Lung Cancer for Thoracic Specialists

GLOBAL EDITION V4 / N6 / DECEMBER 2019 LUNG CANCER FOR THORACIC SPECIALISTS

Read online at LungCancerNews.orgg NEWS & Visit IASLC.org INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER

INSIDE IMMUNOTHERAPYI Ongoing Clinical Challenges: Defi ning Immunotherapy 4 Robust Survival Duration Shown in NSCLC With Pembrolizumab Benefi t for Patients With NSCLC and Poor Performance Status Novel Insights on ctDNA Dynamics During Targeted Therapy and 6 Immune Checkpoint Blockage By Valérie Gounant, MD, and Elisabeth are detected, these patients are treated in NSCLC Quoix, MD, PhD This article is the first in a two- with oncogene-specifi c tyrosine kinase inhibitors, regardless of PS. Expert Perspectives on Liquid Biopsy: part series on ongoing challenges Since the beginning of the 21st century, 7 Results Turnaround and Application using immunotherapy in special in China there have been two major innovations populations. The second part, Current Data in the treatment of advanced NSCLC: with a focus on elderly patients, We have little data about safety and 8 Spotlight on Palliative Care: Canada the use of targeted therapies and the use will run in the February issue and effi cacy in poor PS patients. Currently, of immune checkpoint inhibitors (ICIs). only four prospective trials includ- Rethinking the Future of Hospice online (lungcancernews.org). 10 Care in the United States These modalities have revolutionized ing PS 2 patients have been published; outcomes for patients with metastatic three were in abstract form,4,5,6 and only 11 Spotlight on Palliative Care: China disease. However, the U.S. Food and the absence of a molecular target. Most one7 was an actual journal article. Th ese Drug Administration (FDA) approvals for patients with PS 3-4 die within 2 to 4 included two phase II trials (CheckMate A Balancing Act: Managing atezolizumab, nivolumab, and pembroli- months of diagnosis. 171 with nivolumab4 and PePS2 with 11 Patients’ Expectations zumab were based on the results of phase However, trials dedicated to patients pembrolizumab5) and two phase III/IV 7 12 Diagnostic Oncology: PD-L1 in III clinical trials, which restricted enroll- with advanced NSCLC who harbor onco- trials (CheckMate 153 with nivolumab Cytology Specimens ment to patients with a performance status genic drivers, including activating muta- and CheckMate 817 with nivolumab 6 First-Ever IASLC School of Nursing (PS) of 0 or 1, leaving the thoracic oncol- tions, have been performed in popula- and ipilimumab ). Th ese trials did not 13 Held in Latin America ogy community wondering about optimal tions with such poor general condition,2,3 select their populations based on bio- treatment for patients with poor PS. and safety and effi cacy were consistent markers. Th e results of prospective trials Dr. Richard Pazdur Discusses The prevalence of poor PS (2-4) with results observed in patients with in advanced NSCLC in PS 2 patients 14 Project Facilitate and the Expanded- Access Program patients at time of diagnosis is as high good PS (so-called Lazarus syndrome), are summarized in Table 1 on page 3 as 34%.1 For patients with metastatic leading to general acceptance of these (aft er Passaro8). Th ese trials, apart from STARS Patient Research Advocate NSCLC and PS 3-4, there is no recom- agents independent of PS. Th ese trials PePS2, also included elderly patients and 15 Training Program Seeks Patients and Caregivers mendation for chemotherapy, and best have profoundly changed clinical prac- /or PS 0-1 patients with comorbidities, supportive care is the usual standard in tice; now, if oncogene-addicted tumors continued on page 3

EVOLVING STANDARDS OF CARE Lung Cancer Leading the Charge for Tumor-Agnostic Targeted Therapies

By Robert C. Doebele, MD, PhD that specifi c oncogene mutations oft en BRAF inhibitors in colon cancers harbor- progression-free survival (mPFS) of 9.7 occur in more than one tumor type. Th is ing BRAF V600E mutations. Ultimately, months, leading to European Medicines Early in the drug development of targeted revelation has opened the door for novel, this disappointing clinical fi nding was Agency approval in 2017 and later U.S. therapies, specifi c oncogene mutations tumor-agnostic, drug-development strat- elegantly explained by inadvertent activa- Food and Drug Administration (FDA) were oft en associated with a single dis- egies. tion of EGFR by BRAF inhibitors.1 Recent approval.3 Since this time, BRAF inhibi- ease: HER2 gene amplifi cation with breast clinical trial data support this mechanism tors with or without MEK inhibition have cancer, BCR-ABL fusions with chronic BRAF with triplet combination therapy demonstrated clinical activity in hairy myelogenous leukemia, EGFR mutations BRAF inhibitors alone or of BRAF, MEK, and EGFR cell leukemia and anaplastic thyroid can- with lung cancer, and BRAF mutations in combination dem- inhibition demonstrating cers harboring BRAF V600E mutations. with melanoma. Th us, drug develop- onstrate significant improved activity.2 BRAF Despite these successes across multiple ment and approval proceeded in both clinical benefit in V600E mutations also tumor types, there is no tumor-agnostic a mutation- and tumor-specifi c context patients with mela- occur in lung cancers. approval yet for BRAF V600E mutations. for each of these indications. Th rough noma whose tumors In an early example of the eff orts of Th e Cancer Genome Atlas, harbor BRAF lung cancer provid- ALK the Genomics Evidence Neoplasia V600E. However, an ing a testing ground for Oncogenic ALK gene fusions were fi rst Information Exchange, and other large- early and prominent tumor-agnostic strategies, identifi ed in anaplastic large cell lym- scale pan-tumor sequencing eff orts, as setback for the con- Dr. Robert C. Doebele dabrafenib and trametinib phoma in 1994.4 However, the fi rst clini- well as through the implementation of cept of tumor- (or tissue-) demonstrated signifi cant clinical trial of an ALK inhibitor in cancer multiplexed next-generation sequencing agnostic therapeutic approaches cal activity with an objective response did not begin until aft er the discovery of panels in the clinic, it has become clear came in the form of lack of activity of rate (ORR) of 63% and a durable median continued on page 4

