8 inhibitors should be avoided if possible. If A dedicated renal impairment trial for XTANDI has not N = 183 N = 189 co-administration of XTANDI with a strong CYP2C8 been conducted. Based on the population pharmacokinetic Grade Grade Grade Grade inhibitor cannot be avoided, reduce the dose of XTANDI. analysis using data from clinical trials in patients with a a 1-4 3-4 1-4 3-4 Drugs that Induce CYP3A4 metastatic CRPC and healthy volunteers, no significant (%) (%) (%) (%) difference in enzalutamide clearance was observed Co-administration of rifampin (strong CYP3A4 inducer Overall 94.0 38.8 94.2 37.6 in patients with pre-existing mild to moderate renal and moderate CYP2C8 inducer) decreased the composite impairment (30 mL/min ≤ creatinine clearance [CrCL] General Disorders AUC of enzalutamide plus N-desmethyl enzalutamide ≤ 89 mL/min) compared to patients and volunteers with Asthenic by 37%. Co-administration of strong CYP3A4 inducers b 31.7 1.6 22.8 1.1 baseline normal renal function (CrCL ≥ 90 mL/min). Conditions (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, No initial dosage adjustment is necessary for patients Musculoskeletal And Connective Tissue Disorders rifampin, rifapentine) with XTANDI should be avoided with mild to moderate renal impairment. Severe renal Back Pain 19.1 2.7 18.0 1.6 if possible. St John’s wort may decrease enzalutamide impairment (CrCL < 30 mL/min) and end-stage renal exposure and should be avoided. If co-administration of a disease have not been assessed. Musculoskeletal strong CYP3A4 inducer with XTANDI cannot be avoided, Painc 16.4 1.1 14.3 0.5 increase the dose of XTANDI. Patients with Hepatic Impairment Vascular Disorders Effect of XTANDI on Drug Metabolizing Enzymes Dedicated hepatic impairment trials compared the Hot Flush 14.8 0.0 11.1 0.0 composite systemic exposure of enzalutamide plus Enzalutamide is a strong CYP3A4 inducer and a moderate Hypertension 14.2 7.1 7.4 4.2 N-desmethyl enzalutamide in volunteers with baseline CYP2C9 and CYP2C19 inducer in humans. At steady mild, moderate, or severe hepatic impairment (Child- Gastrointestinal Disorders state, XTANDI reduced the plasma exposure to midazolam Pugh Class A, B, or C, respectively) versus healthy Nausea 14.2 0.0 17.5 0.0 (CYP3A4 substrate), warfarin (CYP2C9 substrate), and controls with normal hepatic function. The composite Constipation 12.6 1.1 13.2 0.5 omeprazole (CYP2C19 substrate). Concomitant use of AUC of enzalutamide plus N-desmethyl enzalutamide XTANDI with narrow therapeutic index drugs that are Diarrhea 11.5 0.0 9.0 1.1 was similar in volunteers with mild, moderate, or severe metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, baseline hepatic impairment compared to volunteers with Infections And Infestations dihydroergotamine, ergotamine, fentanyl, pimozide, normal hepatic function. No initial dosage adjustment is Upper quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., necessary for patients with baseline mild, moderate, or Respiratory 12.0 0.0 6.3 0.5 phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) severe hepatic impairment. Tract Infectiond should be avoided, as enzalutamide may decrease their Investigational exposure. If co-administration with warfarin cannot be OVERDOSAGE In the event of an overdose, stop treatment with XTANDI Weight Loss 10.9 0.5 7.9 0.5 avoided, conduct additional INR monitoring. USE IN SPECIFIC POPULATIONS and initiate general supportive measures taking into a CTCAE v 4. consideration the half-life of 5.8 days. In a dose escalation b Including asthenia and fatigue. Pregnancy c Including musculoskeletal pain and pain in extremity. study, no seizures were reported at ≤ 240 mg daily, d Including nasopharyngitis, upper respiratory tract infection, Risk Summary whereas 3 seizures were reported, 1 each at 360 mg, sinusitis, rhinitis, pharyngitis, and laryngitis. XTANDI is contraindicated for use in pregnant women 480 mg, and 600 mg daily. Patients may be at increased because the drug can cause fetal harm and potential loss risk of seizure following an overdose. Laboratory Abnormalities of pregnancy. XTANDI is not indicated for use in females. In the two randomized placebo-controlled clinical trials, There are no human data on the use of XTANDI in pregnant NONCLINICAL TOXICOLOGY Grade 1-4 neutropenia occurred in 15% of patients treated women. In animal reproduction studies, oral administration Carcinogenesis, Mutagenesis, Impairment of Fertility with XTANDI (1% Grade 3-4) and in 6% of patients treated of enzalutamide in pregnant mice during organogenesis Long-term animal studies have not been conducted to with placebo (0.5% Grade 3-4). The incidence of Grade caused adverse developmental effects at doses lower than evaluate the carcinogenic potential of enzalutamide. 1-4 thrombocytopenia was 6% of patients treated with the maximum recommended human dose. Enzalutamide did not induce mutations in the bacterial XTANDI (0.3% Grade 3-4) and 5% of patients treated Animal Data reverse mutation (Ames) assay and was not genotoxic with placebo (0.5% Grade 3-4). Grade 1-4 elevations in In an embryo-fetal developmental toxicity study in in either the in vitro mouse lymphoma thymidine ALT occurred in 10% of patients treated with XTANDI mice, enzalutamide caused developmental toxicity kinase (Tk) gene mutation assay or the in vivo mouse (0.2% Grade 3-4) and 16% of patients treated with when administered at oral doses of 10 or 30 mg/kg/day micronucleus assay. placebo (0.2% Grade 3-4). Grade 1-4 elevations in throughout the period of organogenesis (gestational days bilirubin occurred in 3% of patients treated with XTANDI Based on nonclinical findings in repeat-dose toxicology 6-15). Findings included embryo-fetal lethality (increased studies, which were consistent with the pharmacological (0.1% Grade 3-4) and 2% of patients treated with placebo post-implantation loss and resorptions) and decreased (no Grade 3-4). activity of enzalutamide, male fertility may be impaired anogenital distance at ≥ 10 mg/kg/day, and cleft palate by treatment with XTANDI. In a 26-week study in rats, Infections and absent palatine bone at 30 mg/kg/day. Doses of atrophy of the prostate and seminal vesicles was observed In Study 1, 1% of patients treated with XTANDI compared 30 mg/kg/day caused maternal toxicity. The doses tested at ≥ 30 mg/kg/day (equal to the human exposure based to 0.3% of patients treated with placebo died from in mice (1, 10 and 30 mg/kg/day) resulted in systemic on AUC). In 4-, 13-, and 39-week studies in dogs, infections or sepsis. In Study 2, 1 patient in each treatment exposures (AUC) approximately 0.04, 0.4 and 1.1 times, hypospermatogenesis and atrophy of the prostate and group (0.1%) had an infection resulting in death. respectively, the exposures in patients. Enzalutamide epididymides were observed at ≥ 4 mg/kg/day (0.3 times Falls and Fall-related Injuries did not cause developmental toxicity in rabbits when the human exposure based on AUC). administered throughout the period of organogenesis In the two randomized placebo-controlled clinical trials, Manufactured for and Distributed by: Astellas Pharma (gestational days 6-18) at dose levels up to 10 mg/kg/day US, Inc., Northbrook, IL 60062 falls including fall-related injuries, occurred in 9% of (approximately 0.4 times the exposures in patients based patients treated with XTANDI compared to 4% of on AUC). Marketed by: patients treated with placebo. Falls were not associated Astellas Pharma US, Inc., Northbrook, IL 60062 Lactation with loss of consciousness or seizure. Fall-related Pfizer Inc., New York, NY 10017 injuries were more severe in patients treated with Risk Summary XTANDI and included non-pathologic fractures, joint XTANDI is not indicated for use in females. There is Revised: July 2017 injuries, and hematomas. no information available on the presence of XTANDI in 16K089-XTA-WPI human milk, the effects of the drug on the breastfed Hypertension infant, or the effects of the drug on milk production. Rx Only In the two randomized placebo-controlled trials, Enzalutamide and/or its metabolites were present in milk © 2017 Astellas Pharma US, Inc. hypertension was reported in 11% of patients receiving of lactating rats. XTANDI and 4% of patients receiving placebo. XTANDI® is a registered trademark of Astellas Pharma Inc. No patients experienced hypertensive crisis. Medical Females and Males of Reproductive Potential history of hypertension was balanced between arms. Contraception Hypertension led to study discontinuation in < 1% of Males patients in each arm. Based on findings in animal reproduction studies, advise Post-Marketing Experience male patients with female partners of reproductive potential to use effective contraception during treatment 076-2626-PM The following additional adverse reactions have been and for 3 months after the final dose of XTANDI. identified during post approval use of XTANDI. Because these reactions were reported voluntarily from a Infertility population of uncertain size, it is not always possible Based on animal studies, XTANDI may impair fertility in to reliably estimate the frequency or establish a causal males of reproductive potential. relationship to drug exposure. Pediatric Use Body as a Whole: hypersensitivity (tongue edema, lip edema, Safety and effectiveness of XTANDI in pediatric patients and pharyngeal edema) have not been established. C 20 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Oncologists in the Philippines That’s exactly what Dr. Francia and lead an ASCO Multidisciplinary Care Table. Top Five Incidences of Cancer in Continued from page 9C Dr. Cauton are pushing for in their own Management Course (MCMC), a pro- the Philippines, Age-Standardized3 institution, and with the help of men- gram intended to improve cancer care Males Females In 2011, out-of-pocket expenditures torship and exposure facilitated through globally by promoting interdisciplinary in the Philippines accounted for 52.7% ASCO’s IDEA-PC program, they’re on cancer management through mock tu- Lung Breast of total household health expenditures, their way to making this a reality. mor boards and education on different Liver Cervix which is over the World Health Organi- aspects of treatment. But Dr. Abrahm’s Prostate Colorectal zation’s threshold for catastrophic ex- Mentorship From Abroad palliative care expertise wasn’t actually Colorectal Lung penditure leading to impoverishment.4 Janet Lee Abrahm, MD, former chief integrated into the mock tumor boards The fi nancial disparity is exacerbated of the Division of Adult Palliative Care and panels on that fi rst trip; she was in- Leukemia Ovary by the fact that not all medications are at the Dana-Farber Cancer Institute/ stead making rounds in the local hospi- marketed and available in the country, Brigham and Women’s Hospital and tals as Dr. Francia’s mentor and serving taken the initiative to establish a full pal- which drives up the prices of those that professor of medicine at Harvard Medi- in the faculty of ASCO’s Palliative Care liative care program at St. Luke’s Medical are available. This often leads patients cal School, was matched through the Train-the-Trainer program, led by Frank Center. In just 3 years, Dr. Francia and with cancer little choice but to discon- IDEA-PC program as a mentor to both Douglas Ferris, MD, of OhioHealth. her colleagues had been able to make a tinue or abandon treatment. Dr. Francia and Dr. Cauton. The program offered MCMC attend- case for a palliative care program and get Today, Dr. Abrahm has an offi cial ees and select nurses from throughout approval from the hospital’s board to be- Barriers to Palliative Care palliative care specialization—but that the Philippines the option to attend gin implementation. Pauline Cauton, MD, also a medical wasn’t always the case. In the early days workshops focusing on strategies for oncologist at St. Luke’s Medical Center of her career, before hospice and pallia- implementing palliative care as well as Areas for Improvement and a 2018 IDEA-PC recipient who works tive medicine became a formal subspe- teaching symptom management and The progress Dr. Abrahm noticed when alongside Dr. Francia, said the public- cialty in 2006, Dr. Abrahm struggled with patient communication. “We were sepa- she returned to the Philippines in 2017 is private dichotomy dictates priorities for many of the same issues facing Filipino rate from the MCMC, so the physicians refl ective of an overall effort to establish Filipino oncologists and their patients. oncologists today. Having experienced had to choose which one to go to,” Dr. multidisciplinary cancer care in the Phil- “In general, just getting the chance to the transition fi rsthand, Dr. Abrahm is Abrahm said. ippines, but the country still has a long receive treatment is the presumed goal. an effective mentor for Dr. Francia and Despite the separation, Dr. Abrahm’s way to go. When all energy and focus is poured Dr. Cauton. trip to the Philippines in 2014 opened “Multidisciplinary care for patients into getting the patient from one with cancer is still not standard in cycle of chemotherapy to the next, the Philippines,” Dr. Francia said, it can get quite diffi cult to start talk- pointing out that the promising in- ing about, say, options for palliative tegration under way at her hospital care,” Dr. Cauton said. in Manila does not necessarily go Palliative care is a complicated hand-in-hand with improvement topic for oncologists in the Philip- across the disparate country. “It is pines. For Dr. Francia and Dr. Cau- not mandatory in all hospitals.” ton, both of whom have taken a “We try to coordinate with a special interest in helping patients multitude of specialties, including with cancer manage pain and dis- surgery, rehabilitation medicine, Dr. Maria Diana tressing symptoms, palliative care’s Dr. Marie Belle Francia Dr. Pauline Cauton Dr. Janet Lee Abrahm and psychiatry,” Dr. Bautista said. lack of integration into the broader Aileen Bautista “But there are still so many things Filipino oncology landscape has needed.” posed a distinct challenge. Dr. Abrahm cited several diffi culties many Filipino oncologists’ eyes to pal- “Here, the primary physician or medi- she faced while providing palliative care liative care integration. Dr. Abrahm re- The Power of Exposure cal oncologist handles palliative care,” without a specialization, all of which are called the impact of a suggestion she As part of the IDEA-PC program, Dr. Dr. Bautista explained. “But there is a concerns in the Philippines today. Prior made for one of the patients in the char- Francia and Dr. Bautista both traveled lack of confi dence in handling pain to 2006, palliative care was no differ- ity hospital during the rounds that trip. to the Unites States—as will Dr. Cauton medications, and there is a lack of com- ent than general oncology in the eyes “The patient had cancer all throughout this June—to attend the ASCO Annual munity understanding about what pal- of insurance companies. “The billing their lungs, and I suggested using an Meeting and spend a week shadowing liative care can offer.” was awkward,” she said. “It looked like opioid for shortness of breath, which their mentors at their institutions. Dr. Cauton added that to most Fili- two oncologists were seeing the same no one had thought of doing before,” “Exposure to integrated cancer manage- pinos, the term “palliative care” simply patient, even though I was providing she said. “The next day, the oncologists ment allowed me to appreciate the level means “we’ve run out of options.” palliative care—a completely different treating that patient told me they had of care offered at a comprehensive cancer “There are few Filipinos who under- service. We had to meet with insurance tried my suggestion and that it had re- center and bring that back to my hospi- stand what [palliative care] is and what companies and prove that all of our con- ally worked—the patient felt much more tal,” Dr. Francia said of the experience. it can do for patients and physicians,” sultations were different.” comfortable. They were so excited and “Seeing the juxtaposition of how she said. Even once palliative care became a encouraged.” things are [in other countries] will move Internationally, published studies subspecialty in the United States, Dr. It was during this fi rst visit that Dr. Filipino oncologists to resolve to make show that integrating palliative care Abrahm continued to struggle with the Abrahm drew a strong connection be- things better,” Dr. Cauton added. “We early on in the course of a patient’s treat- same stigmas and lack of understand- tween palliative care in the Philippines cannot just accept things the way they ment can result in myriad positive re- ing that Dr. Francia, Dr. Cauton, and Dr. and her early years of practicing in the are without trying to do things different- sults; doing so has proven benefi cial to Bautista described. “We needed to show Unites States, thereafter shaping her role ly. We just need to start doing it, even in patients’ overall survival and quality of that we could help patients fi nish cura- as a mentor. the littlest of steps.” life in certain cancers.5 But these studies tive chemoradiotherapy for cancer of Dr. Francia, Dr. Cauton, and Dr. Bautis- have yet to proliferate the Filipino on- the head and neck by controlling their Visible Progress ta all agreed that perhaps the most valu- cology landscape. pain and secretions, not just help at the When she returned to the Philippines able benefi t of the educational programs The lack of understanding when it end-of-life stage,” Dr. Abrahm said. to join another MCMC in October 2017, ASCO has brought—and continues to comes to palliative care is coupled with Over the next decade, exposure, inte- Dr. Abrahm was fully integrated into bring—to the Philippines is simply ex- challenges to access. Although there are gration, and frequent conversations be- the mock tumor boards as a palliative posure to how multidisciplinary care several large hospitals in the Philippines gan to move the culture in the United care consultant—a palpable change she teams can collaborate to treat patients with established palliative care services, States toward accepting and integrat- found extremely promising. from a full spectrum of approaches. Al- Dr. Francia said the majority don’t offer ing palliative care. “I’m hoping I can “In just 3 years, you could really tell though oncologists can read about mul- palliative care to patients with cancer help with that in the Philippines,” Dr. the difference,” Dr. Abrahm said of in- tidisciplinary care and consume didactic during the course of their treatment. Abrahm said. “But fi rst, they need to tegrating palliative care into multidisci- materials available through online learn- “We need places to refer patients who establish a culture in which multidisciplinary education. “I had the same num- ing and textbooks, it is diffi cult to truly would benefi t from palliative care,” Dr. plinary care is the norm.” ber of slides as the medical, surgical, and grasp its benefi ts and understand how it Cauton said. “We hope that exposure radiation oncologists, and the attendees works without experiencing it in person. to palliative care education will inspire Moving Toward Multidisciplinary Care were very receptive to my input.” In multidisciplinary cancer care, “co- and embolden more Filipino oncologists Dr. Abrahm’s fi rst foray into mentor- When Dr. Abrahm met with Dr. Fran- ordination is a key to progress,” Dr. Bau- to ride against the waves of convention ship in the Philippines came in 2014, cia during this recent trip, she was tista said. “As a country, we are getting and establish these services—even if they when she accompanied several col- thrilled to see that Dr. Francia and her there, step by step, with the help of our start with their own private practices.” leagues who were traveling there to colleagues—including Dr. Cauton—had See Oncologists in the Philippines, Page 26C am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 21 C

In the Journals High Mutational Burden Linked With Sensitivity to Immune Checkpoint Inhibition

“Identifying a Clinically Applicable cancer, and bladder-urothelial cancer. from more than Q: What is the signifi cance of this Mutational Burden Threshold as a Tumors with a mutational burden high- 9,000 samples research? Potential Biomarker of Response to er than the threshold (iCAM positive) from 33 solid Dr. Panda: The results of this paper Immune Checkpoint Therapy in also had clear histologic evidence of tumor types suggest that a high mutation burden is Solid Tumors” lymphocytic infi ltration. In published from TCGA, we associated with immune checkpoint ac- datasets of melanoma, lung adenocarci- found eight sol- tivation, and potentially, with response Journal: JCO Precision Oncology noma, and colon cancer, patients with id cancer types to immune checkpoint therapy more DOI: 10.1200/PO.17.00146 iCAM-positive tumors had signifi cantly where mutation generally than previously known. Addi- better response to immune checkpoint burden may tionally, the above mechanism is likely Abstract therapy compared with those with be a predictor operative in four novel cancer types as Purpose: An association between muta- iCAM-negative tumors. Receiver operat- of response to well as the four known cancer types, but Dr. Anshuman Panda tional burden and response to immune ing characteristic analysis using TCGA immune check- is not operative in every cancer type. checkpoint therapy has been document- predictions as the gold standard showed point therapy. This demonstrates that mutation bur- ed in several cancer types. The potential that iCAM-positive tumors are accurate- They included four known cancer types den, although clearly a very important for such a mutational burden threshold ly identifi able using clinical sequencing (melanoma, lung adenocarcinoma, co- marker of response to immune check- to predict response to immune check- assays, such as FoundationOne (Foun- lon adenocarcinoma, and bladder-uro- point therapy, is not the only mecha- point therapy was evaluated in sev- dation Medicine, Cambridge, MA) or thelial cancer) and four novel cancer nism of local immune checkpoint acti- eral clinical datasets, where mutational StrandAdvantage (Strand Life Sciences, types (endometrial cancer, stomach ad- vation in cancer. burden was measured either by whole- Bangalore, India). Using the Foundation enocarcinoma, cervical cancer, and ER- exome sequencing or by using commer- One-derived threshold, an analysis of positive HER2-negative breast cancer). Q: How may this new research cially available sequencing panels. 113 melanoma tumors showed that pa- Additionally, serous ovarian cancer war- infl uence or impact clinical practice? Methods: Whole-exome sequencing tients with iCAM-positive disease have rants further investigation. Dr. Panda: Although immune check- and RNA sequencing data of 33 solid signifi cantly better response to immune Moreover, a substantial fraction of tu- point therapy can lead to dramatic re- cancer types from The Cancer Genome checkpoint therapy. iCAM-positive and mors in these eight cancer types have a sponses in some patients with advanced Atlas (TCGA) were analyzed to deter- iCAM-negative tumors have distinct mutation burden above the identifi ed solid cancers, only a minority of treated mine whether a robust immune check- mutation patterns and different im- threshold, showing that our results can patients have durable clinical benefi t. point–activating mutation (iCAM) bur- mune microenvironments. potentially impact a clinically signifi - Therefore, there is a clear need to devel- den threshold associated with evidence Conclusion: In eight solid cancers, a cant fraction of patients in these cancer op methods to identify which patients of immune checkpoint activation exists mutational burden threshold exists that types. are most likely to benefi t from immune in these cancers that may serve as a bio- may predict response to immune check- Further, we showed that in these can- checkpoint therapy. marker of response to immune checkpoint blockade. This threshold is identi- cer types, it is possible to defi ne a thresh- Once refi ned and validated in pro- point blockade therapy. fi able using available clinical sequencing old on mutation burden, also known as spective trials, iCAM threshold analysis Results: We found that a robust iCAM assays. an iCAM threshold, such that tumors may be useful as a robust biomarker of threshold, associated with signatures of with mutation burden above this thresh- response in multiple solid cancer types, immune checkpoint activation, exists Author Perspective old show evidence of immune activation for prioritizing patients who are likely to in eight of 33 solid cancers: melanoma, Anshuman Panda, PhD, Rutgers and checkpoint pathway up-regulation benefi t from immune checkpoint thera- lung adenocarcinoma, colon adenocar- Cancer Institute of New Jersey and are signifi cantly more likely to re- py. Moreover, because this threshold can cinoma, endometrial cancer, stomach spond to immune checkpoint therapy. be identifi ed with routinely used clinical adenocarcinoma, cervical cancer, estro- Q: What are the major fi ndings from This iCAM threshold can be identifi ed sequencing assays, it can be used in the gen receptor–positive/human epidermal the research discussed in the paper? with high accuracy using routinely used clinic without requiring the develop- growth factor receptor 2–negative breast Dr. Panda: When we analyzed data clinical sequencing assays. ment of additional new assays.