LUNGCANCERNEWS.ORG / DECEMBER 2019 3

Ongoing Clinical Challenges Table 1. Results of Prospective Trials in Advanced NSCLC with ECOG PS 2 Patients from page 1 First Trial Drug Setting PD-L1 No PS 2 ORR PFS mOS 6-mos OS Grade3-4 author stratifi c. (%) patients (%) (mos) (mos) (%) 3-4 toxicity (%) making it diffi cult to draw specifi c con- Popat Phase II Nivolumab ≥ 2 L No 38 11 5.4 46 6 clusions for PS 2 patients, which already CM 171 constitute a very heterogeneous popula- Spigel Phase III-IV CM 153 Nivolumab ≥ 2 L No 128 20 4 41 12 tion. Heightening heterogeneity by the inclusion of elderly patients and PS 0-1 Barlesi Phase III-IV CM 817 Nivolumab + ipilimumab 1L No 139 20 3.6 NA NA 28%* patients with comorbidities introduces Middleton Phase II Pembrolizumab 1/2 L < 1 27 19 3.3 9.8 NA NA PePS2 even more complexity and ambiguity in 1-49 15 33 6.8 NR NA NA interpreting the results. ≥ 50 15 47 8.5 16.6 NA NA Th e incidence of grade 3 to 4 treatment- * This result is not only for the PS2 population but for whole population of cohort A1 with PS2 and patients with PS 0 to 1 and co-morbidities. related adverse events (TRAE; primary Abbreviations: PS, performance status; stratifi c, stratifi cation; ORR, objective response rate; PFS, progression-free survival; mos, months;OS, overall survival; endpoint) was 6% for the PS 2 popula- CM, CheckMate; NR, not reported. tion and 12% for the overall population (including PS 0-1 patients and patients 2 patients, either pretreated or not, with to PS 2 are currently recruiting. However, 4. Popat S, Ardizzoni A, Ciuleanu T, Cobo Dols M, Laktionov K, Szilasi M. Nivolumab in previ- aged 70 years and older) in CheckMate or without the addition of chemotherapy. only two of these trials select the popula- ously treated patients with metastatic squamous 171; comparable fi gures in CheckMate It is worth noting that, although all of the tion based on PD-L1 status: these include NSCLC: results of a European, single arm, phase 153 were 9% for PS 2 and 6% for the crucial phase III studies proving the ben- the trial of the Swiss Group for Clinical 2 trial (CheckMate 171) including patients aged >=70 years or with poor Performance Status. Ann overall population. In CheckMate 817, efi ts of ICIs were limited to PS 0-1 patients, Cancer Research (NCT03620669) and Oncol 2017;28 (Suppl 5): v460-v96. combination immunotherapy was more FDA authorization for the use of ICIs do the SAVIMMUNE trial (NCT04108026) 5. Middleton G, Brock K, Summers Y, Connibear toxic, but the safety profi le was similar not restrict the use of these agents s to PS orchestrated by the French Cooperative J, Shah R, Ottensmeier C. Pembrolizumab in performance status 2 patients with non-small cell between cohort A with PS 0-1 patients 0-1 patients. Th oracic Intergroup (IFCT). lung cancer (NSCLC): results of the PePS2 trial. (35% grade 3-4 TRAE) and cohort A1 Although there are no dedicated trials Th e role of chemotherapy and immu- Ann Oncol 2018;(suppl 8) viii493-viii547. 6. Barlesi F, Audigier-Valette C, Felip E, Ciuleanu with PS 2 patients (28% grade 3-4 TRAE) for PS 3 patients, we previously observed notherapy in combination must also be TE, Jao K, Rijavec E. CheckMate 817: fi rst-line (139/198 patients) and PS 0-1 patients Lazarus-type responses to anti‒PD-1 defi ned in the poor-PS population. A phase Nivolumab + ipilimumab in patients with ECOG with comorbidities. ICIs in two patients with NSCLC in very I trial evaluating the feasibility of weekly PS 2 and other special populations with advanced NSCLC. 2019 World Conference on Lung Cancer Overall survival (OS) was worse in PS 2 poor condition but with very high PD-L1 low-dose carboplatin and paclitaxel with in Barcelona (Spain. patients compared to the entire population expression.9 Such patients improved pembrolizumab for patients with advanced 7. Spigel DR, McCleod M, Jotte RM, Einhorn L, in CheckMate 171 (5.4 vs. 9.9 months) and from PS 3 or higher before the initiation NSCLC and PS 2-3 is ongoing.11 ✦ Horn L, Waterhouse DM, et al. Safety, Effi cacy, and Patient-Reported Health-Related Quality of Life in CheckMate 153 (4 vs. 9.1 months). In of immunotherapy, to PS 0, aft er only and Symptom Burden with Nivolumab in Patients CheckMate 817, in the PS 2 population, 1 month of ICIs; now aft er more than About the Authors: Dr. Gounant is with the with Advanced Non-Small Cell Lung Cancer, Including Patients Aged 70 Years or Older or progression-free survival (PFS) was 3.6 24 months of follow-up, major tumor Thoracic Oncology Department, Hôpital Bichat, with Poor Performance Status (CheckMate 153). J months, with response rate (RR) of 20%, shrinkage continues. Recently, others APHP, France. Prof. Quoix is with the Department Th orac Oncol 2019;14(9):1628-39. with median duration of response of 14.2 have similarly suggested that pembroli- of Pneumology, University hospital of Strasbourg, 8. Passaro A, Spitaleri G, Gyawali B, de Marinis F. Immunotherapy in Non-Small-Cell Lung Cancer months. As expected, PFS was longer in zumab can be considered in critically ill France. Patients With Performance Status 2: Clinical those patients whose tumors had a high patients with NSCLC and PD-L1 expres- Decision Making With Scant Evidence. J Clin PD-L1 expression and/or high tumor sion of 50% or more.10 References: Oncol 2019;37(22):1863-7. 1. Lilenbaum RC, Cashy J, Hensing TA, Young S, 9. Pluvy J, Brosseau S, Naltet C, Opsomer M-A, mutation burden (TMB). In PePS2, RR Cella D. Prevalence of poor performance status in Cazes A, Danel C, et al. Lazarus syndrome in was 19% in patients with PD-L1 expres- Challenges and Potential lung cancer patients: implications for research. J nonsmall cell lung cancer patients with poor per- sion of less than 1%, 33% in patients with Next Steps Th orac Oncol 2008;3(2):125-9. formance status and major leukocytosis following 2. Inoue A, Kobayashi K, Usui K, Maemondo M, nivolumab treatment. Eur Respir J 2017;50(1). PD-L1 expression of 1% to 49%, and 47% Th e main challenge is to select poor PS Okinaga S, Mikami I, et al. First-line gefi tinib 10. McLoughlin EM, Larner JM, Bergman MP, Stelow in patients with PD-L1 expression of 50% populations who are more likely to derive for patients with advanced non-small-cell lung EB, Brady K, Lynch AC, et al. Rapid Response to cancer harboring epidermal growth factor recep- Pembrolizumab in a Critically Ill Mechanically or higher. Median PFS and OS in those a benefi t from immunotherapy. In par- tor mutations without indication for chemother- Ventilated Patient with New Diagnosis of NSCLC. with PD-L1 expression of 50% or higher ticular, it is necessary to defi ne predic- apy. J Clin Oncol 2009;27(9):1394-400. J Th orac Oncol 2019;14(9):e193-5. were 8.5 and 16.6 months, respectively. tive biomarkers in this population: these 3. Iwama E, Goto Y, Murakami H, Harada T, 11. Bonomi M, Ahmed T, Addo S, Kooshki M, Tsumura S, Sakashita H, et al. Alectinib for Palmieri D, Levine BJ, et al. Circulating immune Thus, in selected populations, immu- include tumor biomarkers (e.g., molecu- Patients with ALK Rearrangement-Positive Non- biomarkers as predictors of the response to pem- notherapy may be quite useful in PS 2 lar profi le, PD-L1, and TMB) and patient Small Cell Lung Cancer and a Poor Performance brolizumab and weekly low dose carboplatin and patients. Th is observation must be con- biomarkers (e.g., infl ammatory and nutri- Status (Lung Oncology Group in Kyushu 1401). J paclitaxel in NSCLC and poor PS: An interim Th orac Oncol 2017;12(7):1161-6. analysis. Oncol Lett 2019;17(1):1349-56. fi rmed in dedicated studies confi ned to PS tional markers). Several trials dedicated

LETTER TO THE EDITOR Patient-Driven Research I was so glad to see the article by Dr. Amy Moore on PDX models I can tell you fi rsthand that research matters. It means more and better treatment in the October issue. As a Co-Founder of the EGFR Resisters, our collaboration options for those in our community. It is our lifeline, our future, and it is hope. with the GO2 Foundation for Lung Cancer is empowering patients to participate Many of us are depending on the next promising research advance so that we can in studies that will directly accelerate research in EGFR-positive lung cancer. We continue to see and reach meaningful milestones with our families and friends. are thrilled to be a part of supporting this cutting-edge research that will help Our goal is to change EGFR-positive lung cancer into a man- researchers understand what is causing the cancer to become treatment resistant. ageable chronic disease. (Note: Th is trial is currently enrolling, so please refer all eligible patients. Clinical Our hope is that combining the collective patient voice with Trial ID: NCT03872440) quality research will lead to longer and better lives for people Aft er a dramatic response to initial therapy, it is devastating to develop resistance with EGFR-positive lung cancer. ✦ to treatment. Th ere is a sense of urgency to understand the underlying mechanisms of drug resistance in EGFR-positive lung cancer and to identify new therapeutic Jill Feldman options. We must convert that devastation to hope. EGFR Resisters Co-Founder 4 IASLC LUNG CANCER NEWS / DECEMBER 2019