Smoking Cessation the following: Are ENDS less harmful cessation of combustible tobacco ciga- Continued from page 15C than cigarettes? Do people quit by us- rettes.”11 The U.K. report goes so far as ing ENDS? Do ENDS make it more dif- to say, “Stop-smoking practitioners and cessation in a variety of ways, but many fi cult to quit? Do people reduce or quit health professionals should provide be- do have quitlines and some countries cigarettes completely? Do young adults havioural support to smokers who want even mandate that the national quitline use ENDS and then use cigarettes (thus to use an e-cigarette to help them quit number be printed on the tobacco pack- perpetuating nicotine addiction, using smoking. Stop-smoking service practi- age warning label.9 The details country cigarettes)? Are there nononcologic dis- tioners and health professionals sup- by country are too lengthy to list with- ease outcomes from ENDS such as car- porting smokers to quit should receive in this article, and resources do change diovascular risk and/or infl ammatory education and training in use of e-ciga- over time, so clinicians are encouraged lung diseases? rettes in quit attempts.”12 to investigate what local resources are Two recent reports presented a review The general feel is that: available to their patient population. A of the available literature, and interest- ■ ENDS have short-term scientifi c fi nd- positive example is the United Kingdom, ingly have a bit different results. In the ings that they are probably less harm- which has successfully integrated a to- United States, the federal legislature re- ful than cigarettes. bacco cessation program with specialists quired the U.S. Food and Drug Adminis- ■ People do and have quit smoking into general care. tration to fund the National Academies cigarettes with ENDS. However, the of Science and Engineering to compre- question of how many quit versus Electronic Cigarettes hensively and systematically review the how many “dual use” (smoke ciga- Patients commonly ask about the role literature on the health effects of ENDS.11 rettes and ENDS) appears to still be of electronic cigarettes in cessation. Elec- from a complete ban (but, admittedly The second report from Public Health dependent on the country examined, tronic cigarettes were fi rst developed by a smuggled in) in Australia, to banned if England can be found on the U.K. gov- the survey methods, and timelines. pharmacist in China to stop smoking af- it has nicotine in it in Japan, to “regu- ernment website.12 ■ Young people are using ENDS and ter his father, who smoked heavily, died lated” in the European Union, to going The conclusions between the two re- progressing to cigarettes. of lung cancer.10 Since then, electronic to be regulated in the United States, to ports are not identical. The U.S.-spon- cigarettes, or electronic nicotine delivery endorsed usage in the United Kingdom. sored report has some mixed results in We likely have a few more years of as- systems (ENDS), have swept the world The regulation of ENDS almost varies by its statements including, “Overall, the sessment and intensive research on the with rapid uptake in many countries. the day, depending on which country evidence suggests that while e-cigarettes topic of ENDS, and equally intensive ef- ENDS are variably regulated around the you are reviewing. might cause youth who use them to forts to regulate them. world and in a state of change in many The science is not yet conclusive, transition to use of combustible tobacco places. The regulation of ENDS varies and unsettled topics of concern include products, they might also increase adult See Smoking Cessation, Page 28C C 22 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Medical Marijuana narconon.org/drug-information/ lished March 18, 2009. Accessed January research/health/state-medical-marijuana- Continued from page 14C marijuana-history.html. Accessed January 4. 2018. laws.aspx. Updated September 14, 2017. 4, 2018. 10. Ogden DW. The United States Depart- Accessed January 4, 2018. effect is currently limited. Additional 5. Benson Jr JA, et al. Marijuana and Medicine: ment of Justice Archives. Memorandum 13. National Academies of Sciences, Engineer- research on the medical use of canna- Assessing the Science Base. Washington, for Selected United States Attorneys on ing, and Medicine. The Health Effects of binoids is strongly warranted. The pace D.C.: National Academies Press; 1999. Investigations and Prosecutions in States Cannabis and Cannabinoids: The Current of such research is likely to accelerate as 6. Bonnie RJ, et al. Va L Rev. 1970;56:971- Authorizing the Medical Use of Marijuana. State of Evidence and Recommendations states continue to approve cannabis for 1203. justice.gov/archives/opa/blog/ for Research. Washington, D.C.: National medical purposes. 7. Lee MA. Smoke Signals: A Social History of memorandum-selected-united-state- Academies Press; 2017. Marijuana—Medical, Recreational, and Sci- attorneys-investigations-and- 14. Caulkins JP, et al. Marijuana Legalization: References: entiﬁ c. New York, NY: Simon and Schuster; prosecutions-states. Published October 19, What Everyone Needs to Know. 2nd ed. New 1. Stack P, et al. TIME. Medical Marijuana. 2012. 2009. Accessed January 4, 2018. York, NY: Oxford University Press; 2016. content.time.com/time/health/article/ 8. United States Drug Enforcement Adminis- 11. Cole J. U.S. Department of Justice. Guid- 15. Raber JC, et al. J Toxicol Sci. 2015;40:797- 0,8599,1931247,00.html. Published Octo- tration. Drug Schedules. dea.gov/druginfo/ ance Regarding Marijuana Enforcement. 803 ber 21, 2009. Accessed January 4, 2018. ds.shtml. Accessed January 4, 2018. justice.gov/iso/opa/resources/3052013829 16. Thomas A, et al. Br J Pharmacol. 2. O’Shaughnessy WB. Boston Med Surg J. 9. Johnston D, et al. The New York Times. 132756857467.pdf. Published August 29, 2007;150:613-23. 1840;23:153-5. Obama Administration to Stop Raids on 2013. Accessed January 4, 2018. 17. Mackie K. Annu Rev Pharmacol Toxicol. 3. Wilkie G, et al. JAMA Oncol. 2016;2:670-5. Medical Marijuana Dispensers. nytimes. 12. National Conference of State Legislature. 2006;46:101-22. 4. Narconon. History of marijuana. com/2009/03/19/us/19holder.html. Pub- State Medical Marijuana Laws. ncsl.org/ 18. Bonn-Miller MO, et al. JAMA. 2017;318:1708-9. 19. Brenneisen R, et al. Int J Clin Pharmacol Ther. 1996;34:446-52. 20. Marinol Prescribing Information. rxabbvie.com/pdf/marinol_PI.pdf. Updated August 2017. Accessed January BAVARIAN NORDIC 4, 2018. 21. MEDA Pharmaceuticals. Cesamet Prescrib- IS STRIVING TO ing Information. cesamet.com/pdf/ Cesamet_PI_50_count.pdf. Updated Sep- tember 2013. Accessed January 4, 2018. BRING NOVEL 22. Volkman E. The Motley Fool. GW Pharma- ceuticals Just Delivered Some Good News About Its Marijuana-Based Drug. fool. TARGETED VACCINES com/investing/2017/11/06/gw- pharmaceuticals-just-delivered-some- TO MAXIMIZE good-news-a.aspx. Published November 6, 2017. Accessed January 4, 2018. 23. Gable RS. Addiction. 2004;99:686-96. IMMUNOTHERAPY 24. Iversen LL. The Science of Marijuana. New York, NY: Oxford University Press; 2001. 25. Hall W, et al. Lancet. 2009;374:1383-91. IMPACT FOR CANCER 26. Valeant Pharmaceuticals International. Cesamet. www.accessdata.fda.gov/drug- PATIENTS satfda_docs/label/2006/018677s011lbl. pdf. Updated May 2006. Accessed January 4, 2018. 27. Agrawal A, et al. Addiction. 2014;109:663- 71. 28. Noyes R, et al. Clin Pharmacol Ther. 1975;18:84-9. 29. Volkow ND, et al. N Engl J Med. 2014;370:2219-27. 30. Marconi A, et al. Schizophr Bull. 2016;42:1262-9. 31. Sontineni SP, et al. World J Gastroenterol. Our innovative oncology platform is designed 2009;15:1264-6. to specifically target a variety of challenging 32. Whiting PF, et al. JAMA. 2015;313:2456-73. tumor types. We have developed a portfolio 33. Chepyala P, et al. Clin Gastroenterol Hepa- tol. 2008;6:710-2. of active cancer immunotherapies, designed 34. Lopez-Quintero C, et al. Drug Alcohol to alter the disease course by eliciting a robust Depend. 2011;115:120-30. 35. Reinarman C, et al. J Psychoactive Drugs. and broad anti-cancer immune response while 2011;43:128-35. maintaining a favorable risk-benefit profile. 36. Coffey C, et al. Addiction. 2002;97:187-94. 37. Reiman A. Complement Health Pract Rev. 2007;12:31-50. Multiple clinical trials are ongoing in collab- 38. Webb CW, et al. Hawaii J Med Public oration with the NCI, NIH, academia and industry Health. 2014;73:109-11. 39. Charuvastra A, et al. J Addict Dis. partners. Through numerous industry collab- 2005;24:87-93. orations, we seek to explore the potential 40. Adler JN, et al. N Engl J Med. 2013;368:e30. 41. Andreae MH, et al. J Pain. 2015;16:1221-32. synergies of combining our immunotherapies 42. Smith LA, et al. Cochrane Database Syst Rev. with other immune-modulators. 2015;11:CD009464. 43. Tramèr MR, et al. BMJ. 200;323:16-21. 44. Carley DW, et al. Sleep. 2017;Nov 7 [Epub ahead of print]. BAVARIAN-NORDIC.COM 45. Rocha FCM, et al. J Neurooncol. 2014;116:11-24. 46. Guzman M, et al. Br J Cancer. 2006;95:197- 203. THERE’S MORE TO SOME CANCERS THAN MEETS THE EYE

TRK FUSION PROTEINS ARE A PRIMARY ONCOGENIC DRIVER ACROSS MULTIPLE TUMORS IN ADULTS AND CHILDREN1,2

LOOK BELOW THE SURFACE TO FIND OUT WHAT’S DRIVING THE TUMOR

LEARN MORE ABOUT TRK FUSION CANCER AT TRKCANCER.COM

TRK, tropomyosin receptor kinase.

References: 1. Okimoto RA, Bivona TG. Tracking down response and resistance to TRK inhibitors. Cancer Discov. 2016;6(1):14-16. 2. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34.

© 2018 Bayer and Loxo Oncology, Inc. All rights reserved. Bayer and the Bayer Cross are registered trademarks of Bayer. PP-912-US-0083 03/2018 C 24 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Patient-Reported Outcomes ability for failing to act when a patient nied by manual data entry. Computer- About the Authors Continued from page 12C endorses suicidality, severe depression, ized PRO systems used directly by the or a desire to harm others. PRO systems patient avoid the associated expense Limited data utility may occur when should assess the full range of responses and error, but add costs of information Dr. Berry is the di- PRO data are not timely enough for clini- from patients, but the response should technology (IT) system implementa- rector of the Phyl- cal encounters or are not consistently be appropriate for the setting. In the clin- tion and maintenance. However, PRO lis F. Cantor Center available due to a low completion rate. ic, endorsing self-harm on the suicidality systems may offer signifi cant savings in of the Dana-Farber Clinicians may see little value in support- item of the PHQ-9 should trigger an alert workfl ow, with the potential to reduce Cancer Institute. ing PRO collection among their patients. to clinic staff.29 A similar endorsement labor costs. These could include facili- PRO data must be timely and consistent- while using a home-based tool might of- tating asynchronous or message-based ly available. Data must accurately refl ect fer the patient an alert identifying both communications and the inclusion of Dr. Lober is a the patient’s experiences and outcomes the concern and an action to take, with self-management strategies, such as au- professor of global and must be relevant to the clinician’s appropriate after-hours notifi cation to tomated self-care responses to patients health, biobehav- ioral nursing and care of the patient. Explicit monitoring the clinic. When used in an anonymous with symptoms at the minimal to mod- health informatics, of timeliness, accuracy, completeness, public screening tool, the PHQ-9 suicid- erate level of severity. and a professor and clinical utility supports specifi c ac- ality item triggers only a message of con- Disruption to clinic fl ow may occur of biomedical tivities to understand and improve PRO cern and a general recommendation.30 because PROs add more uncertainty to informatics and data quality. The idea that the patient may feel already numerous factors. Clinic wait medical education at the University of Poor presentation of PRO data may worse has inhibited some clinicians times are highly variable, and PROs add Washington. make it diffi cult for clinicians to ef- from sharing comparative data about pa- variations both in time and support re- fectively use PROs for shared decision- tients’ symptom burden relative to that quired for in-clinic completion. Tracking making. Clinicians may not always re- of similar patients. Urology patients with times for individual components of the clinical services and clinicians. There spond meaningfully to verbal reports worse-than-average urinary symptoms assessment, focusing PROs on clinically may be legitimate benefi t to address- or to electronic summaries of symptom may feel worse about their incontinence actionable domains, and dynamically tai- ing similar domains with different in- management and quality-of-life issues, after realizing other post-treatment pa- loring PRO assessments to current clinic struments in different situations, or sometimes interrupting the patient and tients do better. However, there are a fl ow all address these concerns.31 In ad- clinicians may simply prefer familiar changing the subject.28 Shared review of range of interventions to impact incon- dition, shifting from fi xed kiosks to por- instruments. Strong governance, tied PRO data should support collaborative tinence, and the clinician’s concern for table tablets lets patients begin reporting to clinical services, ensures confl icts discussion and shared decision-making. the patient’s self-image is not suffi cient in the waiting room and continue in the are managed at the same level as other A paper printout with summarized re- reason to deny patients the opportunity exam room, with results still immediately workfl ows and policies, as part of the sponses and trends may facilitate discus- and motivation to seek out treatments available. But perhaps the greatest impact same processes that encourage uniform sion and serve the patient as a reminder that may improve their symptoms. is the ability to shift PRO completion out- clinical care standards, rather than as of the clinical visit. side the clinic to the patient’s own pre- IT questions. Poorly timed information is a com- The health care organization ferred device, place, and time. mon concern when PRO assessments Labor-intensive activities with PRO PROs introduce IT complexity, but Societal concerns include suicidality, making clinicians methods such as paper collection are patient and clinician interests are not Health care access and equity can be and health care organizations wary of li- expensive and more so when accompa- always best served by minimizing this. eroded by technology unless suffi cient In one example, nurses in the bone support is provided to ensure that there marrow transplant service at the Seattle is no widening of the “digital divide” Cancer Care Alliance sustained use of a that separates patients by resources and PRO system for 8 years after the end of literacy.34 Neither lack of technology a PRO trial because of perceived value nor lack of profi ciency should result in of PRO screening.32 The practice ended diminished attention to the symptoms only when a new enterprise EMR was and preferences of patients with less ac- introduced at the institution. However, cess. Although patients across all ages YOUR ONE-STOP SOURCE FOR LIFELONG LEARNING the new electronic system lacked a PRO and socioeconomic statuses increasing- component, and the service began us- ly have access to smartphones as well as ing paper PROs, decreasing functionality the PRO tools and support to use them, and potentially increasing cost. they should still be available in the clin- The EMR is almost universally the ic setting for those who need them.35 medico-legal record, supporting and Patient-centered care is increasingly documenting health care delivery. Risks a priority at a societal level, evidenced of performance impact to the EMR can by funding initiatives from federal agen- be addressed with application program- cies and institutes to better understand ming interface management software, PRO implementations and effects; by managing information fl ow into and the efforts to shift care to better satisfy, out of the EMR, which also helps ad- engage, and empower patients in their dress data privacy and security risks, in own care; by regulatory requirements to concert with the IT governance policies share health information with patients; of a health care organization. and by myriad statements from health PRO systems can be labor intensive care organizations. At the same time, and thus costly. A recent article esti- patient-centered care can be challenging mated and compared requirements of to all stakeholders, including patients, several methods of PRO collection using accustomed to a more traditional mod- UNLIMITED ACCESS EARN CREDITS STAY CURRENT institutionally developed systems, EMR el. PROs have the potential to organize to 100+ courses CME/CE, MOC, Nursing with constantly updated embedded version of the third-party and strengthen the patient’s voice in the at one low price and Pharmacy oncology information PROMIS-CAT system and vendor-based clinical conversation and be a corner- systems.33 The estimates were necessari- stone of patient-centered care. ly uncertain; the authors do not include either the “built-in” questionnaire sys- Successful Clinical Implementation tems offered by the EMR vendors them- Given the barriers enumerated above, ANNUAL SUBSCRIPTION RATE: selves or other noncommercial EMR a clinician may wonder if real-world im- ASCO Members: $347 Nonmember Rate: $434 embedded systems. However, when plementation is feasible, sustainable, and planning implementation of comput- worth the effort. Published examples and erized PROs into clinical practice, it is reports of PRO implementation with- important to delineate the range of pos- out research team coordination are few. SIGN UP NOW FOR A FREE TRIAL sible methods and to understand acqui- Cancer Care Ontario has used screen- university.asco.org/Essentials sition, implementation, and operating ing PROs since 2007 and published re- costs of these systems. ports of signifi cantly reduced emergency Competing and overlapping PRO department visits in women receiving content may be desired by different See Patient-Reported Outcomes, Page 30C Give More Patients the OPDIVO ® Opportunity.

While attending this meeting, please visit us at Booth 6063

OPDIVO® and the related logo are trademarks of Bristol-Myers Squibb Company. © 2018 Bristol-Myers Squibb Company. All rights reserved. 1506US1702870-05-01 02/18 C 26 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

(DFS, 84% for AC-TH vs. 81% for TCH) or OS (92% for AC-TH vs. 91% for TCH) CLINICAL CORNER between the two trastuzumab-containing regimens, although both were statistically better than AC-T (DFS 75% and Anthracycline Chemotherapy in Breast Cancer OS 87%).3 The study was not powered to compare the two trastuzumab-con- egan Kruse, MD, and Jame study of more trials, patients taining arms to each other, so limited Abraham, MD, FACP, answer a than 1,000 with HER2 conclusions can be drawn regarding su- question posed by an attendee women with nonampli- periority of one regimen over another. during a Best of ASCO® Meet- early-stage fi ed early-stage There were numerically more breast Ming. Drs. Kruse and Abraham are medical breast can- breast cancer cancer recurrences in the TCH arm com- oncologists in the breast cancer program cer compared were randomly pared to the AC-TH; however, there at the Cleveland Clinic Taussig Cancer doxorubicin selected to re- were more cases of leukemia and con- Institute, where Dr. Abraham also serves plus cyclophos- ceive TC for six gestive heart failure with anthracycline- as director. phamide (AC) cycles or one of containing chemotherapy. for four cycles several AC plus Based on these data, there continues Question: What patients with early- with docetaxel Dr. Megan Kruse Dr. Jame Abraham taxane regi- to be a role for anthracycline-contain- stage breast cancer should be treated plus cyclophos- mens.2 These ing chemotherapy in the treatment of with anthracyclines? phamide (TC) for four cycles and found studies were designed to assess for non- certain patients with early-stage breast Answer: When choosing an adjuvant an overall survival (OS) benefi t of TC inferiority of TC compared with AC plus cancer. For patients with hormone re- chemotherapy regimen for a patient over AC (HR 0.69, 95% CI [0.50, 0.97]; taxane. Approximately 4,200 patients ceptor–positive disease, those with ag- with early-stage breast cancer, one must p = 0.032) at a median follow-up of 7 were enrolled and randomly assigned by gressive biologic features (especially balance the potential benefi t of therapy years.1 This study demonstrated that a the number of positive lymph nodes and those with at least four lymph nodes with risk of long-term toxicities, as the non-anthracycline regimen is a viable hormone receptor status. involved) should be considered for an- goal of therapy in such patients is cure. and potentially superior approach to At interim analysis, a statistically sig- thracycline plus taxane chemotherapy. As anthracycline chemotherapy agents treatment of early-stage breast cancer nifi cant 2.5% difference in 4-year inva- Those patients with strongly hormone are known to have a risk of treatment- compared to AC; however, many pa- sive disease-free survival was found fa- receptor–positive disease who have no related cardiomyopathy, myelodysplas- tients in clinical practice are treated with voring AC plus taxane over TC (HR 1.23, lymph node involvement or limited tic syndrome, and acute leukemia, much AC and taxane, so the practical applica- 95% CI [1.01, 1.5]; p = 0.04). In explor- lymph node involvement may be better effort has gone into determining which tion of this data w as unclear. atory analyses, the addition of anthracy- served with a non-anthracycline chemo- patients benefi t most from anthracy- The recently published Anthracyclines cline to taxane-based chemotherapy was therapy regimen, particularly those with cline-based therapy in hopes of sparing in Early Breast Cancer trials, consisting found to be more substantial for patients risk factors for cardiomyopathy, includ- those patients who will not derive sig- of a combined analysis of USOR 06-090, with hormone receptor–negative disease, ing diabetes mellitus, hypertension, and nifi cant benefi t from potentially devas- NSABP B-46-I/USOR 07132 and NSABP particularly those with positive lymph coronary artery disease. tating long-term toxicities. B-49, help to address the effi cacy of TC nodes. For hormone receptor–positive For patients with hormone recep- A US Oncology Research, Inc. (USOR) compared to AC plus taxane. In these disease, the benefi t was greatest for those tor−negative disease, the threshold for with four or more lymph nodes involved. including anthracycline is lower given Although these analyses were not pre- the greater risk of recurrence, although planned and thus not powered for, they patients with small tumors that are do suggest patient populations who lymph node−negative may be good can- may derive meaningful benefi t from an- didates for non-anthracycline–contain- thracycline and taxane–containing che- ing chemotherapy. For HER2-amplifi ed motherapy. Of note, fi ve patients in the patients, a non-anthracycline treatment anthracycline-containing chemothera- is generally preferred due to increased py arm developed leukemia compared risk of cardiomyopathy with sequential to zero in the TC arm. anthracycline plus trastuzumab therapy, There is also controversy regarding but use of anthracycline can be consid- use of anthracyclines in the treatment ered for those patients at very high risk of HER2-amplifi ed early-stage breast for disease recurrence. cancer. The BCIRG-006 trial evaluated three different chemotherapy regimens References: (AC plus docetaxel [AC-T]; AC plus 1. Jones S, et al. J Clin Oncol. 2009;27:1177- docetaxel and trastuzumab [AC-TH]; 83. and docetaxel plus carboplatin and 2. Blum JL, et al. J Clin Oncol. 2017;35:2647- trastuzumab [TCH]) in this treatment 55. setting and found no statistically signif- 3. Slamon D, et al. N Engl J Med. icant difference in disease-free survival 2011;36:1273-83.

Oncologists in the Philippines Continued from page 20C

local and international colleagues, our patients, and the whole community.” In collaboration with the Benavides Cancer Institute University of Santo To- mas Hospital, ASCO will be hosting another MCMC in Manila, November 14-16, NEW2018 EDITION! 2018. For more information, visit asco.org/ Released international-programs. –Caroline Hopkins 2012: Philippines. globocan.iarc.fr/Pages/ Spring 2018 fact_sheets_population.aspx. Accessed References: March 5, 2018. 1. UNDP. The Philippines. ph.undp.org/ 4. Van Gijsel N. Third World Health Aid. content/philippines/en/home/ Health Care Access in the Philippines. Order Today at university.asco.org/SEP countryinfo.html. Accessed March 5, 2018. twha.be/sites/default/ﬁ les/generated/ﬁ les/ 2. The World Bank. Philippines. ata. news/positionpaper_gezondheid_ worldbank.org/country/Philippines. philippines_eng_0.pdf. November 7, 2016. Accessed March 5, 2018. Accessed March 5, 2018. 3. World Health Organization: GLOBOCAN 5. Smith TJ, et al. J Clin Oncol. 2012;30:880-7. Innovating antibodies, improving lives Genmab is dedicated to fi nding the latest antibody therapeutics for the treatment of cancer

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Smoking Cessation Most importantly: Ask all patients if References: health-consequences-of-e-cigarettes.aspx. Continued from page 21C they use tobacco. Advise them that it is 1. U.S. Department of Health and Human Accessed February 27, 2018. the most important thing they can do Services. The Health Consequences of 13. Public Health England. Evidence review of The Tobacco Market to help with their cancer treatment. Tell Smoking—50 Years of Progress: A Report e-cigarettes and heated tobacco products On a fi nal note, we would be remiss them that this intervention has nothing of the Surgeon General. Atlanta, GA: 2018: executive summary. gov.uk/ if we did not address a gorilla in the to do with blame or shame, and that no U.S. Department of Health and Human government/publications/e-cigarettes-and- room. Philip Morris International (the one deserves to get cancer. Refer them Services, Centers for Disease Control and heated-tobacco-products-evidence-review/ largest transnational tobacco industry to an effective tobacco cessation pro- Prevention, National Center for Chronic evidence-review-of-e-cigarettes-and- with cigarette market leader Marlboro) gram with which you have established Disease Prevention and Health Promotion, heated-tobacco-products-2018-executive- has launched their new product iQOS a relationship. At each visit with your Offi ce on Smoking and Health; 2014. summary. Updated February 12, 2018. (or, I quit ordinary smoking) in a num- patient, discuss their tobacco use status, 2. Warren GW, et al. J Oncol Pract. 2013; Accessed February 27, 2018. ber of countries. It has seen remarkable just like you check for adverse events or 9:258-62. 14. Velicer C, et al. Tob Control. 2016;25:575- market growth, particularly in Japan. other symptoms. Be sure to congratu- 3. Farber HJ, et al. Am J Respir Crit Care Med. 83. The other large transnational tobacco late them for quitting. It is probably the 2017;196:11-2. 15. Hiscock R, et al. Tob Control. 2017;Oct 9. companies have their own “heated to- hardest thing they’ve ever done, and 4. Soneji S, et al. J Adolesc Health. pii: tobaccocontrol-2017-053891. bacco products” (they are supposedly maybe one of the things they are most 2014;55:209-15. not combusting tobacco, but only heat- proud of doing. 5. American Society of Clinical Oncology. ing it), with British American Tobacco We are passionate about having fewer Tobacco Cessation Tools and Resources. marketing “glo” and Japan Tobacco people die from tobacco. We are part of asco.org/practice-guidelines/cancer-care- International marketing “Ploom.” As a cadre of providers who work in the initiatives/prevention-survivorship/ with ENDS, there are many questions oncology area including many interna- tobacco-cessation-control/tobacco- surrounding these products. Are these tional organizations that share similar cessation-tools-resources. Accessed ASCO’S TOBACCO heated tobacco products less likely to interests, such as ASCO, the American February 27, 2018. CESSATION RESOURCES kill when used as intended (as cigarettes Association for Cancer Research, the 6. Warren GW, et al. J Thorac Oncol. The Tobacco Cessation Guide do)? Will adults who want to quit, com- International Association for the Study 2013;8:543-8. for Oncology Providers is an pletely quit, or just be addicted to a dif- of Lung Cancer, Society of Thoracic 7. National Cancer Institute: Division of evidence-based booklet to help ferent product? And will young people, Surgeons, and the American College of Cancer Control and Population Sciences. oncology providers integrate or people who had previously quit Chest Physicians. As tobacco is a world- 8. Cancer Center Cessation Initiative. tobacco cessation strategies smoking, take up these new technologi- wide problem, so is tobacco control. We cancercontrol.cancer.gov/brp/tcrb/ into their practices by offering cally attractive products? work globally, and offer to help any on- cessation-initiative.html. Accessed practical tips for tobacco use It is too early and we have too little cologist who would like brief advice on February 27, 2018. assessment and treatment, as science to know if we should be recom- how to help their practice address tobac- 9. Shields PG, et al. J Natl Compr Canc Netw. well as information about how to mending heated tobacco products for our co cessation. Obviously we cannot do 2016;14:1430-68. be reimbursed for these services. patients with cancer—the products are it for you, but we will enlist our global 10. North American Quitline Consortium. ASCO’s patient companion just too new and variable. We view them colleagues to see if we can provide help- Tobacco Warning Labels. naquitline.org/? booklet, Stopping Tobacco in the same category as ENDS for now, ful advice or connections. First, read page=TobaccoWarningLabels. Use After a Cancer Diagnosis, 5 and recommend that your patients use ASCO’s materials and then, just start! Accessed February 27, 2018. aims to provide clear, practical approved tobacco cessation products fi rst. 11. Consumer Advocates for Smoke Free Alter- information for patients and If they can’t quit, consider ENDS until About the Authors: Dr. Dresler is a natives Association. A Historical Time- their caregivers on the benefi ts they can also quit ENDS. These new tech- member of ASCO and the International line of Electronic Cigarettes. casaa.org/ of quitting tobacco use after nologies are a moving target and we may Association for the Study of Lung Cancer. historical-timeline-of-electronic-cigarettes. a cancer diagnosis, as well as never get clear, simple data. However, on Dr. Steglia is associate professor of surgery Accessed March 1, 2018. tips for talking with health care a different level, the profi ts from the sale at the Winthrop P. Rockefeller Cancer 12. National Academies of Science, Engineer- professionals about tobacco of these products supports the tobacco Institute, University of Arkansas for Medical ing, and Medicine. Public Health Con- cessation. Learn more industry, which continues to undermine Sciences. sequences of E-Cigarettes. nationalacad- at asco.org. efforts at effective tobacco control.13,14 emies.org/hmd/Reports/2018/public-

® The Imaging course is offered as part ASCO University Unveils New Imaging Course of the Advanced Practitioner Certifi cate Program: Basics 102 through ASCO Uni- nderstanding basic medical imag- who are eligible for surgical treatment, ■ Interventional Radiology will versity. Certifi cate and credit types avail- ing modalities is essential to any as well as those who may not be eligible help learners describe how an able for the course include 4 AMA PRA oncologist, from new physicians for surgery, and offers palliation of can- interventional radiologist can see Category 1 Credits™, ABIM MOC Points, to those reviewing this funda- cer related symptoms.” inside patients without opening them CNE Contact Hours, CPE Credits, ONCC Umental aspect of oncology. The slide-based course with an audio up, discuss some of the treatments ILNA Points, a Certifi cate of Participation, ASCO University®, wanting to assist overlay is divided into four sections interventional radiology can offer and a Certifi cate of Completion. All fi nal medical professionals with this task, has along with a post-test. Designed for ad- to diagnose and treat cancers of the decisions regarding the awarding of cred- launched a new course on medical imag- vanced practitioners, this course benefi ts liver, lung, and kidney, and explain its will be made by the licensing organiza- ing. The course was designed by imaging anyone wanting to learn more about in- the two ways drug-eluting beads (used tion to which the credits are submitted. experts—with specialties including in- terpreting medical imaging, including in DEB TACE) treat hepatocellular The course is also available for pur- terventional radiology, diagnostic radi- when to order and when not to order. carcinoma. chase as part of the ASCO University ology, and nuclear medicine—to create Upon completing the course, users ■ Radiologic Response will help Essentials package, which provides un- a foundational curriculum, especially for will have a better understanding of how learners identify issues and challenges limited access to more than 100 courses those new to practice. to use imaging to guide therapy, includ- with response assessment, explain in the ASCO University course catalog. “Emerging companion diagnostic im- ing the best ways to optimize drug thera- different methods of response An annual subscription also includes a aging and therapeutic agents have the pies, demonstrate targets prior to thera- assessment, discuss the interpretation Personalized Learning Dashboard, an potential to become hallmarks of pre- py, and evaluate the response to certain of each method in clinical context, enhanced self-assessment tool that sup- cision medicine, optimizing selection therapies. and describe future research ports a more individualized approach of patients for individual therapies and The four sections of the course are as considerations. to oncology education, utilizing the en- how these drugs are delivered,” said follows: ■ New and Emerging Imaging hanced self-assessment to offer tailored course faculty member Heather Jacene, ■ Diagnostic Imaging will help Modalities will help learners defi ne content recommendations based on MD, of the Dana-Farber Cancer Institute. learners identify common imaging theranostics, discuss prognostic identifi ed knowledge gaps. Course faculty member Richard Mar- modalities used in oncology, explain versus predictive biomarkers, discuss For more information on the shall, MD, of LSU Health, noted, “Inter- how radiologists use Response applications of molecular imaging ASCO University imaging course, visit ventional radiology [IR] is an integral Evaluation Criteria in Solid Tumors for theranostics and as imaging university.asco.org. component of precision medicine that (RECIST) reporting, discuss the biomarkers, and explain other uses imaging technology to extend can- basic concepts of liver imaging, and applications where imaging can be Reprinted and adapted with permission cer care to patients in a minimally in- describe the basic concepts of rectal used to guide therapy. from the March 2018 issue of ASCO vasive way. IR procedures help patients cancer staging. Connection. H;E;FH6DL6@;A͙4A?Χ:4B

BB͹2>͹GE͹ Χ Π>WZZhGE2͜>>4 ͙2ZZaWUVcbaRbRaeRQ͙ HRajR]W^΢WbMcaMQR\MaY^f]RQâZWPR]bRQOh6ZW>WZZhM]Q4^\_M]h͜WcbbdObWQWMaWRbâMűZWMcRb͙ C 30 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn ASCO Develops Professional Resources for Pain Management Dr. Bishoy M. hen it comes to helping pa- The program explores case scenarios After collecting responses, provid- tients with cancer manage using an interactive question format to ers then determine any areas in which Faltas Takes on pain, education and commu- select a course of action in managing the they need to improve communication. nication are critical. ASCO patient’s pain. The purpose is to provide Once this improvement plan has had Bladder Cancer WUniversity® has developed two resources a safe opportunity where the learner can adequate time to be implemented, pro- for providers to help facilitate educated make clinical decisions without real- viders administer an identical survey to clinical decision-making skills for pain world consequences. After every deci- a different cohort of 25 patients. Com- ladder cancer is the fourth management and feedback from patients sion the learner makes, they will receive paring responses before and after imple- most common cancer among in the forms of the Pain Management feedback on whether the choice was mented changes, providers then assess men. Like many cancers, it Program and the Pain Management Safe- clinically optimal, clinically suitable, or improvements as well as areas that still can be challenging to treat— ty Survey. incorrect. To access the program, visit need work. Bespecially when the cancer develops university.asco.org. “The survey taught us that patients resistance to chemotherapy or im- ASCO University’s Pain need to be told directly by their clinical munotherapy treatments. In such Management Program ASCO’s Pain Management team that they’re supposed to keep pain cases, there is often not much else Updated in February, the Pain Manage- Safety Survey medications in safe spots—possibly even doctors can offer. ment Program is designed to: ASCO offers the Pain Management lock boxes if that is appropriate for the Happily, that is beginning to ■ Apply personalized patient assessment Safety Survey, an activity designed to home situation,” Eric Roeland, MD, of change thanks to the work of re- and follow-up for multidimensional identify gaps in pain management com- the University of California, San Diego, searchers like Bishoy M. Faltas, MD. symptoms; munication. Available free of charge to who participated in the Pain Manage- Dr. Faltas, an assistant professor ■ Defi ne the principles of opioid initia- ASCO members, providers download a ment Safety Survey’s pilot alongside his at Weill Cornell Medicine, has been tion and titration, including recogniz- 26-question survey and administer it to palliative care team, said. studying ing indications and process of rotation; 25 patients, who answer anonymously. For both the Pain Management Pro- the chang- ■ Use general management strategies of Questions, which are directly related to gram and the Pain Management Survey, es in blad- opioid-related adverse effects and en- pain management, follow a yes/no for- participating providers can obtain con- der cancer sure safety, tolerance, and compliance mat and fall into three sections: tinuing medical education certifi cates that lead to with analgesic regimens; and ■ Aspects the provider explained to the (including AMA PRA Category 1 Credits™ treatment ■ Implement multimodal, multidis- patient; to physicians), ABIM MOC points, CNE resistance. ciplinary approaches and universal ■ Questions the provider asked the certifi cates, certifi cates of participation, He has also precautions when caring for all pa- patient; and or certifi cates of completion. To access been de- tients with cancer experiencing pain, ■ Whether the patient felt the commu- the survey, visit university.asco.org and veloping including patients with substance use nication was effective. search “Pain Management.” strategies disorder. –Caroline Hopkins to reverse Dr. Bishoy M. Faltas or prevent resistance so that patients continue Patient-Reported Outcomes 6. Tofthagen C, et al. Nurs Res Pract. oncology-care-with-pros. Published Au- responding to treatment. In 2015, Continued from page 24C 2014;2014:702683. gust 1, 2017. Accessed February 7, 2018. a Young Investigator Award from 7. Cooley ME, et al. Psychooncology. 24. Mandel JC, et al. J Am Med Inform Assoc. ASCO’s Conquer Cancer Founda- adjuvant chemotherapy for breast can- 2017;26:1105-12. 2016;23:899-908. tion, supported by the John and cer, as well as signifi cantly fewer adverse 8. Basch E, et al. J Clin Oncol. 2016;34:557- 25. Bloomfi eld RA, et al. Int J Med Inform. Elizabeth Leonard Family Founda- emotional and physical outcomes.36,37 65. 2017;99:1-10. tion, helped make this work pos- Also in Canada, clinical PRO screening 9. Klinkhammer-Schalke M, et al. Br J Cancer. 26. Berry DL, et al. American Urological Asso- sible. was associated with increased clinician 2012;106:826-38. ciation Annual Meeting. 2017;197:e933. “Even with the new immunother- documentation of pain outcomes as pa- 10. Rosenbloom SK, et al. Psychooncology. 27. Sanger PC, et al. J Am Med Inform Assoc. apy agents, less than one-quarter of tient-reported pain severity increased.38 2007;16:1069-79. 2016;23:514-25. patients will respond at any given Dutch clinicians reported long-term suc- 11. Steel JL, et al. Cancer. 2016;122:1270-82. 28. Sheldon LK, et al. Oncol Nurs Forum. time,” Dr. Faltas said. “I’m trying cess of nurse-coordinated PRO screening 12. Mullen KH, et al. Oncol Nurs Forum. 2011;38:369-75. to identify alternative strategies to with patients with head and neck can- 2004;31:E84-9. 29. Fann JR, et al. Psychooncology. 2009;18:14- target the other three-quarters of cer.39 The notable absence of the United 13. Basch E, et al. Clin Trials. 2016;13:331-7. 22. patients.” States in success stories has much to do 14. Berry DL, et al. J Clin Oncol. 2011;29:1029- 30. Kim EH, et al. IEEE Trans Inf Technol Dr. Faltas and his team are now with the barriers reviewed above. 35. Biomed. 2011;15:301-7. building on the fi ndings of their 15. Howell D, et al. Ann Oncol. 2015;26:1846- 31. Crane HM, et al. AIDS Behav. Conquer Cancer–funded study; Conclusions 58. 2017;21:3111-21. they are developing a small clini- PROs are desired by patients, en- 16. Basch E, et al. JAMA. 2017;318:197-8. 32. McReynolds J. University of Washington. cal trial to test a new treatment ap- able clinicians to effi ciently address the 17. Mooney K, et al. Am Soc Clin Oncol Educ Open-Source Computerized Patient- proach. Eventually, their research whole patient, and make a difference in Book. 2017;37:695-704. Reported Outcomes: Case Studies Il- could lead to better outcomes and clinical outcomes and patients’ experi- 18. Bruner DW. J Clin Oncol. 2007;25:5345-7. lustrating Fifteen Years of Evolution. increased survival for patients with ence of disease. There are many ways in 19. Basch E, et al. Ann Oncol. 2017;28:2332-3. bime.uw.edu/wordpress/wp-content/ bladder cancer. which suboptimal implementation may 20. Snyder CF, et al. Qual Life Res. uploads/2016/11/McReynolds-Justin-Ross- “This work was really critical for increase cost and decrease the value of 2012;21:1305-14. 2016-MS.pdf. 2016. Accessed February 7, my career—but also for our under- PROs, eroding their timeliness, accuracy, 21. Snyder CF, et al. Johns Hopkins Univer- 2018. standing of the biology of the dis- completeness, and personalization, and sity. Users’ Guide to Integrating Patient- 33. Baumhauer JF, et al. The Cost of Patient- ease,” Dr. Faltas said. “I’m hopeful may limit their utility. Computerized Reported Outcomes in Electronic Health Reported Outcomes in Medicine. NEJM that it will lead to signifi cant thera- PRO collection easily available to the pa- Records. pcori.org/sites/default/fi les/ Catalyst. catalyst.nejm.org/cost-pro-collec- peutic advances in the future. tient, increased integration of access and PCORI-JHU-Users-Guide-To-Integrating- tion-patient-reported-outcomes. Published “To me, conquering cancer means data with the EMR, and the ability to per- Patient-Reported-Outcomes-in-Electronic- January 25, 2018. Accessed February 9, translating the laboratory discov- sonalize the PRO experience for individ- Health-Records.pdf. Published May 2017. 2018. eries to new therapies that we can ual patients all contribute to maximizing Accessed February 7, 2018. 34. Chesser A, et al. Inform Health Soc Care. give to patients to hopefully cure feasibility and value. 22. American Society of Clinical Oncology. 2016;41:1-19. them,” Dr. Faltas said. New Articles Highlight the Potentials 35. Mobile Fact Sheet. Pew Research Center: References: of Patient Reported Outcome Tools and Internet and Technology. pewinternet.org/ Dr. Faltas’ 2015 ASCO’s Conquer 1. Jenssen BP, et al. J Gen Intern Med. Measurements. asco.org/advocacy-policy/ fact-sheet/mobile. Published February 5, Cancer Foundation Young Investigator 2016;31:85-92. asco-in-action/new-articles-highlight- 2018. Accessed February 7, 2018. Award was supported by the John and 2. Kai J, et al. Br J Cancer. 2011;105:918-24. potentials-patient-reported-outcome- 36. Barbera L, et al. Support Care Cancer. Elizabeth Leonard Family Foundation. 3. Walsh KE, et al. J Clin Oncol. 2009;27:891- tools-and. Published September 6, 2016. 2015;23:3025-32. 6. Accessed February 7, 2018. 37. Watson L, et al. J Natl Compr Canc Netw. 4. Grothey A, et al. Oncologist. 2014;19:669- 23. Purschel C. Oncology Nursing Society: 2016;14:164-72. 80. ONS VOICE. Improving Cancer Care 38. Seow H, et al. J Oncol Pract. 2012;8:e142-8. 5. Wolpin SE, et al. Health Informatics J. Through Patient-Reported Outcomes. 39. Duman-Lubberding S, et al. Support Care 2015;21:10-23. voice.ons.org/news-and-views/improving- Cancer. 2017;25:3775-83. …our R&D programs harness immuno-oncology, target oncogenic pathways, and investigate DNA Damage Response? Our pipeline may surprise you. Visit us at booth #14030

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Inside: LATE-BREAKING ABSTRACTS PAGES 8D-9D

recent years,” Dr. Partridge said, adding 2018 ASCO Annual Meeting Plenary Session Preview that the abstract results will inform how oncologists care for a large proportion of he 2018 ASCO Annual Meeting ministration The first Plenary abstract, LBA1, is patients with early-stage breast cancer. Plenary Session, which will take approval of the “TAILORx: Phase III trial of chemoendo- “We’ve all been anxiously waiting for place on June 3 from 1 PM to 4 HPV vaccines crine therapy versus endocrine therapy these data,” Dr. Partridge said. Lisa A. T PM in Hall B1, is the most antici- for cervical can- alone in hormone receptor-positive, Carey, MD, of UNC Lineberger Compre- pated event of the Meeting. The session cer prevention. HER2-negative, node-negative breast hensive Cancer Center, will discuss the includes 15-minute didactic presenta- “I am especial- cancer and an intermediate prognosis abstract. tions highlighting abstracts of scientific ly grateful to 21-gene recurrence score,” presented The second Plenary Abstract, LBA2, research deemed to have the highest ASCO for high- by first author Joseph A. Sparano, MD, is titled, “Maintenance low-dose che- merit and greatest impact on oncology lighting our of Montefiore Medical Center. The pro- motherapy in patients with high-risk research and practice. In addition to the translational spective randomized trial looked at en- rhabdomyosarcoma: A report from the abstract presentations, experts in the research, which Dr. Ann H. Partridge docrine therapy versus chemoendocrine European Paediatric Soft Tissue Sar- field serve as discussants, placing the re- is on primary therapy in women with HR-postive, coma Study Group (EpSSG),” and will search findings into context. prevention,” Dr. Lowy said. HER2-negative, axillary node-negative be presented by first author Gianni Bi- Prior to the abstract presentations, As for the abstracts chosen for this breast cancer who had a mid-range On- sogno, MD, of the University of Padova, Douglas R. Lowy, MD, will receive the year’s Plenary Session, Ann H. Partridge, cotype DX Recurrence Score of 11 to 25 in Italy. Approximately 20% to 30% of 2018 Science of Oncology Award. The MD, MPH, FASCO, of the Dana-Farber and tumors 1.1 to 5.0 cm in size. The patients with localized rhabdomyosar- award honors outstanding contribu- Cancer Institute and chair of the Plena- primary endpoint was invasive disease- coma experience disease relapse after tions to basic or translational research ry Session, said the science will impact free survival, and the trial was designed standard treatment, and the prognosis in cancer. Dr. Lowy, the deputy director how oncologists care for patients going to show noninferiority for endocrine is poor. This study tested whether add- of the National Cancer Institute (NCI) forward. “I was so excited when these therapy alone. ing maintenance metronomic chemo- and chief of the NCI’s Laboratory of Cel- abstracts came in,” Dr. Partridge said. “For any breast cancer clinician—or therapy after standard chemotherapy lular Oncology, is being recognized for “I was even more excited to see that anyone who cares for women with breast would improve the survival for patients his work in developing the technology the highest-ranking abstracts covered a cancer—this abstract may be one of the with nonmetastatic rhabdomyosarcoma underlying the U.S. Food and Drug Ad- range of cancer types and specialties.” most important studies to come out in See Plenary Session Preview, Page 16D

7:30 AM–9:30 AM 8:00 AM–9:15 AM Lora Jane Black, RN, MPH, OCN, CCRP Early-Morning Sessions Sanford Research EDUCATION SESSION EDUCATION SESSION Technologies and Resources for Training Program Directors’ Breakfast Beyond Chemotherapy: Checkpoint Implementing Precision Medicine Trials in 7:30 AM–9:15 AM (Training Program Directors and Associate Inhibition and Cell-Based Therapy in Community-Based Settings Directors Only) Non-Hodgkin Lymphoma HIGHLIGHTS OF THE DAY SESSION S103 E450 Panel Question and Answer Highlights of the Day Session I Professional Development Hematologic Malignancies—Lymphoma and Hall D1 Chronic Lymphocytic Leukemia; Developmental 7:30 AM David R. Spigel, MD—Chair Therapeutics and Translational Research; Hematologic Breakfast and Networking EDUCATION SESSION Sarah Cannon Research Institute, Tennessee Malignancies—Leukemia, Myelodysplastic Thinking Beyond RECIST Oncology 7:45 AM Syndromes, and Allotransplant; Immunotherapy S100a Julia Lee Close, MD 7:30 AM Catherine Bollard, MD, MBChB Tumor Biology; Clinical Trials; Developmental University of Florida Joon H. Uhm, MD Children’s National Medical Center Therapeutics and Translational Research Welcome and Introductions Mayo Clinic The Landscape of Anti–CD-19 CAR T Mizuki Nishino, MD, MPH Central Nervous System Tumors 7:55 AM Cells in the Management of Non-Hodgkin Dana-Farber Cancer Institute Frank P. Worden, MD Lymphoma 7:45 AM Is It Time to Move Beyond RECIST Criteria University of Michigan Comprehensive Christophe Le Tourneau, MD, PhD Leo I. Gordon, MD—Chair for Tumor Response Evaluation? Cancer Center Institut Curie Northwestern University Feinberg School of Review of Programs and Resources for Prateek Prasanna, PhD Developmental Therapeutics—Clinical Medicine, Robert H. Lurie Comprehensive Cancer Program Directors Case Western Reserve University Pharmacology and Experimental Center of Northwestern University Novel Quantitative Tumor Imaging: Therapeutics 8:10 AM Cell Therapy in Lymphoma: Practical Techniques and Clinical Applications Frances A. Collichio, MD Applications and New Targets 8:00 AM University of North Carolina School of Medicine Lawrence Howard Schwartz, MD—Chair Patrick Hwu, MD Loretta J. Nastoupil, MD Milestones 2.0 and Harmonized Milestones Columbia University Medical Center, NewYork- The University of Texas MD Anderson The University of Texas MD Anderson Presbyterian Hospital Cancer Center 8:25 AM Cancer Center Incorporating Novel Imaging Techniques and Developmental Therapeutics— Roberto Antonio Leon-Ferre, MD Checkpoint Inhibitors in Lymphoma: Novel Imaging Study End Points in Clinical Immunotherapy Mayo Clinic When and How Trials: Opportunities and Challenges Trainee Council Updates and Sharing 8:15 AM Panel Question and Answer Ethan M. Basch, MD, FASCO Surbhi Sidana, MD Panel Question and Answer The University of North Carolina at Chapel Hill Mayo Clinic Health Services Research, Clinical Trainee Council Updates and Sharing MEET THE PROFESSOR SESSION Informatics, and Quality of Care EDUCATION SESSION Evelyn Mary Brosnan, MD, MBA Overcoming Unique Obstacles to Adjuvant/Neoadjuvant Treatment in 8:30 AM Dartmouth Hitchcock Medical Center Implementing Precision Medicine Trials in Melanoma: Where Surgery Meets Medical Guillermo Garcia-Manero, MD Trainee Council Updates and Sharing the Community Setting Oncology— T Ticketed Session The University of Texas MD Anderson 8:45 AM S100bc E253c Cancer Center Melanoma/Skin Cancers Julia Lee Close, MD, and Developmental Therapeutics and Translational Hematologic Malignancies—Leukemia, Research; Care Delivery and Practice Management; Adaeze Nwosu-Iheme, MD Amod Sarnaik, MD Myelodysplastic Syndromes, and Clinical Trials; Ethics University of Florida Moffitt Cancer Center Allotransplant Implementation of a Bias Curriculum Edward S. Kim, MD—Chair Is Neoadjuvant Treatment for Stage III 8:45 AM Melanoma Ready for Prime Time? 9:10 AM Levine Cancer Institute, Atrium Health Amrita Y. Krishnan, MD Identify Strategies and Best Practices for Frank P. Worden, MD Georgina V. Long, MD, PhD, FRACP City of Hope Precision Medicine Trials University of Michigan Comprehensive Melanoma Institute Australia, The University of Hematologic Malignancies—Plasma Cell Cancer Center Sydney, Mater Hospital, and Royal North Shore Dyscrasia Michael A. Thompson, MD, PhD, FASCO Open Discussion: What Keeps You Up at Aurora Advanced Healthcare Hospital Night? Challenges Conducting Precision Medicine What Is the Rationale for (Neo-)Adjuvant Trials in the Community Therapy in Stage III Melanoma? See Sessions, Page 10D T:10.25” T:14”