JOURNAL RADAR Robust Survival Duration Shown in NSCLC With Pembrolizumab By Suresh Ramalingam, MD selected patients enrolled to a phase term survivors can lead to the develop- Roche. He has received research support I study, the 5-year survival rate of ment of novel approaches to improve (to institution) from Astra Zeneca, Bristol Immune checkpoint inhibition is now approximately 30% for the patients outcomes for all patients with NSCLC. Myers Squibb, and Merck. part of routine care for patients with who received pembrolizumab is a new Combination approaches hold promise, advanced-stage NSCLC. Randomized milestone in lung cancer for metastatic as has already been evidenced by the About the Author: Dr. Ramalingam is a profes- clinical trials have established the effi - disease. Th is robust survival duration integration of chemotherapy and radio- sor of Hematology and Medical Oncology at cacy of checkpoint inhibitors as mono- was noted in patients with high PD-L1 therapy with immune checkpoint inhibi- Emory University School of Medicine, Winship therapy and in combination with che- expression in the fi rst-line setting. Th is tion. Th ere is no doubt that more work Cancer Institute. motherapy. One of the main features group represents approximately 25% to needs to be done; however, it is also with immune checkpoint inhibition 30% of all cases of advanced NSCLC. appropriate to refl ect on the magnitude is the durability of clinical responses Whether response to immunotherapy of progress to date, and the diff erence in a subset of patients; long-term sur- translates into cure for this subset of this makes for our patients’ lives. ✦ IN REFERENCE TO: vival is now possible for patients with patients is subject to debate, which will Garon EB, Hellmann MD, Rizvi NA, et al. advanced-stage NSCLC, even with be answered by continued follow-up. Disclosure: Dr. Ramalingam is a co- Five-Year Overall Survival for Patients With metastatic disease. It is in this con- For now, the focus shift s to under- author of this study; he has received Advanced Non–Small-Cell Lung Cancer text that the publication by Garon et standing the specifi c biologic attributes honorarium for participating in advisory Treated With Pembrolizumab: Results From al. assumes significance. Although of the long-term survivors. Knowledge board meetings/Consultation for Merck, the Phase I KEYNOTE-001 Study. J Clin Oncol. the results describe a cohort of highly regarding the immune milieu of long- Astra Zeneca, Bristol Myers Squibb, and 2019;37(28):2518-2527.

Tumor-Agnostic Targeted Therapies Figure. Models for Drug-Development Strategies from page 1

ALK gene fusions in lung cancer in 2007.5 Currently there are fi ve approved ALK inhibitors for NSCLC, but no tumor- agnostic approval despite the presence of ALK oncogenes in neuroblastoma, infl ammatory myofi broblastic tumors, and many others.6 The My Pathway basket trial (NCT02091141) is evaluating the activity of alectinib in patients with ALK-positive tumors.

ROS1 ROS1 fusions were first identified in glioblastoma in 1987.7 Th e discovery of ROS1 fusions in lung cancer and the readily available ROS1 inhibitor crizo- inhibitors would have activity irrespec- being transaminitis, dizziness, fatigue, with NTRK fusion–positive disease from tinib, which already had safety and effi - tive of tumor type and would target the nausea, and notable increase in body ALKA-372-001 (EudraCT 2012-000148- cacy data in ALK-positive NSCLC, facil- related gene fusions involving NTRK2 weight, which may be an on-target eff ect 88), STARTRK-1 (NCT02097810), and itated rapid development of crizotinib (TRKB) and NTRK3 (TRKC), supportive of TRKB inhibition. Th is trial represented STARTRK-2 (NCT02568267) included as the fi rst approved ROS1 inhibitor in of a tumor-agnostic therapeutic approach a number of fi rsts in oncology includ- only adult patients with 19 diff erent his- ROS1-positive NSCLC.8 Similar to ALK for this oncogene family.12 A review of ing the fi rst oncogene-targeted, tumor- tologies represented.15 Th e ORR was 57%, research, ROS1 fusions have been identi- the literature suggested that NTRK1/2/3 agnostic therapy to be approved (pem- and the mPFS was 11 months. Th e intra- fi ed in a number of other tumor types.9 fusions occur across a number of tumor brolizumab for MSI-high tumors was the cranial ORR (IC-ORR) in 11 patients with Th e STARTRK-2 (NCT02568267, entrec- histologies, and given the relative rarity fi rst tumor-agnostic therapy approved), CNS metastases was similar to the overall tinib) and AcSé (NCT02034981, crizo- of these oncogenes overall,13 a basket trial the first cancer drug to be approved ORR at 54.5%. Entrectinib was well tol- tinib) basket trials are evaluating the role design was pursued from the onset for simultaneously for both adult and pedi- erated; the most common AEs included of ROS1 inhibitors in ROS1 fusion–posi- TRK inhibitors. In 2018, larotrectinib was atric patients, and the fi rst cancer drug dysgeusia, constipation, fatigue, dizziness, tive tumors. the fi rst TRK inhibitor to be approved to be approved for a family of oncogenes. and weight gain. Analysis of 10 patients for the treatment of NTRK1/2/3 fusion– Entrectinib was the second agent to with NSCLC with NTRK1/3 fusions (no NTRK1/2/3 positive cancers. Th is was based on a gain approval (Japan) for NTRK1/2/3 NTRK2 fusions were identifi ed in NSCLC) Gene fusions involving the NTRK1 gene, cohort of 55 adult and pediatric patients fusion–positive cancers. Entrectinib is demonstrated an ORR of 70%, median PFS which encodes the TRKA receptor tyro- representing 17 unique diff erent histolo- an ALK/ROS1/TRK1 inhibitor designed of 14.9 months, and intracranial ORR of sine kinase, were discovered in 1982 in gies that harbored NTRK1/2/3 fusions.14 to have activity in the central nervous 66.7%.16 Notably, these results were similar a single colorectal cancer specimen10; The ORR was 75% by independent system (CNS), an important feature to the entrectinib data for ROS1-positive however, NTRK1 gene fusions in lung review, and mPFS was not yet reached. for tumors with a high propensity for NSCLC with an ORR of 77.4%, mPFS of cancer were fi rst identifi ed much later.11 Overall, the therapy was well tolerated brain metastases, such as lung cancer. 19.0 months, and IC-ORR of 55%.17 Th us, Early preclinical data suggested that TRK with most common adverse events (AEs) Integrated analysis from 54 patients continued on page 9 ONE FDA-APPROVED TEST ANALYZES 324 GENES Our comprehensive genomic proﬁling revolves around your patient.