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077-0151-PM_ASCO_JA_Print_Daily_News_FR.indd 1 PREPARED BY AREA 23 4/6/18 12:44 PM Job #: 10939788 Releasing as: PDFX-1a Production: Anthony McCollin Billing: 10923979 AD: Vinny Ng Colors: 4C Client: Astellas AE: Lauren Rubin x6984 Product: Gilteritnib Bleed: NA Producer: Lisa Pietronuto x6850 Client Code: 077-0151-PM Trim: 10 1/4" x 14" Digital Artist: BB, NJ, BB, nJ Date: April 6, 2018 12:44 PM Safety: NA Add’l Size Info: Proof: FR Fonts: Helvetica (T1), Myriad Pro M1 Spellcheck: WR FR Spellcheck: CC Path:Area23:Astellas:Gilteritnib:10939788:Packaged_Jobs:077-0151-PM_ASCO_JA_Print_Daily_News:077-0151-PM_ASCO_JA_Print_Daily_News_FR 4C ASCO JA Print Daily News am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 3 D

CSS = Clinical Science Symposium ED = Education Session ORAL = Oral Abstract Session SUNDAY: SESSIONS AT A GLANCE T MTP = Meet the Professor Session (ticketed) CPO = T Clinical Problems in Oncology Session (ticketed)

Primary Track 7:30 AM 8:00 AM 9:00 AM 10:00 AM 11:00 AM 12:00 PM CSS: Compelling Combinations: Raising the Bar With Immunotherapy | Hall D1 Special Sessions Highlights of the Day Session I | Hall D1 ED: ASCO/European CanCer Organization (ECCO) Joint Session: Access and Innovation With Multiplex Genomic Testing | S100a

Breast Cancer ORAL: Breast Cancer–Metastatic | Hall D2

Cancer Prevention, Hereditary Genetics ORAL: Cancer Prevention, Hereditary Genetics, and Epidemiology | S404 ED: Lynch Syndrome 360 | S404 and Epidemiology

ED: Filling the Gap: Creating an Care Delivery and Outpatient Palliative Care Program Practice Management in Your Institution | S504

Central Nervous T MTP: Biology and Therapeutic Promise of System Tumors Exploiting IDH Mutations in Gliomas | E253c Developmental ED: Overcoming Unique Obstacles to T MTP: Primary and Acquired Resistance to Therapeutics and Implementing Precision Medicine Trials Checkpoint Inhibitors | E253d Translational Research in the Community Settings | S100bc POSTER DISCUSSION: GI (Colorectal) Cancer POSTER: Gastrointestinal (Colorectal) Cancer | Hall A Gastrointestinal (Colorectal) Cancer | Hall D2

T MTP: How Do I Treat GI (Noncolorectal) Hepatocellular Carcinoma? | E253d Cancer POSTER: Gastrointestinal (Noncolorectal) Cancer | Hall A GU (Nonprostate) ORAL: Genitourinary (Nonprostate) Cancer | Arie Crown Theater Cancer

ED: Management of Biochemically GU (Prostate) Cancer Recurrent Prostate Cancer: Which Imaging, Which Treatment, and When? | S406

T MTP: How to Bring Geriatric Assessment Geriatric Oncology Into Your Practice | E253d Global Health CSS: Engaging the Immune System in Ovarian Cancer ED: Moving From Mutation to Gynecologic Cancer | S406 Actionability | S100bc

T MTP: Treatment Strategies Head and ORAL: Head and Neck Cancer | E451 for Locoregionally Advanced Neck Cancer Nasopharyngeal Cancer: Making Sense of Recent Studies | E253c Health Services Res, ED: Collecting and Using Real-World Evidence: Clinical Informatics, Supplementing and Perhaps Replacing Clinical Trials and Quality of Care (Includes Presentation of Public Service Award) | S100a Heme Malignancies— Leukemia, MDS, and Allotransplant

ED: Beyond Chemotherapy: Checkpoint Heme Malignancies— Inhibition and Cell-Based Therapy in ORAL: Hematologic Malignancies–Lymphoma and Chronic Lymphocytic Leukemia | E450 Lymphoma and CLL Non-Hodgkin Lymphoma | E450

Heme Malignancies— Plasma Cell Dyscrasia

POSTER: Lung Cancer–Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers | Hall A POSTER DISCUSSION: Lung Lung Cancer Cancer–Non-Small Cell POSTER: Lung Cancer–Non-Small Cell Metastatic | Hall A Metastatic | Arie Crown Theater

T MTP: Adjuvant/Neoadjuvant Melanoma/ ED: A New Era in the Management of Treatment in Melanoma: Where Surgery Skin Cancers Melanoma Brain Metastases | S100bc Meets Medical Oncology | E253c

Patient and ED: How Can Genetics Personalize ORAL: Patient and Survivor Care | S102 Survivor Care Cancer Survivorship? | S102

Pediatric Oncology ORAL: Pediatric Oncology II | S504

ED: Training Program Directors’ Breakfast (Training Program Professional CSS: Innovative Approaches to Directors and Associate Training Program Directors Only) | Development Oncology Education | S103 S103 ED: Controversies in Adjuvant/ Sarcoma Neoadjuvant Chemotherapy in Localized Soft Tissue Sarcoma | E451

Tumor Biology ED: Thinking Beyond RECIST | S100a D 4 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Primary Track 1:00 PM 2:00 PM 3:00 PM 4:00 PM 5:00 PM

Plenary Session Including the Science of Post-Plenary Discussion Post-Plenary Discussion Post-Plenary Discussion Post-Plenary Discussion Special Sessions Session I: Breast Session II: Rhabdomyo- Session III: Kidney Session IV: Lung Oncology Award and Lecture | Hall B1 Cancer | S100a sarcoma | S100bc Cancer | S100a Cancer| S100bc (With Simulcast in Hall D1)

The Plenary Session includes abstract presentations ED: Innovative Strategies Targeting Subtypes in Metastatic Breast Cancer of the top practice-changing science, with commentary Breast Cancer | Hall B1 from expert discussants. Cancer Prevention, ED: Lifestyle Modifications for Primary and Secondary Cancer Hereditary Genetics Prevention: Diet, Exercise, Sun Safety, and Alcohol Reduction | and Epidemiology ABSTRACT 1: Breast Cancer S102 ABSTRACT 2: Rhabdomyosarcoma Care Delivery and ABSTRACT 3: Kidney Cancer Practice Management ABSTRACT 4: Lung Cancer Central Nervous System Tumors TODAY’S PLENARY SESSION Developmental Therapeutics and Plenary Session Abstracts: Page 9D Translational Research Plenary Session Program Information: Page 18D

GI (Colorectal) Cancer ATTEND THE POST-PLENARY DISCUSSIONS Breast Cancer | 4:00 PM-4:30 PM, S100a GI (Noncolorectal) Rhabdomyosarcoma | 4:30 PM-5:00 PM, S100bc POSTER DISCUSSION: Gastrointestinal (Noncolorectal) Cancer Cancer | Hall D2 Kidney Cancer | 5:00 PM-5:30 PM, S100a GU (Nonprostate) Lung Cancer | 5:30 PM-6:00 PM, S100bc Cancer

ED: The Winds of Change: Optimizing Immunotherapy, GU (Prostate) Cancer Radiopharmaceuticals, and PARP Inhibition in Prostate Cancer | Hall D1

Geriatric Oncology

Global Health

Gynecologic Cancer

Head and Neck Cancer

Health Services Res, ED: Communicating the Financial Burden of Treatment With Clinical Informatics, Patients | S404 and Quality of Care Heme Malignancies— Leukemia, MDS, and Allotransplant

Heme Malignancies— ED: Common Themes in Uncommon Lymphomas: How Biology Lymphoma and CLL and Novel Treatments Are Changing the Landscape | E450

Heme Malignancies— ED: Global Myeloma, Health Disparities, and the Cost of Plasma Cell Dyscrasia Drugs | E451

POSTER DISCUSSION: Lung Cancer-Non-Small Cell Lung Cancer Local–Regional/Small Cell/Other Thoracic Cancers | Arie Crown Theater

Melanoma/ Skin Cancers

Patient and T MTP: Addressing Fertility in Young Adult Cancer Survivor Care Survivors | E253d

ED: Pediatric Clinical Trials: Economics, Cost, and Value of Pediatric Oncology Investment | S504

Professional T MTP: The Peer-Review Process and Writing an Development Outstanding Manuscript | E253c

ED: Novel Approaches in Bone and Soft Tissue Sarcomas: Sarcoma The Emerging Role of Precision Medicine | S103

ED: Precision Medicine for a Single Patient: What Does It Tumor Biology Really Mean and How Do We Do It? | S406 In indolent NHL… As our knowledge evolves, so should our approach Our understanding of indolent non-Hodgkin lymphoma (NHL), which includes follicular lymphoma (FL) and marginal zone VISIT BOOTH 10097 lymphoma (MZL), has improved greatly. We know that Learn more about Celgene’s indolent NHL is characterized in part by dysfunction within commitment to researching the tumor microenvironment that drives changes to the chemotherapy-free approaches immune system.1,2 for patients with FL or MZL.

Celgene is researching approaches for patients that seek to #Chemosaurus address the underlying immune dysfunction that contributes to these diseases.2

References: 1. Yang ZZ, Ansell SM. The tumor microenvironment in follicular lymphoma. Clin Adv Hematol Oncol. 2012;10(12):810-818. 2. Kridel R, Sehn LH, Gascoyne RD. Pathogenesis of follicular lymphoma. J Clin Invest. 2012;122(10):3424-3431.

Cosmos Communications 1 Q1 Q2 C M Y K rl 37595a 04.24.18 133 1 IN METASTATIC BREAST CANCER EXCEPT HERE. MENOPAUSAL

For nearly 20 years, few large clinical trials have been solely dedicated to premenopausal women with metastatic breast cancer1,*

dedicated studies for studies for POSTMENOPAUSAL PREMENOPAUSAL 28 women with mBC 2 women with mBC *Large clinical trials were de ned as Phase III trials of 200 or more women. Dated April 2018.

It is estimated that as of January 2017, more than 20,000 women with mBC in the US were younger than 502 1 IN 7 WOMEN with mBC were younger than 50

Hear from leading breast cancer experts and learn more at RETHINKPREMENO.COM

Dedicated to building a high standard of evidence speci c to young women living with metastatic breast cancer

mBC=metastatic breast cancer. References: 1. ClinicalTrials.gov. Search results for premenopausal metastatic breast cancer studies recruiting; not yet recruiting; active, not recruiting, completed, enrolling by invitation, suspended, terminated, withdrawn, unknown status; phase 3. Search results for postmenopausal metastatic breast cancer studies recruiting; not yet recruiting; active, not recruiting, completed, enrolling by invitation, suspended, terminated, withdrawn, unknown status; interventional studies; studies with female participants; phase 3. Accessed April 2, 2018. 2. Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation of the number of women living with metastatic breast cancer in the United States. Cancer Novartis Pharmaceuticals Corporation Epidemiol Biomarkers Prev. 2017;26(6):809-815. East Hanover, New Jersey 07936-1080 © 2018 Novartis 4/18 BST-1186891

1013106bi_b.indd All Pages 4/21/18 7:53 AM IN METASTATIC BREAST CANCER EXCEPT HERE. MENOPAUSAL

For nearly 20 years, few large clinical trials have been solely dedicated to premenopausal women with metastatic breast cancer1,*

dedicated studies for studies for POSTMENOPAUSAL PREMENOPAUSAL 28 women with mBC 2 women with mBC *Large clinical trials were de ned as Phase III trials of 200 or more women. Dated April 2018.

It is estimated that as of January 2017, more than 20,000 women with mBC in the US were younger than 502 1 IN 7 WOMEN with mBC were younger than 50

Hear from leading breast cancer experts and learn more at RETHINKPREMENO.COM

Dedicated to building a high standard of evidence speci c to young women living with metastatic breast cancer

1013106bi_b.indd All Pages 4/21/18 7:53 AM D 8 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

} LATE-BREAKING ABSTRACTS: LBA1006 | } LATE-BREAKING ABSTRACTS: LBA3579 |

Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) Comparison of chemotherapy use, cost, and survival in patients with metastatic with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or colorectal cancer in Western Washington and British Columbia. metastatic breast cancer (MBC): Primary analysis from SANDPIPER. GASTROINTESTINAL First Author: Todd Yezefski, MS, MD BREAST CANCER—METASTATIC First Author: Jose Baselga, MD, PhD, FASCO (COLORECTAL) CANCER University of Washington School of Medicine Oral Abstract Session Memorial Sloan Kettering Cancer Center Poster Session (Board #72) Sunday, 8:00 AM-11:00 AM Discussant: Cynthia X. Ma, MD, PhD Sunday, 8:00 AM-11:30 AM Location: Hall D2 Washington University School of Medicine in St. Louis Location: Hall A

Background: Taselisib, a potent, selective PI3K inhibitor, has enhanced activity in PIK3CA- Background: Few studies have directly compared health care utilization, costs, and MUT BC cell lines and confirmed partial responses in PIK3CA-MUT BC as a single-agent or outcomes between geographically similar patients (pts) treated in the U.S.’ multi-payer with FULV. We assessed taselisib + FULV in pts with ER-positive, HER2-negative, PIK3CA- health system versus Canada’s single-payer system. Using cancer registry and claims MUT locally advanced or MBC. Methods: SANDPIPER (NCT02340221) is a double-blind, data, we assessed systemic therapy (ST) use, cost, and survival for metastatic colorectal placebo (PBO)-controlled, randomized, phase III study. Postmenopausal pts with disease cancer (mCRC) pts in Western Washington (WW) and British Columbia (BC). Methods: Pts recurrence or progression during or after an aromatase inhibitor were randomized 2:1 age ≥ 18 diagnosed with mCRC in 2010 and later were identified from 1) the BC Cancer to receive taselisib (4 mg oral, qd) or PBO + FULV (500 mg). Stratification factors were: Agency database and 2) a regional database linking WW SEER to claims from two large visceral disease, endocrine sensitivity, and geographic region. Pts with PIK3CA-MUT commercial insurers. Demographic and treatment characteristics for the two populations tumors, assessed by central cobas PIK3CA Mutation Test, were randomized separately were compared using two-sample T tests. ST costs (first-line and lifetime) were expressed from non-MUT tumors. The primary endpoint was investigator-assessed progression- as mean per patient per month costs; Canadian costs were expressed in US dollars using free survival (INV-PFS) in pts with PIK3CA-MUT tumors. Secondary endpoints included the Purchasing Power Parity for Health in 2009. Median survival was reported for both objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), duration populations. Results: 1622 BC pts and 575 WW pts were included in the analysis. BC pts of objective response (DoR), PFS by blinded independent central review (BICR-PFS), were more likely to be older (median age 60 vs 66) and male (57% vs 48%, p = < 0.01). A and safety. Results: 516 pts were randomized in the PIK3CA-MUT intention-to-treat greater proportion of WW versus BC pts received ST (79% vs. 68%, p < 0.01). FOLFIRI plus (ITT) population. Efficacy is shown in the Table. Taselisib + FULV significantly improved bevacizumab was the most common first-line regimen in BC (32%) while FOLFOX was the INV-PFS (hazard ratio [HR] 0.70) as confirmed by BICR-PFS (HR 0.66). OS is immature. most common first-line regimen in WW (39%). The mean monthly cost of first-line therapy The most common grade ≥3 adverse events (AEs; preferred terms) in the taselisib + per patient was significantly higher in WW than BC ($12,345 vs $6,195, p = < 0.01), and FULV arm in safety-evaluable pts who received ≥ 1 dose of treatment were diarrhea this was true for all regimens assessed. Mean lifetime monthly ST costs were significantly (12%), hyperglycemia (10%), colitis (3%), and stomatitis (2%). AEs led to more taselisib higher in WW ($7,883 vs $4,830, p = < 0.01). There was no difference in median overall discontinuations (17% v 2%) and dose reductions (37% v 2%), v PBO. Conclusions: survival between populations among those receiving ST (21.4 months (95% CI 18.0-26.2) Taselisib + FULV significantly improved INV-PFS, v PBO + FULV, in pts with ER-positive, in WW and 22.1 months (20.5-23.7) in BC) or among those not receiving ST (5.4 months HER2-negative, PIK3CA-MUT locally advanced or MBC. The safety profile is largely (2.4-7.7) WW versus 6.3 months (5.2-7.3) BC). Conclusions: Utilization and cost of ST for consistent with previous studies. Clinical trial information: NCT02340221. mCRC was significantly higher for patients in WW compared to BC without differences in overall survival in treated and untreated patients. ITT PBO + FULV Taselisib + FULV Median INV-PFS, mo N=176 N=340 5.4 7.4 HR 0.70 (p=.0037) Baseline measurable disease n=134 n=264 ORR, % 11.9 28.0 p=.0002 CBR, % 37.3 51.5 DoR, mo n=16 n=74 7.2 8.7

See full session details p. 10D See full session details p. 16D

} LATE-BREAKING ABSTRACTS: LBA6002 | } LATE-BREAKING ABSTRACTS: LBA10003 |

Are women with head and neck cancer undertreated? Improving communication with older patients with cancer using geriatric assessment (GA): A University of Rochester NCI Community Oncology Research Program HEAD AND NECK CANCER First Author: Annie Park, MD (NCORP) cluster randomized controlled trial (CRCT). Oral Abstract Session Kaiser Permanente Sunday, 8:00 AM-11:00 AM Discussant: Faye M. Johnson, MD, PhD PATIENT AND SURVIVOR CARE First Author: Supriya Gupta Mohile, MD, MS Location: E451 The University of Texas MD Anderson Cancer Center Oral Abstract Session University of Rochester Medical Center Sunday, 8:00 AM-11:00 AM Discussant: Ethan M. Basch, MD, FASCO Background: Generalized competing event (GCE) models have been used to stratify Location: S102 The University of North Carolina at Chapel Hill patients with cancer according to their relative hazard for cancer death versus death from other causes. We evaluated outcomes for head and neck cancer (HNC) patients Background: GA includes validated measures that assess age-related health domains treated at Kaiser Permanente Northern California (KPNC) based on demographic data and (e.g., function, cognition) known to increase adverse outcomes. In this PCORI and comorbidities using a GCE model. Methods: We identified 884 HNC patients diagnosed NCI funded CRCT, we evaluated if providing a GA summary and recommendations 2000-2015 from the KPNC cancer registry, age 18-85 and stage II-IVB by AJCC 7th edition. for GA-guided interventions improves communication about age-related concerns for Using the GCE proportional relative hazards model, controlling for age, sex, tumor site, older patients (pts) with cancer. Methods: Pts aged ≥ 70 with advanced solid tumors and Charlson comorbidity index (CCI), we identified associations between these factors or lymphoma and at least 1 impaired GA domain were enrolled. Oncology practices and the relative hazard for HNC-specific mortality ω( + ratio, ‘gcerisk’ package in R). Death, were randomized to intervention (oncologists received GA summary) or usual care (no disenrollment, and end of study (12/31/2016) were used as censoring events. Logistic summary provided). The primary outcomes were: 1) number of discussions about age- regression models estimated the odds of receiving intensive treatment (platinum based related concerns (the clinic visit after GA was audio-recorded and transcribed; 2 blinded regimen), adjusting for the same covariates plus stage, smoking, and alcohol abuse coders evaluated quality of communication and plan for follow-up interventions) and 2) history. Results: With a median follow-up of 2.9 years, 271 patients died of cancer, and telephone surveys of patient satisfaction (modified Health Care Climate Questionnaire 93 of non-cancer causes. Compared to male, females were less likely to receive intensive [HCCQ-age] scored 7-35). Outcomes were analyzed using linear mixed models with chemotherapy (35% vs. 46%, p = 0.006) and radiation (60% vs. 70%, p = 0.008). On GCE arm as the fixed effect, controlling for practice.Results: From 2014-17, 544 pts (295 in analysis, female patients had an increased relative hazard ratio (RHR) for death from HNC GA) were enrolled from 31 practices. There were no differences in demographics by vs. other causes (adjusted RHR 1.92; 95% CI 1.07-3.43), indicating they may be relatively arm (mean age 77 yrs; 49% female). More patients in usual care had impaired physical undertreated. Conclusions: Female patients in our cohort may be undertreated in clinical performance (96% vs 92%, p = 0.03) and social support (33% vs 25%, p = 0.05). In practice, potentially missing the opportunity to aggressively treat their HNC. This study 530 evaluable pts, the overall mean number of discussions was 6.3 (SD: 4.0). The GA supports the use of a GCE methodology to objectively identify patients more likely to arm had 3.5 more discussions about age-related concerns (95% CI: 2.28-4.72, p = 10-6; benefit from treatment intensification. These findings may help guide future research in intraclass correlation coefficient [ICC] = 0.24) compared to usual care; of these, in the health disparities. GA arm, 2.0 more discussions on average had higher quality communication (95% CI: 1.20-2.69; p = 6x10-6) and 1.9 more led to interventions (95% CI: 1.14-2.73; p = 1.6x10-5). ω+ ratio and odd ratio for select variables. The GA arm had significantly more discussions for almost all GA domains. In 511 pts with HCCQ-age, the mean score was 22.9 (SD 4.5); the score was 1.12 points higher in the GA Covariate Adjusted RHR (ω+ ratio) Intensive Radiation OR Surgery OR for cancer vs. non-cancer chemotherapy (95% CI) (95% CI) arm (95% CI: 0.23-2.03; p = .027; ICC = 0.02). Conclusions: Providing a GA summary to mortality (95% CI) OR (95% CI) oncologists increases the number and quality of discussions about age-related concerns Female 1.92 (1.07-3.43) 0.68 (0.48, 0.98) 0.79 (0.56, 1.11) 1.04 (0.72, 1.53) and improves pt satisfaction. Clinical trial information: NCT02107443. CCI > = 1 0.75 (0.46-1.24) 0.78 (0.68-0.89) 0.96 (0.86-1.07) 1.02 (0.91-1.15) Age (per 0.78 (0.62-0.99) 0.88 (0.75-1.02) 0.90 (0.77-1.05) 0.70 (0.59-0.82) 10 years)

See full session details p. 10D See full session details p. 15D am.asco.org/dn ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 9 D

} LATE-BREAKING ABSTRACTS: LBA1 | } LATE-BREAKING ABSTRACTS: LBA2 |

TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone Maintenance low-dose chemotherapy in patients with high-risk (HR) in hormone receptor-positive, HER2-negative, node-negative breast cancer and an rhabdomyosarcoma (RMS): A report from the European Paediatric Soft Tissue intermediate prognosis 21-gene recurrence score. Sarcoma Study Group (EpSSG).

BREAST CANCER—LOCAL/ First Author: Joseph A. Sparano, MD PEDIATRIC ONCOLOGY First Author: Gianni Bisogno, MD REGIONAL/ADJUVANT Montefiore Medical Center Plenary Session University Hospital of Padova Plenary Session Discussant: Lisa A. Carey, MD Sunday, 1:00 PM-4:00 PM Discussant: Douglas S. Hawkins, MD Sunday, 1:00 PM-4:00 PM The University of North Carolina at Chapel Hill Location: Hall B1 Seattle Children’s Hospital, University of Washington, Location: Hall B1 Fred Hutchinson Cancer Research Center

Background: In hormone receptor (HR)-positive, HER2-negative, axillary node (AN)- Background: Most patients with localized RMS achieve complete remission during negative breast cancer, the 21-gene expression assay (Oncotype DX Recurrence Score standard (std) treatment but approximately 20-30% of them relapse and chance of [RS]) is prognostic for distant recurrence, prognostic for low recurrence with endocrine salvage is poor. We tested whether adding maintenance metronomic chemotherapy therapy alone if low (0-10), and predictive of chemotherapy benefit if high (26 or after std chemotherapy would improve survival for patients with non metastatic RMS higher). We performed a prospective, randomized trial of endocrine therapy (ET) versus defined as HR according to EpSSG stratification.Methods: Patients (pts) age >6 months chemoendocrine therapy (CET) in women with a mid-range RS of 11-25. Methods: <21 years, with N0 alveolar (A)RMS or incompletely resected (Group II or III) embryonal Eligibility criteria included women 18-75 years of age with HR-positive, HER2-negative, (E)RMS arising in an unfavorable primary site and/or N1 in complete remission after std axillary node (AN)-negative breast cancer and tumors 1.1-5.0 cm in size (or 0.6-1.0 cm treatment including 9 cycles of ifosfamide, vincristine and actinomycin D +/- doxorubicin, and int/high grade) and agreed to have chemotherapy assigned or randomized based on surgery and/or radiotherapy were eligible for randomization to stop treatment (Std-arm) the RS. Women with a mid-range RS (11-25) were randomized to receive ET or CET. The or receive maintenance chemotherapy (M-arm) with 6 28-day cycles of iv vinorelbine 25 primary endpoint was invasive disease-free survival (iDFS), and the trial was designed mg/m2 on day 1,8,15 of each cycle and continuous daily oral cyclophosphamide 25 mg/ to show non-inferiority for ET alone by not rejecting equality (hazard ratio [HR] margin m2. The study was initially designed with 80% power (5% 2-sided alpha level) to detect up to 1.322 for omission of chemotherapy, 1-sided type I error rate 10%, type II error an increase in 3 yr Event Free Survival (EFS) from 55% to 67%, a Hazard Ratio of 0.67, rate 5%). The target sample size was adjusted to compensate for non-adherence to but was successively amended to allow a detection of a relative reduction in the relapse randomized treatment, and the protocol-specified final analysis was triggered after 835 rate of 50% in the M-arm, with 80% power, testing at the 5% significance level (2-sided). iDFS events. Results: Of the 10,253 eligible women enrolled between 4/7/06-10/6/10, Results: 670 pts were entered between 4/2006-12/2016, with 371 confirmed eligible and 6711 (65.5%) had a RS of 11-25 and adequate information. There were 836 iDFS events 186 assigned to the std-arm and 185 to M-arm. Clinical features were well balanced in the at final analysis with a median followup of 90 months. ET was non-inferior to CET for iDFS two arms and included ERMS 67%, ARMS 33%, age 10+ years 21%; IRS Group III 86%; (HR 1.08, 95% confidence intervals [CI] 0.94, 1.24, p=0.26) in the intention-to-treat (ITT) N1 16%. Most common primary tumor sites were parameningeal (32%) and “other” sites population. ET was also non-inferior for distant recurrence-free interval (DRFI; HR 1.03, (23%). With median follow up of 5 years in surviving pts, 3 yr EFS and overall survival p=0.80), recurrence-free interval (RFI; HR 1.12, p=0.28), and overall survival (OS; HR (OS) in M-arm vs Std-arm were respectively: EFS 78.4% (95% IC -71.5-83.8) vs 72.3% 0.97, p=0.80). Nine year rates were similar for iDFS (83.3% vs. 84.3%), DRFI (94.5% vs. (95% IC -65.0-78.3) (p 0.061) and OS 87.3% (95% IC 81.2-91.6) vs 77.4 (95% IC 70.1-83.1) 95.0%), RFI (92.2% vs. 92.9%), and OS (93.9% vs. 93.8%). Recurrence accounted for 338 (p = 0.011). Toxicity in the M-arm was manageable: grade 3/4 febrile neutropenia in 25% (41.6%) the first iDFS event, of which 199 (23.8%) were distant recurrences. Treatment of pts, grade 4 neurotoxicity in 1.1%. Conclusions: The addition of maintenance after interaction tests were significant for age (iDFS p=0.03; RFI p= 0.02), but not menopause, std treatment significantly improves OS in HR RMS patients and support its inclusion in tumor size, grade, or RS (continuous or RS 11-15, 16-20, 21-25). Conclusions: In women future EpSSG trials. Clinical trial information: 2005-000217-35. with HR-positive, HER2-negative, AN-negative breast cancer and a RS of 11-25, adjuvant ET was not inferior to CET in the ITT analysis. (Funded by NCI, BCRF, and Komen Foundation.) Clinical trial information: NCT00310180.

See full session details p. 20D See full session details p. 20D

} LATE-BREAKING ABSTRACTS: LBA3 | } LATE-BREAKING ABSTRACTS: LBA4 |

CARMENA: Cytoreductive nephrectomy followed by sunitinib versus sunitinib alone Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line in metastatic renal cell carcinoma—Results of a phase III noninferiority trial. therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. GENITOURINARY (NONPROSTATE) First Author: Arnaud Mejean, MD, PhD CANCER Hôpital Européen Georges-Pompidou, Paris Descartes LUNG CANCER—NON–SMALL First Author: Gilberto Lopes, MD, MBA Plenary Session University CELL METASTATIC Sylvester Comprehensive Cancer Center, University of Sunday, 1:00 PM-4:00 PM Discussant: Daniel J. George, MD Plenary Session Miami Health System Location: Hall B1 Duke University Sunday, 1:00 PM-4:00 PM Discussant: Leena Gandhi, MD, PhD Location: Hall B1 NYU Perlmutter Cancer Center Background: Cytoreductive nephrectomy (CN) has been the standard of care in mRCC in the past twenty years, supported by randomized and large retrospective studies. Background: In KEYNOTE-024, pembro significantly improved PFS (primary end point) However the efficacy of targeted therapies has challenged this standard. CARMENA was and OS (secondary end-point) over chemo as first-line therapy for metastatic NSCLC designed to answer the question of whether upfront CN should continue to be performed without targetable alterations and PD-L1 TPS ≥50%. In KEYNOTE-042, we compared before sunitinib. Methods: CARMENA was a randomized phase III trial. Patients (pts) pembro with chemo at the lower TPS of ≥1%. Methods: Eligible patients (pts) were with synchronous mRCC, amenable to CN, were enrolled after confirmation of clear cell randomized 1:1 to ≤35 cycles of pembro 200 mg Q3W or investigator’s choice of ≤6 histology on biopsy if PS 0-1, absence of symptomatic brain metastasis, acceptable organ cycles of paclitaxel + carboplatin or pemetrexed (peme) + carboplatin with optional function and eligible for sunitinib therapy. Pts were randomized 1:1 to either CN followed peme maintenance (nonsquamous only). Randomization was stratified by region (east by sunitinib (arm A) or sunitinib alone (arm B), and stratified by MSKCC risk groups. Asia vs non-east Asia), ECOG PS (0 vs 1), histology (squamous vs nonsquamous), and Sunitinib was given at 50 mg/d, 4/6wk with dose adaptation to routine practice. In arm A, TPS (≥50% vs 1-49%). Primary end-points were OS in pts with TPS ≥50%, ≥20%, and sunitinib had to start 4 to 6 wk after surgery. Primary endpoint was overall survival (OS). ≥1%. OS differences were assessed sequentially using the stratified log-rank test. Efficacy A total of 576 pts had to be enrolled to demonstrate non inferiority hypothesis (H0: λE/ boundaries at the prespecified second interim analysis were one-sided P = .0122, .01198, λC > 1.20), with 80% power at a 1-sided significance level of 5%.Results: 450 pts were and .01238, respectively. Results: 1274 pts were randomized: 637 to each arm. 599 included from 9/09 to 9/17, 226 and 224 in arm A and B, respectively. Median age was pts (47.0%) had TPS ≥50%, 818 (64.2%) had TPS ≥20%. After 12.8-mo median follow- 62, ECOG-PS was 0 in 56% and 1 in 44%. MSKCC risk groups were intermediate/poor in up, 13.7% were still on pembro and 4.9% were receiving peme maintenance. Pembro 55.6/44.4% (arm A) and in 58.5/41.5% (arm B). In arm A, 6.7% did not have CN and 22.5% significantly improved OS in pts with TPS≥ 50% (HR 0.69), TPS ≥20% (HR 0.77), and never received sunitinib. In arm B, 4.9 % never received sunitinib and 17% had secondary TPS ≥1% (HR 0.81) (Table). Grade 3-5 drug-related AEs were less frequent with pembro nephrectomy. At the time of the analysis, 326 deaths have been observed with a median (17.8% vs 41.0%). The external DMC recommended continuing the trial to evaluate PFS follow-up of 50.9 mo. OS was not inferior in arm B, overall as well as by MSKCC risk (secondary end-point). Conclusion: KEYNOTE-042 is the first study with a primary end- groups (table). No difference in response rate and PFS was observed. Safety of sunitinib point of OS to demonstrate superiority of pembro over platinum-based chemo in pts was as expected in both arms. Conclusions: Sunitinib alone is not inferior to CN followed with previously untreated advanced/metastatic NSCLC without sensitizing EGFR or ALK by sunitinib in synchronous mRCC both in intermediate and poor MSKCC risk groups. CN alterations and a PD-L1 TPS ≥1%. These data confirm and potentially extend the role of should not be anymore the standard of care when medical treatment is required. Clinical pembro monotherapy as a standard first-line treatment for PD-L1-expressing advanced/ trial information: NCT00930033. metastatic NSCLC. Clinical trial information: NCT02220894. PD-L1 TPS Arm A Arm B HR [CI95%] OS Median (mo) [CI95%] 13.9 [12-18] 18.4 [15-23] 0.89 [0.71-1.10] ≥50% ≥20% ≥1% MSKCC Intermediate 19.0 [12-28] 23.4 [17-32] 0.92 [0.68-1.24] Pembro Chemo Pembro Chemo Pembro Chemo N = 299 N = 300 N = 413 N = 405 N = 637 N = 637 MSKCC Poor 10.2 [9-14] 13.3 [9-17 0.85 [0.62-1.17] OS ORR 35.9% 35.9% HR (95% CI) 0.69 (0.56-0.85) 0.77 (0.64-0.92) 0.81 (0.71-0.93) PFS Median (mo) [CI95%] 7.2 [6.2-8.5] 8.3 [6.2-9.9] P .0003 .0020 .0018 Median 20.0 12.2 17.7 13.0 16.7 12.1 (95% CI), mo (15.4-24.9) (10.4-14.2) (15.3-22.1) (11.6-15.3) (13.9-19.7) (11.3-13.3)

See full session details p. 20D See full session details p. 20D D 10 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Sessions 10:00 AM Discussion 9:24 AM Continued from page 1D Phase III study of taselisib (GDC-0032) 9:36 AM Cctg BL12: Randomized phase II trial + fulvestrant (FULV) v FULV in patients comparing nab-paclitaxel (Nab-P) to Mark E. Burkard, MD, PhD (pts) with estrogen receptor (ER)-positive, paclitaxel (P) in patients (pts) with (Discussion of Abstracts 1503-1505) PIK3CA-mutant (MUT), locally advanced advanced urothelial cancer progressing on University of Wisconsin Carbone Cancer Center MEET THE PROFESSOR SESSION or metastatic breast cancer (MBC): Primary or after a platinum containing regimen Patient Evaluation in an Expanding Genetic How Do I Treat Hepatocellular analysis from SANDPIPER. (Abstract (NCT02033993). (Abstract 4505) World: Multiple Genes, Multiple Cancers, Carcinoma?— T Ticketed Session LBA1006) E253d Multiple Molecular Signatures Srikala S. Sridhar, MD, FRCPC Jose Baselga, MD, PhD, FASCO Gastrointestinal (Noncolorectal) Cancer 9:48 AM Discussion Anthony B. El-Khoueiry, MD 10:12 AM Panel Question and Answer AZD5363 plus paclitaxel versus placebo 9:36 AM USC Norris Comprehensive Cancer Center 10:00 AM plus paclitaxel as first-line therapy for Andrea B. Apolo, MD New Trends for Advanced Metastatic A breast cancer risk model as a predictor of metastatic triple-negative breast cancer (Discussion of Abstracts 4503-4505) Hepatocellular Carcinoma interval cancer rate and tumor characteristics. (PAKT): A randomised, double-blind, placebo- Genitourinary Malignancies Branch, Center for (Abstract 1506) Graziano Oldani, MD controlled, phase II trial. (Abstract 1007) Cancer Research, National Cancer Institute at the HepatoPancreato-Biliary Centre, Geneva Nickolas Dreher National Institutes of Health University Hospitals Peter Schmid, MD, PhD, FCRP Nonimmunotherapy Strategies in Advanced 10:12 AM When Should I Indicate Surgical Procedures 10:24 AM Bladder Cancer Validation of a combined residual risk score for Hepatocellular Carcinoma? Overall survival (OS) update of the double- for healthy unaffected women presenting 9:48 AM blind placebo (PBO)-controlled randomized to breast cancer (BC) screening centers. Panel Question and Answer phase 2 LOTUS trial of first-line ipatasertib 8:00 AM–11:00 AM (Abstract 1507) (IPAT) + paclitaxel (PAC) for locally 10:00 AM ORAL ABSTRACT SESSION advanced/metastatic triple-negative breast Kathryn Dalton, DO, FACS A phase II study investigating the safety and Breast Cancer—Metastatic cancer (mTNBC). (Abstract 1008) efficacy of neoadjuvant atezolizumab in Hall D2 10:24 AM muscle invasive bladder cancer (ABACUS). Rebecca Alexandra Dent, MD Polygenic risk score for breast cancer in high- (Abstract 4506) Beverly Moy, MD, FASCO—Co-Chair risk women. (Abstract 1508) Massachusetts General Hospital Cancer Center Discussion Thomas Powles, MD Mary Helen Black, PhD, MS Ruth O’Regan, MD—Co-Chair 10:36 AM 10:12 AM University of Wisconsin Carbone Cancer Center Cynthia X. Ma, MD, PhD Discussion Preoperative pembrolizumab (pembro) before (Discussion of Abstracts 1005-1008) radical cystectomy (RC) for muscle-invasive 8:00 AM 10:36 AM Washington University School of Medicine in St. urothelial bladder carcinoma (MIUC): Interim Ribociclib (RIB) + fulvestrant (FUL) in Antonis Antoniou, PhD Louis clinical and biomarker findings from the postmenopausal women with hormone (Discussion of Abstracts 1506-1508) receptor-positive (HR+), HER2-negative The PI3K-AKT-mTOR Pathway: Are We phase 2 PURE-01 study. (Abstract 4507) Making Headway? University of Cambridge (HER2–) advanced breast cancer (ABC): Controversies in Cancer Risk Modeling: Andrea Necchi, MD Results from MONALEESA-3. (Abstract 1000) 10:48 AM Breast Density and Polygenic Risk Scores 10:24 AM Panel Question and Answer Dennis J. Slamon, MD, PhD 10:48 AM Multicenter randomized phase 2 trial of 8:12 AM Panel Question and Answer paclitaxel, ifosfamide, and cisplatin (TIP) Genetic landscape of resistance to CDK4/6 versus bleomycin, etoposide, and cisplatin inhibition in circulating tumor DNA ORAL ABSTRACT SESSION (BEP) for first-line treatment of patients (pts) Cancer Prevention, Hereditary Genetics, (ctDNA) analysis of the PALOMA3 trial of ORAL ABSTRACT SESSION with intermediate- or poor-risk germ cell and Epidemiology palbociclib and fulvestrant versus placebo Genitourinary (Nonprostate) Cancer tumors (GCT). (Abstract 4508) S404 Arie Crown Theater and fulvestrant. (Abstract 1001) Darren R. Feldman, MD Veda N. Giri, MD—Co-Chair Nicholas C. Turner, MD, PhD Amishi Yogesh Shah, MD—Co-Chair The Sidney Kimmel Cancer Center at Thomas The University of Texas MD Anderson Discussion 8:24 AM Jefferson University Cancer Center 10:36 AM Abemaciclib for pre/perimenopausal women Noelle K. LoConte, MD—Co-Chair Matt D. Galsky, MD with HR+, HER2- advanced breast cancer. Matthew R. Zibelman, MD—Co-Chair University of Wisconsin Carbone Cancer Center (Discussion of Abstracts 4506-4508) (Abstract 1002) Fox Chase Cancer Center Icahn School of Medicine at Mount Sinai/Tisch 8:00 AM Patrick Neven, MD, PhD 8:00 AM Cancer Institute Low-fat dietary pattern and all cancer Pembrolizumab monotherapy as first-line Neoadjuvant Immunotherapy in Localized Discussion mortality in the Women’s Health Initiative therapy in advanced clear cell renal cell Bladder Cancer: Frontline Management of (WHI) randomized trial. (Abstract 1500) carcinoma (accRCC): Results from cohort A of High-Risk Germ Cell Cancer 8:36 AM KEYNOTE-427. (Abstract 4500) Angela DeMichele, MD, MSCE Rowan T. Chlebowski, MD, PhD, FASCO 10:48 AM David F. McDermott, MD (Discussion of Abstracts 1000-1002) 8:12 AM Panel Question and Answer Penn Medicine Abramson Cancer Center Pre- and post-treatment body weight and 8:12 AM Present and Future of CDK Inhibitors prognosis in a multiethnic cohort of breast A randomized, open label, multicenter phase 8:48 AM cancer patients. (Abstract 1501) 2 study, to evaluate the efficacy of sorafenib ORAL ABSTRACT SESSION (So) in patients (pts) with metastatic renal Panel Question and Answer Lihua Shang, MD Head and Neck Cancer cell carcinoma (mRCC) after a radical E451 9:00 AM 8:24 AM resection of the metastases: RESORT trial. Phase III multicenter, randomized study Cardiorespiratory fitness and incident (Abstract 4502) Charu Aggarwal, MD, MPH—Co-Chair of utidelone plus capecitabine versus lung and colon cancer: FIT-Cancer Cohort. Abramson Cancer Center capecitabine alone for heavily pretreated, Giuseppe Procopio, MD (Abstract 1502) Jessica Ruth Bauman, MD—Co-Chair anthracycline- and taxane-refractory 8:24 AM Catherine Handy, MD, MPH Fox Chase Cancer Center metastatic breast cancer. (Abstract 1003) Patient-reported outcomes (PROs) in 8:00 AM Binghe Xu, MD, PhD Discussion IMmotion151: Atezolizumab (atezo) + bevacizumab (bev) vs sunitinib (sun) in Results of a randomized phase III study 9:12 AM 8:36 AM treatment (tx) naive metastatic renal cell of nimotuzumab in combination with Efficacy of sacituzumab govitecan (anti- Jennifer A. Ligibel, MD carcinoma (mRCC). (Abstract 4511) concurrent radiotherapy and cisplatin versus Trop-2-SN-38 antibody-drug conjugate) (Discussion of Abstracts 1500-1502) radiotherapy and cisplatin alone, in locally for treatment-refractory hormone-receptor Dana-Farber Cancer Institute Bernard Escudier, MD advanced squamous cell carcinoma of the positive (HR+)/HER2- metastatic breast cancer The Role of Diet and Fitness in Optimizing head and neck. (Abstract 6000) (mBC). (Abstract 1004) Cancer Prevention and Outcomes Discussion Vijay Maruti Patil, MD, MBBS 8:36 AM Aditya Bardia, MD, MPH 8:48 AM Toni K. Choueiri, MD 8:12 AM Panel Question and Answer Discussion (Discussion of Abstracts 4500-4511) Definitive cetuximab-based (CRT-CX) vs. 9:00 AM Dana-Farber Cancer Institute non-cetuximab based chemoradiation 9:24 AM Inherited mutations in breast cancer patients Optimizing Systemic Therapy in Advanced (CRT) in older patients with squamous cell Virginia G. Kaklamani, MD with and without multiple primary cancers. Renal Cell Carcinoma carcinoma of the head and neck (HNSCC): (Discussion of Abstracts 1003-1004) (Abstract 1503) Analysis of the SEER-Medicare linked The University of Texas Health Science Center 8:48 AM database. (Abstract 6001) HER2-Negative Metastatic Breast Cancer: Kara Noelle Maxwell, MD, PhD Panel Question and Answer Dan Paul Zandberg, MD Chemotherapy With a Twist 9:12 AM 9:00 AM 9:36 AM Frequency of actionable cancer predisposing First results from the primary analysis 8:24 AM Panel Question and Answer germline mutations in patients with lung population of the phase 2 study of erdafitinib Are women with head and neck cancer cancers. (Abstract 1504) (ERDA; JNJ-42756493) in patients (pts) undertreated? (Abstract LBA6002) 9:48 AM with metastatic or unresectable urothelial Semanti Mukherjee, PhD Annie Park, MD Everolimus (EVE) + exemestane (EXE) vs carcinoma (mUC) and FGFR alterations EVE alone or capecitabine (CAP) for estrogen 9:24 AM (FGFRalt). (Abstract 4503) receptor-positive (ER+), human epidermal Discussion Pathogenic somatic mutation (SM) Arlene O. Siefker-Radtke, MD growth factor receptor 2-negative (HER2-) of mismatch repair (MMR) genes and 8:36 AM advanced breast cancer (ABC): BOLERO-6, an associations with microsatellite instability 9:12 AM Faye M. Johnson, MD, PhD open-label phase 2 study. (Abstract 1005) (MSI), tumor mutational burden (TMB) and Updated results from the enfortumab vedotin (Discussion of Abstracts 6000-LBA6002) The University of Texas MD Anderson Guy Heinrich Maria Jerusalem, MD, PhD SM in other DNA repair pathways in 24,223 phase 1 (EV-101) study in patients with tumor genomic profiles. (Abstract 1505) metastatic urothelial cancer (mUC). Cancer Center (Abstract 4504) Redefining Perceptions in Locally Joseph Nicholas Bodor, MD, PhD Advanced Disease Jonathan E. Rosenberg, MD See Sessions, Page 14D NEW INDICATION FOR THE TREATMENT OF METASTATIC EGFRm NSCLC

FIRST-LINE TAGRISSO® GROUNDBREAKING EFFICACY 18.9 vs10.2 months median PFS vs erlotinib/ge tinib in the FLAURA study

INDICATION TAGRISSO is indicated for the rst-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

SELECT SAFETY INFORMATION • There are no contraindications for TAGRISSO • Interstitial lung disease (ILD)/pneumonitis occurred in 3.9% of the 1142 TAGRISSO-treated patients; 0.4% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (eg, dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is con rmed

Please see Brief Summary of Prescribing Information on adjacent pages.