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*Available on the same test requisition form as FoundationOne CDx FoundationOne®CDx is a next-generation sequencing based in vitro test intended for use by healthcare professionals for advanced cancer patients with solid tumors. The test analyzes 324 genes as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) and is FDA-approved as a companion diagnostic to identify patients who may benefit from treatment with a specific list of therapies (listed in Table 1 in the Technical Information at www.foundationmedicine.com/ f1cdx) in accordance with the approved therapeutic product labeling. Additional genomic findings, other than those listed in Table 1, may be reported and are not prescriptive or conclusive for labeled use of any specific therapeutic product. Use of the test does not guarantee a patient will be matched to a treatment or clinical trial option, or that all relevant alterations will be detected. Some patients may require a biopsy. For the complete label, including important risk information, please visit www.foundationmedicine.com/f1cdx. © 2019 Foundation Medicine, Inc. | MKT-0287-01 6 IASLC LUNG CANCER NEWS / DECEMBER 2019

A DEEPER DIVE

Novel Insights on ctDNA Dynamics During Targeted Th erapy and Immune Checkpoint Blockage in NSCLC

By Christian Rolfo, MD, PhD, patients with metastatic NSCLC with EGFR evaluated the role of noninvasive monitor- MBA, Dr.h.c. or HER2 mutations during treatment with ing of ctDNA using the TEC-Seq approach in Liquid biopsy (LBx) is a new, powerful tool diff erent classes of TKIs. They collected serial a longitudinal study of T-cell receptor (TCR) for the molecular profi ling of patients with blood draws from 28 patients with meta- repertoire during immune checkpoint inhi- NSCLC that can help oncologists with appro- static NSCLC at baseline and over the course bition. The study included 24 patients with priate treatment selection in oncogene- of treatment until disease progression, metastatic NSCLC treated with ICIs and 14 addicted NSCLCs. Circulating tumor DNA evaluating the changes of a new metric, cell patients with resectable NSCLC (stage I-IIIA) (ctDNA) assays for detection of both EGFR free tumor load (cfTL), which was defi ned receiving nivolumab as neoadjuvant treat- sensitizing and resistance mutations have as the contribution of the most abundant ment. At least two serial samples (range 2-8) already entered clinical practice in NSCLC,1 alterations in ctDNA at any particular time were collected for all patients. To avoid the and recently, the NILE study provided evi- point. Changes in cfTL were compared with potential eff ect of clonal hematopoiesis,5 dence that a 73-gene next-generation tumor burden assessed in patients with ctDNA analysis was focused only on genetic sequencing (NGS) panel can detect bio- detectable sequence clones (24 patients) Dr. Christian Rolfo alterations identifi ed through NGS in paired- markers (including EGFR, ALK, ROS1, BRAF, or the qualitative assessment of change matched tissue samples. In the metastatic RET, MET, HER2, and KRAS) at a rate similar from aneuploidy to normal ploidy in those acquired resistance compared with conven- cohort, 19 of 24 patients had ctDNA detect- to standard-of-care tissue genotyping tests, without detectable sequence clones (4 tional radiologic methodologies. However, able levels (median mutant allele fraction with a faster turnaround time; it can also patients). They reported that both ctDNA to date, it is unclear whether this might be of 1.87%) either at baseline or other time provide the opportunity to rescue patients levels and clonal heterogeneity dramati- associated with changes in the treatment points, whereas 7 of 14 patients in the early- who were incompletely genotyped or whose cally reduced in responding patients due strategy before radiographic progression or stage cohort had detectable ctDNA (median initial tissue analysis proved negative for to the selective pressure of targeted ther- not. The randomized phase II EORTC APPLE allele fraction of 0.34%). They identifi ed three “actionable” biomarkers.2 apy with a signifi cant reduction of cfTL trial (NCT02856893) will likely provide fur- patterns of molecular response in ctDNA: compared to baseline levels ther evidence on the utility of this strategy. molecular response, corresponding to a dra- LIQUID BIOPSY EXPERT VOICES (average of 10.8% at baseline Interestingly, cfTL reduction at a median matic reduction of ctDNA to undetectable In addition to tumor genotyping, LBx vs. 0.18% at a median time of 19 days after of 19 days was a more accurate predictor of levels; molecular resistance, associated with may potentially allow real-time monitor- treatment start; p < 0.001); they also noted clinical outcome compared with initial CT limited fl uctuations or a rise of ctDNA levels; ing of response in patients with cancer. a decrease of plasma aneuploidy scores imaging performed after an average of 47 and molecular acquired resistance, where This application may be particularly useful (average decrease of 92%; p = 0.002), and days (p < 0.0001), allowing a more precise tumor-specifi c variants were undetectable at in patients treated with targeted agents a reduction of average number of observed evaluation of patients with nonmeasur- the time of response followed by increase in favoring early identification of mecha- alterations (from 3.6 to 1.1 mutations per able disease or with radiographic SD. This, mutant allele fraction at the time of acquired nisms of acquired resistance that inevita- patient; p < 0.01). In contrast, patients with in turn, may allow a better characterization resistance. Reduction of ctDNA to undetect- bly occur after initial response, as well as stable disease (SD) and progressive disease of these patients and, in turn, overcome the able levels was associated with longer PFS (p in those treated with immune checkpoint exhibited a less pronounced (average of limits of conventional radiographic meth- = 0.001) and OS (p = 0.008) compared with inhibitors (ICIs) in which radiographic 2.24% at baseline vs. 1.04% after treatment; odologies. Finally, the authors reported no evidence of ctDNA elimination. Once interpretation of response might be chal- p = 0.03) or limited variation of cfTL (aver- that, in a subset of patients, the eff ect of the again, in patients with radiographic SD (12 lenging, thereby overcoming the limits of age of 14.23% at baseline vs. 11.84% after fi rst dose of treatment after 4 to 12 hours patients), the molecular response pattern conventional radiologic assessment meth- treatment; p = 0.6), respectively, and no showed a 110-fold increase in the rate of correlated with clinical benefi t from immune ods. Recently, the American Association for signifi cant change in the number of muta- emerging mutations, with a relative sta- checkpoint blockade and better predicted Cancer Research published two interesting tions observed. Despite the limited sample bility of ctDNA amounts. This fi nding may the magnitude of therapeutic response papers addressing this issue. number, this study further confi rmed the potentially aff ect future combinatorial strat- than CT imaging. Furthermore, molecular Phallen et al. evaluated the role of serial fi ndings of previous reports suggesting egies, allowing us to add diff erent inhibi- response was associated with major or par- ultrasensitive LBx with targeted error cor- a potential role for LBx as a non-invasive tors to EGFR blockade based on emerging tial pathologic response in the neoadjuvant rection sequencing (TEC-Seq) as an early drug-monitoring method,3,4 allowing an mechanisms of resistance. cohort, whereas molecular resistance was non-invasive detection tool of response in earlier identification of mechanisms of In a companion study, Anagnostou et al. associated with no pathologic response.