US-15964+US-15637 Tagrisso ASCO Daily News Morning Edition.indd 1 5/8/18 10:03 AM CHOOSE FIRST-LINE TAGRISSO: A NEW STANDARD OF CARE

TAGRISSO nearly doubled median PFS and cut the risk of FOR THE TREATMENT OF METASTATIC EGFRm NSCLC progression or death by 54% vs EGFR TKI comparator1 Demonstrated unprecedented 18.9 months median PFS vs 10.2 months PFS for EGFR TKI comparator1 Hazard ratio=0.46 (95% CI: 0.37, 0.57); N=556 1.0 • Hazard ratio=0.46 (95% CI: 0.37, 0.57), P<0.0001

3 ALL Delivered consistent PFS results across all subgroups 0.8 months 18.9 SUBGROUPS • Including patients with or without CNS metastases median PFS (95% CI: 15.2, 21.4)

0.6 Osimertinib (TAGRISSO) is an NCCN-recommended rst-line therapy option4 0.4 Probability of PFS

10.2 months TAGRISSO median PFS Randomized, double-blind, active-controlled trial in 556 patients with metastatic EGFRm NSCLC who had not received prior systemic treatment for advanced disease. Patients were 0.2 P<0.0001 (95% CI: 9.6, 11.1) randomized 1:1 to either TAGRISSO (n=279; 80 mg orally, once daily) or EGFR TKI comparator (n=277; ge tinib 250 mg or erlotinib 150 mg orally, once daily). Crossover was allowed for patients in the EGFR TKI comparator arm at con rmed progression if positive for the EGFR T790M resistance mutation. Patients with CNS metastases not requiring steroids and with stable EGFR TKI neurologic status were included in the study. The primary endpoint of the study was PFS based on investigator assessment (according to RECIST v1.1). Secondary endpoints included ORR, Comparator* DOR, OS, and safety.1,3 0.0 0 3 6 9 12 15 18 21 24 27 SELECT SAFETY INFORMATION Months • Keratitis was reported in 0.7% of 1142 patients treated with TAGRISSO in clinical trials. Promptly refer patients *In the FLAURA study, all US patients in the comparator arm received erlotinib.2 with signs and symptoms suggestive of keratitis (such as eye in ammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist SELECT SAFETY INFORMATION • Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women • Heart rate-corrected QT (QTc) interval prolongation occurred in TAGRISSO-treated patients. Of the 1142 TAGRISSO- of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treated patients in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase treatment with TAGRISSO and for 6 weeks after the nal dose. Advise males with female partners of reproductive from baseline QTc > 60 msec. No QTc-related arrhythmias were reported. Conduct periodic monitoring with ECGs potential to use effective contraception for 4 months after the nal dose and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or • Most common adverse reactions (≥20%) were diarrhea, rash, dry skin, nail toxicity, stomatitis, fatigue and those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients decreased appetite who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia

• Cardiomyopathy occurred in 2.6% of the 1142 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were Abbreviations: CNS, central nervous system; DOR, duration of response; EGFRm, epidermal growth factor receptor mutation-positive; fatal. A decline in left ventricular ejection fraction (LVEF) ≥10% from baseline and to <50% LVEF occurred in 3.9% of NSCLC, non–small-cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria In Solid Tumors; TKI, tyrosine kinase inhibitor. 908 patients who had baseline and at least one follow-up LVEF assessment. Conduct cardiac monitoring, including REFERENCES: 1. TAGRISSO [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018. 2. Soria JC, Ohe Y, Vansteenkiste J, et assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125 [protocol]. 3. Soria JC, who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC V.3.2018. © National permanently discontinue TAGRISSO Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed March 1, 2018. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. To view the most recent and complete version of the guideline, go online to NCCN.org.

TAGRISSO is a registered trademark of the AstraZeneca group of companies. ©2018 AstraZeneca. All rights reserved. US-15964 4/18 LEARN MORE AT TagrissoHCP.com First-line treatment of metastatic EGFRm NSCLC

US-15964+US-15637 Tagrisso ASCO Daily News Morning Edition.indd 2 5/8/18 10:03 AM CHOOSE FIRST-LINE TAGRISSO: A NEW STANDARD OF CARE

3 ALL Delivered consistent PFS results across all subgroups 0.8 months 18.9 SUBGROUPS • Including patients with or without CNS metastases median PFS (95% CI: 15.2, 21.4)

0.6 Osimertinib (TAGRISSO) is an NCCN-recommended rst-line therapy option4 0.4 Probability of PFS

US-15964+US-15637 Tagrisso ASCO Daily News Morning Edition.indd 2 5/8/18 10:03 AM D 14 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Sessions A propensity score matched analysis of 10:12 AM 10:48 AM population level data. (Abstract 6005) Continued from page 10D Phase II trial of high-dose melatonin oral Panel Question and Answer gel for the prevention and treatment of oral Sibo Tian, MD 8:48 AM mucositis in H&N cancer patients undergoing Panel Question and Answer Discussion chemoradiation (MUCOMEL). (Abstract ORAL ABSTRACT SESSION 6007) 9:00 AM 9:36 AM Patient and Survivor Care Treatment deintensification to surgery only Sharon Spencer, MD Alicia Lozano, MD S102 for stage I human papillomavirus-associated (Discussion of Abstracts 6003-6005) 10:24 AM Piyush Srivastava, MD—Co-Chair oropharyngeal cancer. (Abstract 6003) University of Alabama at Birmingham Multicenter phase II trial of palbociclib, a Kaiser Permanente HPV: Will Less Be More? selective cyclin dependent kinase (CDK) John David Cramer, MD Martin R. Stockler, MBBS, MS, FRACP— 4/6 inhibitor, and cetuximab in platinum- 9:48 AM Co-Chair 9:12 AM resistant HPV unrelated (-) recurrent/ Panel Question and Answer NHMRC Clinical Trials Centre, The University Phase II study: Induction chemotherapy metastatic head and neck squamous cell of Sydney and transoral surgery as definitive treatment 10:00 AM carcinoma (RM HNSCC). (Abstract 6008) (Tx) for locally advanced oropharyngeal Results of a randomized, placebo (PBO) 8:00 AM Douglas Adkins, MD squamous cell carcinoma (OPSCC): A novel controlled, double-blind P2b trial of GC4419 Omega-3 fatty acid use for obese breast approach. (Abstract 6004) (avisopasem manganese) to reduce duration, cancer patients with aromatase inhibitor- incidence and severity and delay onset of Discussion Robert S. Siegel, MD related arthralgia (SWOG S0927). severe radiation-related oral mucositis (SOM) 10:36 AM (Abstract 10000) 9:24 AM in patients (pts) with locally advanced Stuart J. Wong, MD Survival outcomes by HPV status in nonsquamous cell cancer of the oral cavity (OC) (Discussion of Abstracts 6006-6008) Sherry Shen, MD TRIM SIZE: 8.5” X 11” oropharyngeal head and neck cancers: or oropharynx (OP). (Abstract 6006) Medical College of Wisconsin Potpourri of Stuff That Matters (Really) Carryn M. Anderson, MD

TAGRISSO® (osimertinib) tablets, for oral use QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation Brief Summary of Prescribing Information. with signs/symptoms of life-threatening arrhythmia [see Dosage and Administration (2.4) in the full For complete prescribing information consult official package insert. Prescribing Information]. Cardiomyopathy INDICATIONS AND USAGE Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, First-line Treatment of EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 2.6% of the TAGRISSO is indicated for the first-line treatment of patients with metastatic non-small cell lung 1142 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or A decline in left ventricular ejection fraction (LVEF) ≥ 10% from baseline and to less than 50% LVEF exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration occurred in 3.9% of 908 patients who had baseline and at least one follow-up LVEF assessment. (2.1) in the full Prescribing Information]. Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in DOSAGE AND ADMINISTRATION patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or Patient Selection symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue Select patients for the first-line treatment of metastatic EGFR-positive NSCLC with TAGRISSO TAGRISSO [see Dosage and Administration (2.4) in the full Prescribing Information]. based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in tumor or plasma Keratitis specimens [see Clinical Studies (14) in the full Prescribing Information]. If this mutation is not Keratitis was reported in 0.7% of 1142 patients treated with TAGRISSO in clinical trials. Promptly detected in a plasma specimen, test tumor tissue if feasible. refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, Information on FDA-approved tests for the detection of EGFR mutations is available at lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist. http://www.fda.gov/companiondiagnostics. Embryo-Fetal Toxicity Recommended Dosage Regimen Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm The recommended dosage of TAGRISSO is 80 mg tablet once a day until disease progression or when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post- unacceptable toxicity. TAGRISSO can be taken with or without food. implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended clinical dose. When males were treated prior to mating with If a dose of TAGRISSO is missed, do not make up the missed dose and take the next dose as untreated females, there was an increase in preimplantation embryonic loss at plasma exposures scheduled. of approximately 0.5 times those observed at the recommended dose of 80 mg once daily. Verify Administration to Patients Who Have Difficulty Swallowing Solids pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant Disperse tablet in 60 mL (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into women of the potential risk to a fetus. Advise females of reproductive potential to use effective small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males or ultrasonicate during preparation. Rinse the container with 120 mL to 240 mL (4 to 8 ounces) of with female partners of reproductive potential to use effective contraception for 4 months after the water and immediately drink. final dose [see Use in Specific Populations (8.1, 8.3) in the full Prescribing Information]. If administration via nasogastric tube is required, disperse the tablet as above in 15 mL of ADVERSE REACTIONS non-carbonated water, and then use an additional 15 mL of water to transfer any residues to the The following adverse reactions are discussed in greater detail in other sections of the labeling: syringe. The resulting 30 mL liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 mL). Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1) in the full Prescribing Information] Dosage Modifications QTc Interval Prolongation [see Warnings and Precautions (5.2) in the full Prescribing Information] Adverse Reactions Cardiomyopathy [see Warnings and Precautions (5.3) in the full Prescribing Information] Table 1. Recommended Dosage Modifications for TAGRISSO Keratitis [see Warnings and Precautions (5.4) in the full Prescribing Information] Target Clinical Trials Experience a Organ Adverse Reaction Dosage Modification Because clinical trials are conducted under widely varying conditions, adverse reaction rates Pulmonary Interstitial lung disease (ILD)/Pneumonitis Permanently discontinue TAGRISSO. observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. QTc† interval greater than 500 msec on at Withhold TAGRISSO until QTc interval least 2 separate ECGsb is less than 481 msec or recovery to The data in the Warnings and Precautions section reflect exposure to TAGRISSO in 1142 patients baseline if baseline QTc is greater than with EGFR mutation-positive NSCLC who received TAGRISSO at the recommended dose of 80 mg or equal to 481 msec, then resume at once daily in two randomized, active-controlled trials [FLAURA (n=279) and AURA3 (n=279)], Cardiac 40 mg dose. two single arm trials [AURA Extension (n=201) and AURA2 (n=210)], and one dose-finding study, AURA1 (n=173) [see Warnings and Precautions (5) in the full Prescribing Information]. QTc interval prolongation with signs/ Permanently discontinue TAGRISSO. symptoms of life-threatening arrhythmia The data described below reflect exposure to TAGRISSO (80 mg daily) in 558 patients with EGFR mutation-positive, metastatic NSCLC in two randomized, active-controlled trials [FLAURA (n=279) Symptomatic congestive heart failure Permanently discontinue TAGRISSO. and AURA3 (n=279)]. Patients with a history of interstitial lung disease, drug induced interstitial Adverse reaction of Grade 3 or greater Withhold TAGRISSO for up to 3 weeks. disease or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc severity interval greater than 470 msec on electrocardiogram were excluded from enrollment in these studies. Other If improvement to Grade 0-2 within 3 weeks Resume at 80 mg or 40 mg daily. Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer If no improvement within 3 weeks Permanently discontinue TAGRISSO. The safety of TAGRISSO was evaluated in FLAURA, a multicenter international double-blind a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events randomized (1:1) active controlled trial conducted in 556 patients with EGFR exon 19 deletion version 4.0 (NCI CTCAE v4.0). or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received b ECGs = Electrocardiograms previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO † QTc = QT interval corrected for heart rate was 16.2 months. The most common adverse reactions (≥20%) in patients treated with TAGRISSO were diarrhea Drug Interactions (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis (29%), and decreased appetite Strong CYP3A4 Inducers (20%). Serious adverse reactions were reported in 4% of patients treated with TAGRISSO; the If concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when coadministering most common serious adverse reactions (≥1%) were pneumonia (2.9%), ILD/pneumonitis (2.1%), with a strong CYP3A inducer. Resume TAGRISSO at 80 mg 3 weeks after discontinuation of the and pulmonary embolism (1.8%). Dose reductions occurred in 2.9% of patients treated with strong CYP3A4 inducer [see Drug Interactions (7) and Clinical Pharmacology (12.3) in the full TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were Prescribing Information]. prolongation of the QT interval as assessed by ECG (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients CONTRAINDICATIONS treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of None. TAGRISSO was ILD/pneumonitis (3.9%). WARNINGS AND PRECAUTIONS Tables 2 and 3 summarize common adverse reactions and laboratory abnormalities which Interstitial Lung Disease/Pneumonitis occurred in FLAURA. FLAURA was not designed to demonstrate a statistically significant reduction Interstitial lung disease (ILD)/pneumonitis occurred in 3.9% of the 1142 TAGRISSO-treated in adverse reaction rates for TAGRISSO, or for the control arm, for any adverse reaction listed in patients; 0.4% of cases were fatal. Tables 2 and 3. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening Table 2. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA* of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Adverse Reaction TAGRISSO EGFR TKI comparator Permanently discontinue TAGRISSO if ILD is confirmed[see Dosage and Administration (2.4) and (N=279) (gefitinib or erlotinib) Adverse Reactions (6) in the full Prescribing Information]. (N=277) QTc Interval Prolongation Any Grade Grade 3 or Any Grade Grade 3 or Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. (%) higher (%) (%) higher (%) Of the 1142 patients treated with TAGRISSO in clinical trials, 0.9% were found to have a QTc Gastrointestinal Disorders > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec [see Clinical a Pharmacology (12.2) in the full Prescribing Information]. No QTc-related arrhythmias were Diarrhea 58 2.2 57 2.5 reported. Stomatitis 29 0.7 20 0.4 Clinical trials of TAGRISSO did not enroll patients with baseline QTc of > 470 msec. Conduct periodic Nausea 14 0 19 0 monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive Constipation 15 0 13 0 heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the Vomiting 11 0 11 1.4

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8:12 AM (NCORP) cluster randomized controlled trial 9:36 AM Discussion The effect of acupuncture versus cognitive (CRCT). (Abstract LBA10003) Panel Question and Answer behavior therapy on insomnia in cancer 10:24 AM Supriya Gupta Mohile, MD, MS survivors: A randomized clinical trial. Shelly S. Lo, MD 9:48 AM (Abstract 10001) 9:00 AM (Discussion of Abstracts 10006-10008) Does timing of palliative care consults impact Symptom burden in hospitalized patients Loyola University Medical Center Jun J. Mao, MD end-of-life health services utilization in with curable and incurable cancers. (Abstract The Sooner the Better: Palliative Care and pancreatic cancer patients? (Abstract 10006) End-of-Life Discussions Discussion 10004) Nizar Bhulani, MD, MPH 8:24 AM Richard Newcomb, MD 10:00 AM 10:36 AM Gabriel Lopez, MD 9:12 AM Patient (Pt) and oncologist (MD) discordance Panel Question and Answer (Discussion of Abstracts 10000-10001) Randomized trial of a symptom monitoring in goals of care in end of life (EOL) decision The University of Texas MD Anderson Cancer intervention for hospitalized patients with making. (Abstract 10007) Center cancer. (Abstract 10005) ORAL ABSTRACT SESSION Integrating Integrative Medicine Into Sara L. Douglas, PhD Pediatric Oncology II Supportive Care: Are We Ready? Charn-Xin Fuh 10:12 AM S504 8:36 AM Discussion Understanding factors contributing Jacqueline Casillas, MD—Co-Chair Panel Question and Answer 9:24 AM to geographic variations in end-of-life University of California, Los Angeles expenditures. (Abstract 10008) 8:48 AM Ethan M. Basch, MD, FASCO Sogol Mostoufi-Moab, MD, MSCE—Co-Chair Improving communication with older (Discussion of Abstracts LBA10003-10005) Nancy Lynn Keating, MD, MPH The Children’s Hospital of Philadelphia patients with cancer using geriatric The University of North Carolina at Chapel Hill TRIM SIZE: 8.5” X 11” assessment (GA): A University of Rochester Patient-Reported Assessments: Tell Us How 8:00 AM NCI Community Oncology Research Program You Really Feel Subsequent malignant neoplasms (SMNs) among non-irradiated survivors of childhood cancer treated with chemotherapy in the Childhood Cancer Survivor Study. (Abstract TAGRISSO® (osimertinib) tablets, for oral use 2 10509) Table 2. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA* Monitor for adverse reactions of the BCRP substrate, unless otherwise instructed in its approved Lucie Marie Turcotte, MD (cont’d) labeling, when coadministered with TAGRISSO. Adverse Reaction TAGRISSO EGFR TKI comparator Drugs That Prolong the QTc Interval 8:12 AM (N=279) (gefitinib or erlotinib) The effect of coadministering medicinal products known to prolong the QTc interval with Risk-adapted therapy for pediatric Hodgkin (N=277) TAGRISSO is unknown. When feasible, avoid concomitant administration of drugs known to lymphoma (HL) results in lower risk of late Any Grade Grade 3 or Any Grade Grade 3 or prolong the QTc interval with known risk of Torsades de pointes. If not feasible to avoid concomitant effects: a report from the Childhood Cancer (%) higher (%) (%) higher (%) administration of such drugs, conduct periodic ECG monitoring [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Survivor Study (CCSS). (Abstract 10510) Skin Disorders Rashb 58 1.1 78 6.9 USE IN SPECIFIC POPULATIONS Kevin C. Oeffinger, MD Dry skinc 36 0.4 36 1.1 Pregnancy d 8:24 AM Nail toxicity 35 0.4 33 0.7 Risk Summary Mortality following breast cancer in survivors Prurituse 17 0.4 17 0 Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) of childhood cancer: A report from the Metabolism and Nutrition Disorders in the full Prescribing Information], TAGRISSO can cause fetal harm when administered to a Decreased appetite 20 2.5 19 1.8 pregnant woman. There are no available data on TAGRISSO use in pregnant women. Administration Childhood Cancer Survivor Study. (Abstract Respiratory, Thoracic and Mediastinal Disorders of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at 10511) plasma exposures 1.5 times the exposure at the recommended clinical dose (see Data). Advise Cough 17 0 15 0.4 pregnant women of the potential risk to a fetus. Chaya S. Moskowitz, PhD Dyspnea 13 0.4 7 1.4 In the U.S. general population, the estimated background risk of major birth defects and Neurologic Disorders miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Discussion Headache 12 0.4 7 0 Data Cardiac Disorders 8:36 AM f Animal Data Prolonged QT Interval 10 2.2 4 0.7 When administered to pregnant rats prior to embryonic implantation through the end of Patricia A. Ganz, MD, FASCO General Disorders and Administration Site Conditions organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma (Discussion of Abstracts 10509-10511) Fatigueg 21 1.4 15 1.4 exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation University of California, Los Angeles Pyrexia 10 0 4 0.4 loss and early embryonic death. When administered to pregnant rats from implantation through Defining the Risks of Secondary Malignancies Infection and Infestation Disorders the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1 in Childhood Cancer Survivors Upper Respiratory 10 0 7 0 times the AUC observed at the recommended clinical dose of 80 mg once daily), an equivocal Tract Infection increase in the rate of fetal malformations and variations was observed in treated litters relative 8:48 AM * NCI CTCAE v4.0 to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day Panel Question and Answer a One grade 5 (fatal) event was reported (diarrhea) for EGFR TKI comparator during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss b Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period 9:00 AM rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that Association of exercise with late mortality in acneiform, drug eruption, skin erosion. increased in magnitude between lactation days 4 and 6. c Includes dry skin, skin fissures, xerosis, eczema, xeroderma. adult survivors of childhood cancer: A report d Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail Lactation disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychoclasis, onycholysis, onychomadesis, Risk Summary from the Childhood Cancer Survivor study. onychomalacia, paronychia. There are no data on the presence of osimertinib or its active metabolites in human milk, the (Abstract 10512) e Includes pruritus, pruritus generalized, eyelid pruritus. f effects of osimertinib on the breastfed infant or on milk production. Administration to rats during The frequency of “Prolonged QT Interval” represents reported adverse events in the FLAURA study. gestation and early lactation was associated with adverse effects, including reduced growth rates Jessica Scott, PhD Frequencies of QTc intervals of >500 ms or >60 ms are presented in Section 5.2. g and neonatal death [see Use in Specific Populations (8.1) in the full Prescribing Information]. 9:12 AM Includes fatigue, asthenia. Because of the potential for serious adverse reactions in breastfed infants from osimertinib, advise Table 3. Laboratory Abnormalities Worsening from Baseline in ≥ 20% of Patients in FLAURA women not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose. Impact of exercise on psychological burden in adult survivors of childhood cancer: A TAGRISSO EGFR TKI comparator Females and Males of Reproductive Potential (N=279) (gefitinib or erlotinib) Pregnancy Testing report from the Childhood Cancer Survivor (N=277) Verify the pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Study (CCSS). (Abstract 10513) Laboratory Change from Change from Change from Change from Contraception a,b Emily S. Tonorezos, MD Abnormality Baseline All Baseline to Baseline Baseline to TAGRISSO can cause fetal harm when administered to pregnant women [see Use in Specific Grades Grade 3 or All Grades Grade 3 or Populations (8.1) in the full Prescribing Information]. (%) Grade 4 (%) Grade 4 9:24 AM (%) (%) Females Patient-level predictors of lack of healthcare Hematology Advise females of reproductive potential to use effective contraception during treatment with provider recommendation for human TAGRISSO and for 6 weeks after the final dose [see Use in Specific Populations (8.1) in the full Lymphopenia 63 5.6 36 4.2 Prescribing Information]. papillomavirus (HPV) vaccination as reported Anemia 59 0.7 47 0.4 Males by childhood cancer survivors and their Thrombocytopenia 51 0.7 12 0.4 Advise male patients with female partners of reproductive potential to use effective contraception families. (Abstract 10514) Neutropenia 41 3.0 10 0 during and for 4 months following the final dose of TAGRISSO [see Nonclinical Toxicology (13.1) Chemistry in the full Prescribing Information]. Jocelyn York Hyperglycemiac 37 0 31 0.5 Infertility Hypermagnesemia 30 0.7 11 0.4 Based on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential. Discussion Hyponatremia 26 1.1 27 1.5 The effects on female fertility showed a trend toward reversibility. It is not known whether the effects 9:36 AM Increased AST 22 1.1 43 4.1 on male fertility are reversible [see Nonclinical Toxicology (13.1) in the full Prescribing Information]. Leontien Kremer, MD, PhD Increased ALT 21 0.7 52 8 Pediatric Use Hypokalemia 16 0.4 22 1.1 The safety and effectiveness of TAGRISSO in pediatric patients have not been established. (Discussion of Abstracts 10512-10514) Hyperbilirubinemia 14 0 29 1.1 Geriatric Use Emma Children’s Hospital and Academic a NCI CTCAE v4.0 Forty-three percent (43%) of the 1142 patients in FLAURA (n=279), AURA3 (n=279), AURA Medical Center b Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline Extension (n=201), AURA2 (n=210), and AURA1, (n=173) were 65 years of age and older. No Cancer Prevention Strategies in Childhood and at least one on-study laboratory measurement available (TAGRISSO range: 267 - 273 and EGFR TKI overall differences in effectiveness were observed based on age. Exploratory analysis suggests Cancer Survivors comparator range: 256 - 268) a higher incidence of Grade 3 and 4 adverse reactions (13.4% versus 9.3%) and more frequent c Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TAGRISSO (179) and EGFR comparator (191) dose modifications for adverse reactions (13.4% versus 7.6%) in patients 65 years or older as 9:48 AM compared to those younger than 65 years. Panel Question and Answer DRUG INTERACTIONS Renal Impairment Effect of Other Drugs on Osimertinib No dose adjustment is recommended in patients with mild, [creatinine clearance (CLcr) 10:00 AM Strong CYP3A Inducers 60-89 mL/min, as estimated by the Cockcroft Gault method (C-G)], moderate, (CLcr 30-59 mL/min) Targeted resequencing of pediatric Coadministering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib or severe (CLcr 15-29 mL/min) renal impairment. There is no recommended dose of rhabdomyosarcoma: report from the compared to administering TAGRISSO alone [see Clinical Pharmacology (12.3) in the full TAGRISSO for patients with end-stage renal disease [see Clinical Pharmacology (12.3) in the Children’s Oncology Group, the Children’s full Prescribing Information]. Prescribing Information]. Decreased osimertinib exposure may lead to reduced efficacy. Cancer and Leukaemia Group, The Institute Hepatic Impairment Avoid coadministering TAGRISSO with strong CYP3A inducers. Increase the TAGRISSO dosage of Cancer Research UK, and the National when coadministering with a strong CYP3A4 inducer if concurrent use is unavoidable [see Dosage No dose adjustment is recommended in patients with mild hepatic impairment [total bilirubin ≤ > Cancer Institute. (Abstract 10515) and Administration (2.4) in the full Prescribing Information]. No dose adjustments are required upper limit of normal (ULN) and AST ULN or total bilirubin between 1 to 1.5 times ULN and when TAGRISSO is used with moderate and/or weak CYP3A inducers. any AST] or moderate hepatic impairment (total bilirubin between 1.5 to 3 times ULN and any AST). There is no recommended dose for TAGRISSO for patients with severe hepatic impairment John Frederick Shern, MD Effect of Osimertinib on Other Drugs [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Coadministering TAGRISSO with a BCRP substrate increased the exposure of the BCRP substrate compared to administering the BCRP substrate alone [see Clinical Pharmacology (12.3) in the full Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Prescribing Information]. Increased BCRP substrate exposure may increase the risk of exposure- TAGRISSO is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2018 Rev. 04/18 US-15637 4/18 related toxicity. See Sessions, Page 16D

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Sessions EDUCATION SESSION 9:57 AM Discussion Continued from page 15D ASCO/European CanCer Organization Randomized phase II neoadjuvant study 10:09 AM (GeparNuevo) to investigate the addition (ECCO) Joint Session: Access and Leisha A. Emens, MD, PhD of durvalumab to a taxane-anthracycline 10:12 AM Innovation With Multiplex Genomic Testing (Discussion of Abstracts 5509-5510) containing chemotherapy in triple negative A prospective study of pediatric renal cell S100a The Sidney Kimmel Comprehensive Cancer breast cancer (TNBC). (Abstract 104) carcinoma: A report from the Children’s Global Health Center at Johns Hopkins and Bloomberg-Kimmel Oncology Group study AREN0321. Bruce E. Johnson, MD, FASCO—Co-Chair Sibylle Loibl, MD, PhD Institute for Cancer Immunotherapy (Abstract 10516) Vaccines: Beyond Prevention Dana-Farber Cancer Institute 10:09 AM James I. Geller, MD Philip Poortmans, MD, PhD—Co-Chair Phase 3 study of carboplatin-paclitaxel/ 10:21 AM 10:24 AM Institut Curie nab-paclitaxel (Chemo) with or without Antitumor activity and safety of Hope and benefit-finding among adolescents pembrolizumab (Pembro) for patients (Pts) pembrolizumab in patients with advanced Kojo Elenitoba-Johnson, MD with metastatic squamous (Sq) non-small cell recurrent ovarian cancer: Interim results from and young adults with cancer: Results from Perelman School of Medicine at the University the PRISM randomized controlled trial. lung cancer (NSCLC). (Abstract 105) the phase 2 KEYNOTE-100 study. of Pennsylvania (Abstract 5511) (Abstract 10517) Utilization of Multiplex Testing in the Luis G. Paz-Ares, MD, PhD Ursula A. Matulonis, MD Abby R. Rosenberg, MD, MS, MA, FAAP United States 10:21 AM Matti S. Aapro, MD TOPACIO/Keynote-162 (NCT02657889): 10:33 AM Discussion Cancer Center, Clinique de Genolier A phase 1/2 study of niraparib + Association of high tumor mutation (TMB) 10:36 AM Utilization of Multiplex Testing in Europe pembrolizumab in patients (pts) with with DNA damage repair (DDR) alterations Todd Michael Cooper, DO advanced triple-negative breast cancer or and better prognosis in ovarian cancer. David R. Spigel, MD (Discussion of Abstracts 10515-10517) recurrent ovarian cancer (ROC)—Results from (Abstract 5512) Sarah Cannon Research Institute, Tennessee Seattle Children’s Cancer and Blood Disorders ROC cohort. (Abstract 106) Oncology Wenjuan Tian, MD Center, University of Washington Reimbursement and Payment of Multiplex Panagiotis A. Konstantinopoulos, MD, PhD Innovative Trials in Pediatric Cancer Discussion Testing in the United States 10:33 AM 10:48 AM Jan Geissler, MBA Epacadostat (E) plus pembrolizumab (P) 10:45 AM Panel Question and Answer Leukemia Patient Advocates Foundation versus pembrolizumab alone in patients Janos Laszlo Tanyi, MD, PhD European Patient Perspective (pts) with unresectable or metastatic (Discussion of Abstracts 5511-5512) 8:00 AM–11:30 AM melanoma: Results of the phase 3 ECHO-301/ University of Pennsylvania Panel Question and Answer KEYNOTE-252 study. (Abstract 108) Immune Therapy in Ovarian Cancer: The POSTER SESSIONS Continuing Search for Biomarkers Hall A Georgina V. Long, MD, PhD, FRACP 10:57 AM MEET THE PROFESSOR SESSION Discussion Panel Question and Answer Boards 1-112b Biology and Therapeutic Promise of Gastrointestinal (Colorectal) Cancer Exploiting IDH Mutations in Gliomas— 10:45 AM T Ticketed Session Charles G. Drake, MD, PhD 9:45 AM–12:45 PM Boards 198-333b E253c (Discussion of Abstracts 104-106) ORAL ABSTRACT SESSION Gastrointestinal (Noncolorectal) Cancer Columbia University Herbert Irving Central Nervous System Tumors; Developmental Hematologic Malignancies—Lymphoma Comprehensive Cancer Center Therapeutics and Translational Research and Chronic Lymphocytic Leukemia Boards 114-190b Putting It Together: Have Combinations E450 Lung Cancer—Non–Small Cell Local- Daniel P. Cahill, MD, PhD Come of Age? Regional/Small Cell/Other Thoracic Cancers Massachusetts General Hospital Christopher Flowers, MD, MS, FASCO— 10:57 AM Update on the Biology of IDH Mutations Co-Chair Panel Question and Answer Boards 335-433b Ranjit Bindra, MD Emory University, Winship Cancer Institute Lung Cancer—Non–Small Cell Metastatic Yale University Barbara Pro, MD—Co-Chair Updates in Therapeutic Strategies Toward CLINICAL SCIENCE SYMPOSIUM Northwestern University Feinberg School of 9:45 AM–11:00 AM Exploitation of IDH Mutations Engaging the Immune System in Medicine Ovarian Cancer EDUCATION SESSION S406 9:45 AM A New Era in the Management of MEET THE PROFESSOR SESSION Gynecologic Cancer RELEVANCE: Phase III randomized study Melanoma Brain Metastases How to Bring Geriatric Assessment Into of lenalidomide plus rituximab (R2) versus S100bc Your Practice— T Ticketed Session Marcus O. Butler, MD—Co-Chair chemotherapy plus rituximab, followed by Melanoma/Skin Cancers; Central Nervous System E253d Princess Margaret Cancer Centre, University rituximab maintenance, in patients with Tumors; Immunotherapy Geriatric Oncology; Care Delivery and Practice Health Network previously untreated follicular lymphoma. Management (Abstract 7500) Grant A. McArthur, MBBS, PhD, FRACP Kunle Odunsi, MD—Co-Chair Peter MacCallum Cancer Centre and University Shabbir M.H. Alibhai, MD Roswell Park Comprehensive Cancer Center Nathan Hale Fowler, MD of Melbourne University Health Network 9:45 AM 9:57 AM Biology of Melanoma Brain Metastases: How to Bring Geriatric Assessment to Your Dendritic cell vaccine (DCVAC) with Acalabrutinib in patients (pts) with Incidence, Prognosis, Surveillance, and More Practice chemotherapy (ct) in patients (pts) with Waldenström macroglobulinemia (WM). Caroline Robert, MD, PhD epithelial ovarian carcinoma (EOC) after (Abstract 7501) Gustave Roussy Institute 9:45 AM–11:15 AM primary debulking surgery (PDS): Interim Different Combinations of Systemic Therapy CLINICAL SCIENCE SYMPOSIUM analysis of a phase 2, open-label, randomized, Roger Owen, MD multicenter trial. (Abstract 5509) for Melanoma Brain Metastases Compelling Combinations: Raising the Bar 10:09 AM Hussein Abdul-Hassan Tawbi, MD, PhD— With Immunotherapy Lukas Rob, MD, PhD Phase 2 CAPTIVATE results of ibrutinib (ibr) Chair Hall D1 plus venetoclax (ven) in first-line chronic 9:57 AM The University of Texas MD Anderson lymphocytic leukemia (CLL). (Abstract 7502) David C. Smith, MD—Chair Clinical data from the DeCidE1 trial: Cancer Center University of Michigan Assessing the first combination of DPX- William G. Wierda, MD, PhD What to Do First in Case of Melanoma Survivac, low dose cyclophosphamide (CPA), Brain Metastases and Simultaneous Discussion and epacadostat (INCB024360) in subjects Discussion Extracerebral Disease 9:45 AM with stage IIc-IV recurrent epithelial ovarian 10:21 AM Solange Peters, MD, PhD cancer. (Abstract 5510) Panel Question and Answer Bruce D. Cheson, MD, FASCO Centre Hospitalier Universitaire Vaudois - CHUV Oliver Dorigo, MD, PhD (Discussion of Abstracts 7500-7502) Setting the Stage: Where Are We Now With Georgetown University Hospital, Lombardi Immunotherapy? Comprehensive Cancer Center Toward a Chemotherapy-Free Future in Lymphoid Malignancies See Sessions, Page 18D

Plenary Session Preview astatic renal cell carcinoma (mRCC)— standard of care in the era of improved level, phase III KEYNOTE-042 study.” Continued from page 1D Results of a phase III noninferiority targeted therapy for patients with The study looked at progression-free sur- trial.” For 2 decades, CN has been stan- mRCC,” Dr. Partridge said. “In this case, vival as a primary endpoint and overall defined as high risk according to the dard of care in mRCC—but the efficacy the big question at hand is whether or survival as a secondary endpoint. EpSSG stratification. of targeted therapies has challenged this not the affected kidney tumor needs to “Potentially expanding the substan- “This study aims to improve out- standard as of late. The CARMENA study be removed.” tial role that checkpoint inhibitors play comes for a historically difficult disease was designed to determine if upfront Finally, Gilberto de Lima Lopes Jr., in helping patients with advanced lung to treat,” Dr. Partridge said. Douglas S. CN should continue to be performed MD, MBA, FAMS, of the Sylvester Com- cancer is an important therapeutic goal,” Hawkins, MD, of Seattle Cancer Care Al- before sunitinib therapy. The random- prehensive Cancer Center at the Uni- Dr. Partridge said. “This abstract repre- liance, will discuss the abstract. ized phase III trial enrolled patients versity of Miami, will present LBA4, sents a groundbreaking study testing Arnaud Mejean, MD, PhD, of Paris with synchronous mRCC, amenable to “Pembrolizumab versus platinum-based first-line chemotherapy versus pembro- Descartes University, in France, will CN, with the primary endpoint of over- chemotherapy as first-line therapy for lizumab in patients with 1% or greater then present LBA3, “CARMENA: Cytore- all survival. advanced/metastatic non–small cell PD-L1 positivity.” ductive nephrectomy (CN) followed by “CARMENA is an excellent study that lung cancer (NSCLC) with a PD-L1 tu- –Caroline Hopkins sunitinib versus sunitinib alone in met- is challenging conventional wisdom and mor proportion score (TPS) ≥ 1%: Open- Find Your Next Career Opportunity ASCO CAREER CENTER

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Sessions Discussion Elizabeth H. Baldini, MD, MPH—Chair Daniel Eidelberg Spratt, MD Dana-Farber Cancer Institute and Brigham and University of Michigan Continued from page 16D 12:06 PM Women’s Hospital Precision Risk Stratification and Treatment in Neil Howard Segal, MD, PhD Is There a Role for Neoadjuvant Biochemical-Recurrent Prostate Cancer (Discussion of Abstracts 3514-3515) 10:33 AM Chemoradiation in High-Risk Extremity Soft Memorial Sloan Kettering Cancer Center Alicia K. Morgans, MD, MPH—Chair Panel Question and Answer Tissue Sarcoma? Immune Therapy: Why Don’t We Have the Vanderbilt University Medical Center 10:45 AM KEY for VICTORy? Biochemical Recurrence: Judicious Clinical Panel Question and Answer Randomized phase III study comparing an Management of an Evolving Disease State early PET driven treatment de-escalation to 12:18 PM Panel Question and Answer a not PET-monitored strategy in patients Panel Question and Answer with advanced stages Hodgkin lymphoma: EDUCATION SESSION Final analysis of the AHL2011 LYSA study. Discussion Filling the Gap: Creating an Outpatient Palliative Care Program in Your Institution (Abstract 7503) 12:24 PM EDUCATION SESSION S504 Dustin A. Deming, MD Moving From Mutation to Actionability Olivier Casasnovas, MD Care Delivery and Practice Management; Global (Discussion of Abstracts 3516-3518) S100bc Health; Health Services Research, Clinical Informatics, 10:57 AM University of Wisconsin Carbone Cancer Center Gynecologic Cancer; Care Delivery and Practice and Quality of Care; Patient and Survivor Care; Value Activity and tolerability of the first-in- Biomarkers and New Approaches in Management; Developmental Therapeutics and class anti-CD47 antibody Hu5F9-G4 with Anorectal Cancer Esme Finlay, MD Translational Research rituximab tolerated in relapsed/refractory University of New Mexico Cancer Research and Amit M. Oza, MD—Chair non-Hodgkin lymphoma: Initial phase 1b/2 Posters discussed in this session are on display in Treatment Center Princess Margaret Cancer Centre, University results. (Abstract 7504) the Gastrointestinal (Colorectal) Cancer Poster How to Obtain Buy-in From Stakeholders to Health Network Session. See the iPlanner for poster titles and Support Outpatient Palliative Care Ranjana H. Advani, MD The Role of Targeted Therapy in Gynecologic presenters. 11:09 AM Michael Rabow, MD Cancers University of California, San Francisco Updated safety and long term clinical Shannon Neville Westin, MD Understanding the Finances of Outpatient outcomes in TRANSCEND NHL 001, pivotal The University of Texas MD Anderson POSTER DISCUSSION SESSION Palliative Care Programs trial of lisocabtagene maraleucel (JCAR017) in Cancer Center R/R aggressive NHL. (Abstract 7505) Lung Cancer—Non–Small Cell Metastatic Arie Crown Theater Mary K. Buss, MD, MPH—Chair Tumor Sequencing: Who, What, When, and Jeremy S. Abramson, MD Beth Israel Deaconess Medical Center Why to Order Tumor Mutation Analysis Joshua Bauml, MD—Co-Chair Peering Behind the Curtain: Examples of Elise C. Kohn, MD University of Pennsylvania Successful Palliative Care Practices and Why Discussion National Cancer Institute at the National They Work 11:21 AM Heather A. Wakelee, MD—Co-Chair Institutes of Health Stanford Cancer Institute Rational Approach to Utilizing Genetic Caron Alyce Jacobson, MD Panel Question and Answer (Discussion of Abstracts 7503-7505) Information Dana-Farber Cancer Institute Discussion CAR T and Other Vehicles for 11:30 AM EDUCATION SESSION Panel Question and Answer Immunotherapy Stephen V. Liu, MD How Can Genetics Personalize Cancer (Discussion of Abstracts 9012-9014) Survivorship? 11:33 AM MEET THE PROFESSOR SESSION Georgetown University Medical Center S102 Panel Question and Answer Primary and Acquired Resistance to Novel Approaches for EGFR-Mutant Patient and Survivor Care; Cancer Prevention, 11:45 AM Non–Small Cell Lung Cancer Hereditary Genetics, and Epidemiology Checkpoint Inhibitors— T Ticketed Session Randomized phase 2 trial of polatuzumab E253d 11:42 AM vedotin (pola) with bendamustine and Lindsay M. Morton, PhD—Chair Developmental Therapeutics and Translational Panel Question and Answer rituximab (BR) in relapsed/refractory (r/r) FL National Cancer Institute at the National Research; Immunotherapy; Lung Cancer; Melanoma/ and DLBCL. (Abstract 7507) Institutes of Health Skin Cancers Discussion Germline Genomics and the Risk of Charles G. Drake, MD, PhD Laurie Helen Sehn, MD, MPH 11:48 AM Developing Treatment-Related Subsequent Neoplasms Columbia University Herbert Irving 11:57 AM D. Ross Camidge, MD, PhD Comprehensive Cancer Center High, durable minimal residual disease (Discussion of Abstracts 9015-9019) Sarah L. Kerns, PhD, MPH Approach to Primary and Acquired negativity (MRD–) with venetoclax + University of Colorado, Denver University of Rochester Medical Center Resistance to Checkpoint Inhibitors: rituximab (VenR) in relapsed/refractory (R/R) Old Targets Revisited, New Drug Discovery Using Genetic Information for Risk Genitourinary Cancers CLL: MRD kinetics from phase 3 MURANO 12:00 PM Prediction of Radiotherapy Toxicity study. (Abstract 7508) Scott N. Gettinger, MD Panel Question and Answer M. Eileen Dolan, PhD Yale Cancer Center, Yale New Haven Hospital Peter Hillmen, MBChB The University of Chicago Approach to Primary and Acquired Resistance Discussion Role of Genomics in Precision Management to Checkpoint Inhibitors: Lung Cancer Discussion 12:09 PM of Chemotherapy-Induced Ototoxicity and 12:09 PM Jhanelle Elaine Gray, MD Neuropathy Alison J. Moskowitz, MD (Discussion of Abstracts 9020-9021) MEET THE PROFESSOR SESSION (Discussion of Abstracts 7507-7508) Moffitt Cancer Center Panel Question and Answer Treatment Strategies for Locoregionally Memorial Sloan Kettering Cancer Center What Immunotherapy Means to Patients Advanced Nasopharyngeal Cancer: Making Tailoring Therapy in Lymphoid Malignancies Sense of Recent Studies— 12:21 PM EDUCATION SESSION T Ticketed Session 12:21 PM Panel Question and Answer Lynch Syndrome 360 E253c Panel Question and Answer S404 Head and Neck Cancer; Global Health Discussion Cancer Prevention, Hereditary Genetics, and Epidemiology; Gastrointestinal (Colorectal) Cancer; Anthony T. C. Chan, MD 11:30 AM–12:45 PM 12:27 PM State Key Laboratory of Oncology in South Sarah B. Goldberg, MD Gynecologic Cancer; Immunotherapy POSTER DISCUSSION SESSION China, The Chinese University of Hong Kong (Discussion of Abstracts 9022-9023) Heather Hampel, MS Gastrointestinal (Colorectal) Cancer Locoregionally Advanced Nasopharyngeal Yale Cancer Center The Ohio State University Comprehensive Cancer Hall D2 Cancer: Making Sense of Recent Studies Optimizing the Use of Immunotherapy Center Mark Kozloff, MD—Co-Chair Identification of Lynch Syndrome: From Sue Sun Yom, MD, PhD Ingalls Memorial Hospital Posters discussed in this session are on display Universal Testing to Tumor Sequencing in University of California, San Francisco in the Lung Cancer—Non–Small Cell Metastatic Colorectal and Endometrial Cancer Locoregionally Advanced Nasopharyngeal Chi Lin, MD, PhD—Co-Chair Poster Session. See the iPlanner for poster titles Cancer: Making Sense of Recent Studies University of Nebraska Medical Center and presenters. Luis A. Diaz, MD Memorial Sloan Kettering Cancer Center Discussion The Treatment of Lynch Syndrome- 11:30 AM–1:00 PM Associated Advanced Malignancy CLINICAL SCIENCE SYMPOSIUM 11:30 AM EDUCATION SESSION Innovative Approaches to Oncology Alberto F. Sobrero, MD Controversies in Adjuvant/Neoadjuvant Matthew B. Yurgelun, MD—Chair Education (Discussion of Abstracts 3508-3511) Chemotherapy in Localized Soft Tissue Dana-Farber Cancer Institute S103 IRCCS A.O.U. San Martino IST Sarcoma Lynch Syndrome: Update on Comprehensive Professional Development My Take: Timing of EGFR-Directed Therapy E451 Screening and Risk Reduction 11:42 AM Sarcoma; Care Delivery and Practice Management; James A. Stewart, MD, FACP, FASCO—Chair Panel Question and Answer Panel Question and Answer Gynecologic Cancer; Pediatric Oncology Baystate Medical Center Jonathan C. Trent, MD, PhD Discussion Discussion Sylvester Comprehensive Cancer Center EDUCATION SESSION 11:48 AM Neoadjuvant/Adjuvant Chemotherapy Management of Biochemically Recurrent 11:30 AM Ryan Bruce Corcoran, MD, PhD Should Be Considered Standard in High-Risk Prostate Cancer: Which Imaging, Which James A. Stewart, MD, FACP, FASCO (Discussion of Abstract 3513) Extremity Soft Tissue Sarcoma Treatment, and When? Baystate Medical Center Massachusetts General Hospital Axel Le Cesne, MD S406 Introduction Molecular Subsets: Prognosis and Prediction Genitourinary (Prostate) Cancer Gustave Roussy Cancer Campus 11:35 AM 12:00 PM Neoadjuvant/Adjuvant Chemotherapy Michael J. Morris, MD Addressing the burden of cancer in East Panel Question and Answer Should Be Considered Experimental in High- Memorial Sloan Kettering Cancer Center Africa through cascaded training and Risk Extremity Soft Tissue Sarcoma Lifting the Veil on Micrometastatic Disease: education by local doctors. (Abstract 11000) Emerging Imaging Strategies in Biochemical Jennifer Eastin Recurrence

See Sessions, Page 20D RET alterations can act as primary > VISIT OUR BOOTH oncogenic drivers in many cancer types1 AT THE 2018 ASCO ANNUAL MEETING LOXO ONCOLOGY IS INVESTIGATING A NEW APPROACH TO TREATING RET-ALTERED CANCERS

RET=rearranged during transfection.