References: 1. Rolfo C, Mack PC, Scagliotti GV, et al. Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC. J Th orac Oncol. 2018;13(9):1248-1268. 2. Leighl NB, Page RD, Raymond VM, et al. Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer. Clin Cancer Res. 2019 Apr 15. [Epub ahead of print]. 3. Oxnard GR, Paweletz CP, Kuang Y, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res. 2014;20(6):1698-1705. 4. Chia PL, Do H, Morey A, et al. Temporal changes of EGFR mutations and T790M levels in tumour and plasma DNA following AZD9291 treatment. Lung Cancer. 2016;98:29-32. 5. Hu Y, Ulrich BC, Supplee J, et al. False-Positive Plasma Genotyping Due to Clonal Hematopoiesis. Clin Cancer Res. 2018;24(18):4437-4443. 6. Cabel L, Proudhon C, Romano E, et al. Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy. Nat Rev Clin Oncol. 2018;15(10):639-650. 7. Goldberg SB, Narayan A, Kole AJ, et al. Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA. Clin Cancer Res. 2018;24(8):1872-1880. 8. Roh W, Chen PL, Reuben A, et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci Transl Med. 2017;9(379): pii: eaah3560. LUNGCANCERNEWS.ORG / DECEMBER 2019 7

IN REFERENCE TO: EXPERT PERSPECTIVE Phallen J, Leal A, Woodward BD, et al. Early Noninvasive Detection of Response to Targeted Improved Turnaround Times for Biopsy Results Therapy in Non-Small Cell Lung Cancer. Cancer Res. 2019;79(6):1204-1213. Matters More Th an Type of Biopsy