RET alterations can result in STUDY DESIGN constitutively active RET signaling Advanced solid tumor that promotes cancer growth1-3 LOXO-292, an investigational selective RET inhibitor, is currently in clinical development. Target exposure NCT03157128: Phase 1 Study of LOXO-292 in Patients With Advanced Solid Tumors, Dose escalation Dose Advanced solid tumor with RET-Fusion Lung Cancer, and Medullary RET alteration/increased RET activity Thyroid Cancer* Prior therapy with multikinase inhibitors (MKIs) that inhibit RET allowed A phase 1, open-label, first-in-human study designed to evaluate LOXO-292 in patients with MTD/recommended dose expansion advanced solid tumors, including RET-fusion non–small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and other tumors with increased RET activity. 1 2 3 Primary Outcome Measures: Maximum tolerated dose (MTD)/recommended dose for further study Advanced Advanced Advanced Advanced RET-altered RET-fusion† RET-fusion† RET-mutant† RET-mutant† solid tumor, Secondary Outcome Measures: NSCLC NSCLC MTC MTC including: • Safety • Median duration • ≥ 1 prior MKI No prior MKI ≥ 1 prior MKI No prior MKI Disease not • Pharmacokinetics of progression-free measurable that inhibits that inhibits that inhibits that inhibits • Other RET • Overall response rate survival Dose expansion RET RET RET RET alterations • Duration of response • Median overall • cfDNA for RET alteration • Clinical benefit rate survival • RET mutation- negative MTC *Information consistent with ClinicalTrials.gov as of March 7, 2018. • Any prior MKI that inhibits RET

†Bona fide RET fusion, ATA moderate- and high-risk RET mutation.

To enroll, patients must meet eligibility requirements, including: For more information about the RET • Locally advanced or • Age ≥ 12 program or to participate as a trial site, visit metastatic solid tumor • Any number or call which progressed of prior MKIs LoxoRETtrials.com 1-855-RET-4-292. following standard • ECOG score ≤ 2 therapy, or for whom no • Life expectancy of standard therapy exists at least 3 months For full eligibility requirements, visit ClinicalTrials.gov.

References: 1. Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Onc. 2018;15(3):151-167. 2. Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367(6461):375-376. 3. Grieco M, Santoro, M, Berlingieri, MT, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell. 1990;23(60):557-563. Copyright © Loxo Oncology, Inc, 2018, All Rights Reserved. LMA.CPA1.2018Apr10.03

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Sessions Katherine Elizabeth Reeder-Hayes, MD, Discussion Discussion MBA, MS Continued from page 18D 3:00 PM 5:21 PM The University of North Carolina at Chapel Hill Daniel J. George, MD Rachna T. Shroff, MD Yin and Yang: Leveraging Clinical Trials and Duke University (Discussion of Abstracts 4014-4016) 11:47 AM Real-World Data to Inform Evidence-Based University of Arizona Bridging the gap in global advanced radiation Cancer Care 3:15 PM Moving Beyond Gemcitabine Therapy in oncology training: Impact of a web-based Pembrolizumab (pembro) versus platinum- Sean Khozin, MD, MPH Pancreatic and Biliary Cancers? open-access interactive three-dimensional based chemotherapy (chemo) as first-line U.S. Food and Drug Administration contouring atlas on radiation oncology therapy for advanced/metastatic NSCLC with 5:33 PM FDA’s Informed: Real-World Evidence Comes practice in Russia. (Abstract 11001) a PD-L1 tumor proportion score (TPS) ≥ 1%: Panel Question and Answer of Age Open-label, phase 3 KEYNOTE-042 study. Natalia Dengina, MD 5:39 PM Jinani Jayasekera, PhD (Abstract LBA4) Jordan Berlin, MD, FASCO 11:59 AM Lombardi Cancer Center MedStar Georgetown Gilberto Lopes, MD, MBA (Discussion of Abstract(s) 4017-4020) The teaching of multi-disciplinary cancer University Hospital care: A flipped classroom approach. Simulation Modeling of Cancer Clinical Vanderbilt University Ingram Cancer Center Discussion (Abstract 11002) Trials: Drawing New Conclusions From Expanding the Treatment Landscape in Hepatocellular Carcinoma Helen Sarah Winter, MBBS Old Trials 3:30 PM Leena Gandhi, MD, PhD 5:51 PM 12:11 PM Panel Question and Answer NYU Perlmutter Cancer Center Panel Question and Answer Professional development improves geriatric focused oncology activities in settings across Posters discussed in this session are on display the nation. (Abstract 11003) Mid-Day Sessions Late-Afternoon Sessions in the Gastrointestinal (Noncolorectal) Cancer Denice Economou, MSN Poster Session. See the iPlanner for poster titles and presenters. Discussion 1:00 PM–4:00 PM 4:00 PM–4:30 PM 12:23 PM PLENARY SESSION POST-PLENARY SESSION Leora Horn, MD POSTER DISCUSSION SESSION Plenary Session Including the Science of Post-Plenary Discussion Session I: (Discussion of Abstracts 11000-11003) Lung Cancer—Non–Small Cell Local- Oncology Award and Lecture Breast Cancer Vanderbilt University Medical Center Regional/Small Cell/Other Thoracic Cancers Hall B1 S100a Innovative Approaches, Evaluation, and Arie Crown Theater Simulcast Location: Hall D1 Outcomes From a Domestic Perspective Elizabeth A. Mittendorf, MD, PhD—Chair David R. Gandara, MD, FASCO—Co-Chair Bruce E. Johnson, MD, FASCO—Co-Chair Dana-Farber/Brigham and Women’s University of California, Davis Discussion Dana-Farber Cancer Institute Cancer Center Kristin Ann Higgins, MD—Co-Chair 12:35 PM Joseph A. Sparano, MD Ann H. Partridge, MD, MPH, FASCO— Winship Cancer Institute of Emory University Frank Douglas Ferris, MD Co-Chair Montefiore Medical Center OhioHealth Dana-Farber Cancer Institute Panelist Discussion Innovative Approaches, Evaluation, and 1:00 PM Lisa A. Carey, MD 4:45 PM Outcomes From an International Perspective Bruce E. Johnson, MD, FASCO, and The University of North Carolina at Chapel Hill Mark G. Kris, MD, FASCO 12:47 PM Ann H. Partridge, MD, MPH, FASCO Panelist (Discussion of Abstracts 8508-8510) Dana-Farber Cancer Institute Panel Question and Answer Eric P. Winer, MD, FASCO Memorial Sloan Kettering Cancer Center Welcome and Introductions Dana-Farber Cancer Institute What, When, and How? Juggling Sequence 1:05 PM Panelist and Agent Choices EDUCATION SESSION Daniel F. Hayes, MD, FACP, FASCO 4:57 PM Collecting and Using Real-World Evidence: University of Michigan Comprehensive 4:30 PM–5:00 PM Panel Question and Answer Supplementing and Perhaps Replacing Cancer Center Clinical Trials (Includes Presentation of Presentation of the 2018 Science of POST-PLENARY SESSION Discussion Public Service Award) Oncology Award Post-Plenary Discussion Session II: S100a Rhabdomyosarcoma 5:03 PM Health Services Research, Clinical Informatics, 1:10 PM S100bc Alexander V. Louie, MD, PhD, MSc, FRCPC and Quality of Care; Care Delivery and Practice Douglas R. Lowy, MD (Discussion of Abstracts 8511-8513) Management; Clinical Trials; Patient and Survivor Care National Institutes of Health Richard Aplenc, MD—Chair London Regional Cancer Program Preventing HPV-Associated Cancers by Children’s Hospital of Philadelphia Rethinking Radiation: Is The Stereo(tactic) Monica M. Bertagnolli, MD, FACS, FASCO Vaccination Too Loud? Dana-Farber-Cancer Institute, Brigham and Douglas S. Hawkins, MD Women’s Hospital, and Harvard Medical School 1:40 PM Seattle Children’s Hospital, University of 5:15 PM Presentation of the 2018 Public Service Award Bruce E. Johnson, MD, FASCO, and Washington, Fred Hutchinson Cancer Panel Question and Answer Ann H. Partridge, MD, MPH, FASCO Research Center Gideon Michael Blumenthal, MD Dana-Farber Cancer Institute Panelist Discussion U.S. Food and Drug Administration Introduction to Plenary Session Public Service Award Recipient Gianni Bisogno, MD 5:21 PM 1:45 PM University Hospital of Padova Charu Aggarwal, MD, MPH Lynne Penberthy, MD—Chair TAILORx: Phase III trial of chemoendocrine Panelist (Discussion of Abstracts 8514-8516) National Cancer Institute at the National Abramson Cancer Center therapy versus endocrine therapy alone Robin Lewis Jones, MD, MBBS, MRCP Institutes of Health in hormone receptor-positive, HER2- New Targets: Time To Get Excited? NCI-SEER Now and Into the Future as a Royal Marsden Hospital, The Institute of Cancer negative, node-negative breast cancer and an Research 5:33 PM Partner in Real-World Evidence Generation intermediate prognosis 21-gene recurrence Panelist Panel Question and Answer score. (Abstract LBA1) Discussion Joseph A. Sparano, MD 4:45 PM–6:00 PM 5:39 PM POSTER DISCUSSION SESSION Discussion Corey J. Langer, MD 2:00 PM Gastrointestinal (Noncolorectal) Cancer (Discussion of Abstracts 8517-8519) Lisa A. Carey, MD Hall D2 University of Pennsylvania Perelman School ASCO MEMBERSHIP The University of North Carolina Vaibhav Sahai, MBBS, MS—Co-Chair of Medicine FOR ONCOLOGY PD-L1, CTLA-4, Cyclin D, Oh My! 2:15 PM University of Michigan Comprehensive ADMINISTRATORS Cancer Center Maintenance low-dose chemotherapy Posters discussed in this session are on display ASCO knows how important in patients with high-risk (HR) Sunil Sharma, MD, FACP, MBA—Co-Chair in the Lung Cancer—Non–Small Cell Local- rhabdomyosarcoma (RMS): A report from Translational Genomics Research Institute Regional/Small Cell/Other Thoracic Cancers oncology administrators are the European Paediatric Soft Tissue Sarcoma in all practice settings. ASCO Poster Session. See the iPlanner for poster titles Study Group (EpSSG). (Abstract LBA2) Discussion and presenters. Clinical Affairs is focused Gianni Bisogno, MD 4:45 PM on providing administrators Joseph Chao, MD educational resources, practical Discussion (Discussion of Abstracts 4009-4011) EDUCATION SESSION tools, and services to help 2:30 PM City of Hope Common Themes in Uncommon Gastroesophageal Cancers: What Can We enhance business operations Douglas S. Hawkins, MD Lymphomas: How Biology and Novel Learn From Randomized Trials? Treatments Are Changing the Landscape and deliver high-quality, high- Seattle Children’s Hospital, University of Washington, Fred Hutchinson Cancer 4:57 PM E450 value care. ASCO now offers a Research Center Panel Question and Answer Hematologic Malignancies—Lymphoma and membership category specific Chronic Lymphocytic Leukemia; Central Nervous 2:45 PM Discussion System Tumors to oncology administrators and CARMENA: Cytoreductive nephrectomy those who monitor and supervise followed by sunitinib versus sunitinib alone 5:03 PM Francine M. Foss, MD—Chair the business operations of an in metastatic renal cell carcinoma—Results of Daniel Tandel Chang, MD Yale Cancer Center (Discussion of Abstracts 4012-4013) Emerging Role of Novel Therapies in oncology practice, cancer center, a phase III noninferiority trial. (Abstract LBA3) Stanford University School of Medicine Cutaneous T-Cell Lymphoma or facility. Stop by ASCO Central Esophageal Cancer: Is More Really More? Arnaud Mejean, MD, PhD on-site to learn more about 5:15 PM membership and what Clinical Panel Question and Answer Affairs has to offer. See Sessions, Page 22D ©2018 City of Hope we’ve BEEN PIONEERING CAR T CELL THERAPIES FOR OVER 20 YEARS AND WE’RE NOT STOPPING NOW.

It’s a new day for research and patient care in CAR T cell therapies. City of Hope has been accelerating innovative CAR T research for more than 20 years, developing novel CAR T cell therapies for blood and solid tumors, as well as partnering with global biopharmaceutical companies for clinical trials. • Over 180 patients currently being treated with CAR T cell therapies • 14 open CAR T cell therapy trials with several more opening this year • Authorized site for both tisagenlecluecel (Kymriah) and axicabtagene ciloleucel (Yescarta) Find out more about City of Hope’s CAR T cell therapies program. Go to CityofHope.org/CAR-T or call our dedicated CAR T cell therapy line: 833-310-CART (2278).

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A Cancer Center Designated by the National Cancer Institute D 22 ASCO DAILY NEWS • SUNDAY, JUNE 3, 2018 am.asco.org/dn

Sessions EDUCATION SESSION Mark D. Pegram, MD Matthew Meyerson, MD, PhD Stanford School of Medicine Dana-Farber Cancer Institute Continued from page 20D Global Myeloma, Health Disparities, and the Cost of Drugs Overcoming Resistance in HER2+ Metastatic Role of Big Data and Informatics in Christian Grommes, MD E451 Breast Cancer Precision Medicine Memorial Sloan Kettering Cancer Center Hematologic Malignancies—Plasma Cell Dyscrasia; Amy E. McKee, MD Panel Question and Answer Treatment of Primary Central Nervous Disparities; Global Health; Value U.S. Food and Drug Administration System Lymphoma: From Chemotherapy to Timothy Rebbeck, PhD Regulatory Science: The Challenges with Small Molecules Harvard T. H. Chan School of Public Health and EDUCATION SESSION “SMALL DATA”: Small Trials, Off-Label Use, Thierry Lamy, MD, PhD Dana Farber Cancer Institute Lifestyle Modifications for Primary and Single Patient INDs—Are We Doing Centre Hospitalier Universitaire Pontchaillou Myeloma Outcomes and Disparities in and Secondary Cancer Prevention: Enough? Latest Advances in the Diagnosis and African Americans Diet, Exercise, Sun Safety, and Alcohol Treatment of Large Granular Lymphocytic Panel Question and Answer Philippe Moreau, MD—Chair Reduction Leukemia CHU de Nantes-Hôtel Dieu S102 Global Approaches in Myeloma: Critical Cancer Prevention, Hereditary Genetics, and EDUCATION SESSION Panel Question and Answer Trials That May Change Practice Epidemiology; Breast Cancer; Gastrointestinal The Winds of Change: Optimizing (Colorectal) Cancer; Head and Neck Cancer; Patient Immunotherapy, Radiopharmaceuticals, S. Vincent Rajkumar, MD and Survivor Care and PARP Inhibition in Prostate Cancer EDUCATION SESSION Mayo Clinic Hall D1 Debate: Value and Cost of Myeloma Noelle K. LoConte, MD—Chair Communicating the Financial Burden of University of Wisconsin Carbone Cancer Center Genitourinary (Prostate) Cancer; Immunotherapy Treatment With Patients Therapy—We Cannot Afford It Alcohol and Cancer: A Review of the ASCO Martin Pomper, MD S404 Rafael Fonseca, MD Position Paper Johns Hopkins University School of Medicine Health Services Research, Clinical Informatics, Mayo Clinic Radiopharmaceuticals: Emitting the Right and Quality of Care; Care Delivery and Practice Jeffrey E. Gershenwald, MD Debate: Value and Cost of Myeloma Signals in Prostate Cancer Management; Disparities; Ethics; Patient and Therapy—We Can Afford It The University of Texas MD Anderson Survivor Care; Value Cancer Center Carmel Jo Pezaro, MBChB Malignant Melanoma Prevention: Lifestyle Monash University Ryan David Nipp, MD—Chair Panel Question and Answer Changes and Legislation Optimal Integration of PARP Inhibitors for Massachusetts General Hospital Prostate Cancer: Which Test, Which Patient, The Clinician’s Perspective on Discussing Jennifer A. Ligibel, MD and Which Therapy? Costs With Patients EDUCATION SESSION Dana-Farber Cancer Institute Innovative Strategies Targeting Subtypes Diet and Exercise: Role in Primary Cancer Ravi Amrit Madan, MD—Chair Gery Guy, PhD, MPH in Metastatic Breast Cancer Prevention and Cancer Recurrence National Cancer Institute at the National Centers for Disease Control and Prevention Hall B1 Institutes of Health Cost in the Era of Targeted Therapies and Breast Cancer Panel Question and Answer Immunotherapy in Prostate Cancer: Immunotherapies for Cancer The Path Forward Matthew P. Goetz, MD Ellen Sonet, MBA, JD Mayo Clinic CancerCare EDUCATION SESSION Panel Question and Answer ER+ Metastatic Breast Cancer: Assisting Patients With the Cost Burden Novel Approaches in Bone and Soft Tissue Beyond CDK Inhibitors of Cancer Diagnosis and Treatment: Next- Sarcomas: The Emerging Role of Precision MEET THE PROFESSOR SESSION Generation Sequencing Testing, Off-Label Medicine Stacy L. Moulder, MD, MS—Chair Addressing Fertility in Young Adult Cancer Medications, and More The University of Texas MD Anderson S103 Survivors— T Ticketed Session Cancer Center Sarcoma; Developmental Therapeutics and E253d Panel Question and Answer Novel Druggable Pathways in Triple-Negative Translational Research; Immunotherapy; Pediatric Patient and Survivor Care; Pediatric Oncology Breast Cancer Oncology Seth Pollack, MD Karine Chung, MD Fred Hutchinson Cancer Research Center USC Fertility Is There a Role for Immunotherapy in Fertility and Pregnancy Outcomes: Current Sarcomas? Trends in Preservation and Reproductive Health and Communicating Fertility-Related Emanuela Palmerini, MD Information Istituto Ortopedico Rizzoli Precision Medicine in Bone Tumors MEET THE PROFESSOR SESSION Daniela Katz, MD—Chair The Peer-Review Process and Writing an Assaf Harofeh Medical Center Outstanding Manuscript— Over 50 Subtypes of Soft Tissue Sarcoma: Can T Ticketed Session We Ever Have a Specific Treatment for Each? E253c Professional Development I AM Panel Question and Answer Stephen A. Cannistra, MD, FASCO a clinical investigator. Beth Israel Deaconess Medical Center ASCO fills a special EDUCATION SESSION Pediatric Clinical Trials: Economics, Cost, 5:00 PM–5:30 PM niche in promoting and Value of Investment POST-PLENARY SESSION and supporting the S504 Post-Plenary Discussion Session III: Pediatric Oncology; Clinical Trials; Patient and Survivor Kidney Cancer careers of clinical Care; Value S100a investigators Sharon M. Castellino, MD, MSc Toni K. Choueiri, MD—Chair Children’s Healthcare of Atlanta Dana-Farber Cancer Institute in oncology. I am Proof-of-Paradigm of Cost-Effectiveness Analysis Within a Therapeutic Clinical Trial Daniel J. George, MD Duke University Susan K. Parsons, MD—Chair Panelist Tufts Medical Center ASCO Arnaud Mejean, MD, PhD Financial Consideration of Novel Therapeutics Within the Setting of Pediatric Hôpital Européen Georges-Pompidou-Paris Oncology Descartes University Panelist K. Robin Yabroff, PhD Dr. Allison Kurian American Cancer Society David Chen, MD Financial Hardship Associated With Cancer Fox Chase Cancer Center Survivorship Panelist

Panel Question and Answer 5:30 PM–6:00 PM POST-PLENARY SESSION Post-Plenary Discussion Session IV: EDUCATION SESSION Lung Cancer Precision Medicine for a Single Patient: S100bc What Does It Really Mean and How Do We Do It? Melissa Lynne Johnson, MD—Chair S406 Sarah Cannon Research Institute Tumor Biology; Care Delivery and Practice Gilberto Lopes, MD, MBA Management; Developmental Therapeutics and Sylvester Comprehensive Cancer Center, Translational Research; Health Services Research, University of Miami Health System Clinical Informatics, and Quality of Care JOIN ASCO Panelist Victoria Meucci Villaflor, MD—Chair Leena Gandhi, MD, PhD Northwestern University Visit a Member Services NYU Perlmutter Cancer Center Complexity of Delivering Precision Medicine: Panelist Desk to Apply Challenges and Opportunities Scott Joseph Antonia, MD, PhD Moffitt Cancer Center Panelist Visit us at the Accelerate Innovation Pharmacyclics Through Enrollment booth 13081

Renal cell carcinoma, Key eligibility criteria • Pathologically conﬁ rmed RCC (clear cell), urothelial carcinoma urothelial carcinoma, (transitional cell), gastric or gastroesophageal junctional (GEJ) adenocarcinoma, or K-RAS wild-type EGFR expressing CRC gastric adenocarcinoma, and • Renal cell carcinoma: 1-4 previous lines of therapy; ECOG 0-1 colorectal adenocarcinoma— (2 may be acceptable) • Urothelial carcinoma: 1-2 previous lines of therapy; ECOG 0-1 relapsed/refractory • Gastric or GEJ adenocarcinoma: 1-3 previous lines of therapy; ECOG 0-1 PCYC-1128-CA (NCT02599324) • Colorectal adenocarcinoma: 2-4 previous lines of therapy; A phase 1b/2 study of ibrutinib combination therapy in ECOG 0-1 (2 may be acceptable) selected advanced gastrointestinal and genitourinary tumors.

Study Locations View location details at clinicaltrials.gov (search: NCT02599324)

Huntsville, AL Lafayette, IN Hershey, PA La Jolla, CA Fairway, KS Philadelphia, PA Los Angeles, CA Metairie, LA Nashville, TN US San Francisco, CA Boston, MA Galveston, TX Santa Monica, CA Detroit, MI Temple, TX Norwalk, CT Omaha, NE Fairfax, VA Washington, DC Winston-Salem, NC Wenatchee, WA Jacksonville, FL Portland, OR

Hwasun Santander Sutton Seongnam-si Barcelona Glasgow South Seoul Spain Madrid UK London Korea Seville Manchester

For the most up-to-date enrollment information, contact Medical Affairs at [email protected] or 1-877-877-3536.

The safety and efﬁ cacy of the investigational use of this product have not been determined. There is no guarantee that the investigational uses listed will be ﬁ led with and/or approved for marketing by any regulatory agency. CMRC-02660 04/18

10484_PCYC_ASCO_RecruitmentAd_042018_RL.indd 1 4/12/18 2:20 PM THE MERCK ACCESS PROGRAM

May Help Answer Questions About • Beneﬁ t investigations • Referral to the Merck Patient Assistance Program for eligibility • Billing and coding determination (provided through the Merck Patient Assistance Program, Inc) • Product distribution • Co-pay assistance for eligible patients • Prior authorizations and appeals

Contact The Merck Access Program (MAP). Visit merckaccessprogram-keytruda.com. Call 855-257-3932 Monday through Friday, 8 AM to 8 PM ET.

Register for the secure Merck Access Portal to Complete the MAP enrollment form online and submit it electronically. The Portal provides for the use of electronic signatures

Track beneﬁ t investigation and enrollment requests to help you monitor where your patients are in the enrollment or beneﬁ t investigation process

Receive notiﬁ cations and update practice information from a central dashboard

To register your practice for the Merck Access Portal, visit merckaccessprogram-keytruda.com.