Anagnostou V, Forde PM, White JR, et al. 1 Dynamics of Tumor and Immune Responses Regarding “Liquid Biopsy for NILE study. Th e fi rst 10 patients had a have to rush to during Immune Checkpoint Blockade in Assessing Response or Progression median cf-DNA TAT of 14 days (range change therapy Dr. Edgardo S. Santos Non-Small Cell Lung Cancer. Cancer Res. in Advanced NSCLC” by Dr. Geoff rey 11-30 days) versus the last 10 patients, for a patient who Castillero 2019;79(6):1214-1225. R. Oxnard published in the October issue who had a median TAT of 7 days (range has been well of the IASLC Lung Cancer News, I would 5-9 days). As a pioneer in this fi eld, the monitored. Hence, to wait just 3-7 cal- Moreover, 24 patients with metastatic like to comment on the issue of turn- Guardant Health test has been challenged endar days to obtain a “genomic snap- disease had available samples from both around time (TAT), which is a topic that by other competitors, such as Biodesix’s shot” of our patients is probably as good is extremely critical in the treatment of Genestrat, which uses digital droplet as it gets. Th e TAT for NGS in tumor tumor infi ltrating lymphocytes and periph- patients with cancer. polymerase chain reaction (ddPCR) tissue has also signifi cantly improved, eral blood lymphocytes for analysis of TCR Significant improvement has been technology and has an average TAT of with some vendors in the private sector clonal dynamics. Consistent with the cDNA observed regarding TAT since the 3 days. Th is test analyzes six actionable reporting NGS in 5 calendar days. In my analysis, distinct patterns in TCR clonotype Guardant360 became commercially genomics abnormalities (EGFR, ALK, opinion, to wait more than 14 calendar dynamics were observed with a signifi cant available in 2014. Th is test uses next- ROS1, RET, BRAF, and KRAS) in lung days for an NGS report, regardless of oligoclonal expansion in peripheral blood generation sequencing (NGS) to deter- cancer. Inivata also uses NGS with its whether derived from blood or tissue ✦ of pre-existing intratumoral T-cell clones, mine the genomic alterations in blood InvisionFirst-Lung test to analyze 36 specimen, is unacceptable. after cell-free DNA (cf-DNA) from genes relevant to patients with advanced – Edgardo S. Santos Castillero, MD, FACP followed by a signifi cant decrease after cancer cells is captured. Initially, the NSCLC, with a TAT of 7 calendar days acquired resistance. In contrast, in patients Reference. test consisted of 58 genes, with a TAT of or fewer from blood draw. As a clinician, 1. Leighl NB, Page RD, Raymond VM, et al. with primary resistance, no evidence of approximately 10-12 calendar days. Th e this is amazing. We can diagnose driver Clinical Utility of Comprehensive Cell-free TCR clonal expansion of intratumoral TCR test was increased to 73 genes, but its mutations, resistant mutations, and, per- DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic repertoire was observed. TAT has been reduced to only 7 calendar haps in the future, monitor our patients Non-Small Cell Lung Cancer. Clin Cancer Res. 2019;25(15):4691-4700. The results of this study have several days as demonstrated in the prospective in a seamless manner. Only rarely do we potential clinical implications. First, ctDNA dynamics might complement standard imaging approaches in the therapeutic EXPERT PERSPECTIVE management of patients with NSCLC treated with ICIs,6,7 allowing a better Th e Application of Liquid Biopsy in characterization of pseudo-progression Lung Cancer: Th e View from China or mixed/dissociated responses. In addi- Th e application of liquid biopsy in strongly recommended for EGFR mutation, the clearance of ctDNA, if validated lung cancer is increasing in China. tion detection according to guidelines by Dr. Caicun Zhou in large prospective studies, might repre- For patients with insufficient tumor the Chinese Society of Clinical Oncology Dr. Fei Zhou sent a valid tool that would allow a better tissue, liquid biopsy could provide tumor (CSCO). Super-ARMS has been T790M mutations in plasma is being selection of patients who can benefi t from cell-derived genomic landscape for pre- approved by National Medical Products used to predict effi cacy and clinical out- elective discontinuation strategies after cision therapy. Due to its minimally Administration (NMPA) for EGFR comes of patients treated with EGFR- selected treatment duration and might invasive nature, liquid biopsy can also mutation detection using ctDNA. Other TKIs, allowing longitudinal monitoring be repeated serially for longitudinally validated PCR-based assays, including of patients during treatment.6,7 However, help to identify patients who can benefi t monitoring treatment response, detect- cobas and digital droplet PCR (ddPCR) serial ctDNA for assessing response or from combinatorial approaches instead of ing the emergence of drug resistance, are also acceptable. CSCO guidelines progression has not been used routinely single-agent ICI therapy. Finally, this study and tracking tumor evolution.1 Here, also moderately recommend validated in China, just serving as a complement further confi rms that more clonal T cell rep- inspired by the October IASLC Lung next-generation sequencing (NGS) mul- to imaging and clinical evaluation or for ertoire is predictive of response ICIs target- Cancer News article “Liquid Biopsy for tiplex panels for initial molecular diag- scientifi c purposes. ing PD-1/PD-L18 and TCR clonal dynamics Assessing Response or Progression in nosis using ctDNA for patients without Despite considerable promising might guide treatment management. Advanced NSCLC” by Dr. Geoff rey R. obtainable tumor tissue specimens. advances that liquid biopsy has made, Oxnard, we briefl y discuss how liquid For patients for whom first- or challenges remain. For EGFR muta- Further prospective studies in large biopsy has been used in China, as well second-generation EGFR-TKI treatment tion detection using ctDNA, although patient population should validate these as its challenges and drawbacks. fails, T790M secondary mutation is the high specifi city and concordance with preliminary data and may support the Th e successful development of tar- predominant acquired resistance mech- tumor tissue have been achieved with incorporation of dynamic ctDNA analysis geted therapy for advanced NSCLC anism,2 which can be eff ectively inhib- super-ARMS, sensitivity varies from in clinical trials evaluating targeted thera- is based on molecular classification, ited by the third-generation EGFR-TKI 76%-82%.8,9 Th erefore, negative results 3 pies and immunotherapy in NSCLC. ✦ including EGFR sensitizing mutations, osimertinib. ctDNA has been advocated should be interpreted with caution, ALK/ ROS1/RET rearrangements, and as a feasible source to identify T790M and a more sensitive method (such as BRAFV600E mutations. Genomic pro- mutations, as a complement to routine ddPCR or NGS approach) or using About the Author: Dr. Rolfo is professor files are recommended to be evalu- tissue-based genotyping according to the DNA from tissue biopsy should be per- of Medicine and director of Th oracic ated in treatment-naive patients with guidelines. ctDNA is also clinical avail- formed to rule out false negatives. On Medical Oncology and Early Clinical Trials advanced NSCLC in China, especially able to comprehensively understand the other hand, NGS-based approaches at University of Maryland Greenebaum Comprehensive Cancer Center and in those with non-squamous NSCLC. the acquired resistance mechanisms of could provide more comprehensive University of Maryland School of Medicine. For patients with insufﬁcient tumor osimertinib to further guide subsequent molecular profiles of tumors rather He is vice-president of the International tissue, circulating-free DNA (cfDNA) personalized therapy.4,5 Furthermore, than PCR-based approaches; however, Society of Liquid Biopsy. or circulating-tumor DNA (ctDNA) is dynamic monitoring of ctDNA or continued on page 9 8 IASLC LUNG CANCER NEWS / DECEMBER 2019

SUPPORTIVE CARE Palliative Care: Combating Stigma and Enhancing Quality of Care— A Worldwide Perspective Jennifer Temel, MD, and colleagues1 showed in a small but well-conducted phase III trial that a proactive, intensive palliative care program compared to our more typical reactive approach could lead to improved outcomes in advanced NSCLC, including better quality of life, decreased anxiety and depression, fewer hospitalizations at the end of life, more use of hospice, and improved survival, at minimal cost. But take-up of this strategy has been slow and sporadic, hindered by issues of reimbursement and by the stigma the term “palliative care” carries. In this issue as well as in those following , the IASLC Lung Cancer News has gathered multiple perspectives on the role of formal palliative care programs around the world and their challenges and successes. ✦ – Corey J. Langer, MD, FACP Dr. Corey J. Langer

Reference: 1. Temel JS, Greer JA, Muzikansky A, et al. Early Palliative Care for Patients with Metastatic Non–Small-Cell Lung Cancer. N Engl J Med. 2010;363:733-742 SPOTLIGHT ON PALLIATIVE CARE

SUPPORTIVE CARE Palliative Care in Canada

from patients and healthcare provid- services from 5% to 10% and in a • Educating the public on the basics of SPOTLIGHT ON ers to discuss palliative care and the reduction in hospital admission/read- palliative care and advance care plan- PALLIATIVE CARE dying process contributes to the delay mission, as well as an improved expe- ning to help eliminate the stigma. for palliative care services 2 rience for patients and their families.2 By Jehanara Chagani, RN, MSc(N), • Providing palliative care to patients Palliative care has progressed and CHPCN(C) Role of Nurses in Palliative Care in the home, clinics, shelters, and improved signifi cantly in Canada since Palliative care is a highly valued and spe- mental health facilities as nurse its inception. Such progress includes the In Canada, palliative care is promoted cialized form of nursing practice. Nurses practitioners. For example, as part of expansion of palliative care to patients’ as an approach that puts recipi- provide palliative care in various the Ontario government plan, “Th e homes, growing awareness of palliative ents and their families at roles, including as nurse prac- Attending Nurse Practitioners in care with conditions other than cancer, the center of services and titioners, care coordina- Long-Term Care Homes (LTCH)” and increasing emphasis on early and decision making. The tors, home care nurses, initiative will fund 75 nurse practitio- integrated care. Nurses have played provision of palliative and advanced practice ner full-time positions over 3 years to an essential role in this progress and care is supported in nurses. They engage provide services in LTCHs including will continue to be an integral part in combination with with patients and their reduction of unnecessary hospital improving and strengthening palliative other treatment plans families, assess suff er- admissions and improved patient care in Canada. ✦ and is off ered in all set- ing and survival, support experience through adequate pallia- tings. Th e “Framework on patients as they progress tive care provision.4 About the Author: Ms. Chagani is an advanced Palliative Care in Canada” Ms. Jehanara Chagani through the process of dying • Advocating for patients with pallia- practice nurse-clinical nurse specialist with summarizes the provision of and death, and ensure that tive care needs and their caregivers Central West Palliative Care Network, in Ontario, palliative care, setting the World Health patients remain comfortable and die in earlier in their disease trajectory and Canada. She supports patients, families, nurses, Organization’s defi nition in the Canadian the environment of their choice.3 connecting them to the appropriate physicians and other healthcare providers in context by developing a set of guiding Some nurse-led initiatives to improve resources. optimizing hospice palliative care through principles. Th ese principles highlight palliative care include: • Building capacity in healthcare pro- capacity building, education, consultation, that palliative care should be integrated, • Strengthening palliative care through fessionals through formal and infor- research and symptom management. holistic, equitable, high quality, and evi- early identifi cation of patients with mal educational initiatives. Some of dence based. Palliative care should recog- palliative care needs and leading the the formal initiatives are courses run References: 1. Health Canada. Framework on Palliative Care in nize the diversity of Canadians, improve goals of care discussions in long- by nurses, including “Learning essen- Canada. canada.ca/content/dam/hc-sc/ quality of life, and be a responsibility term care facilities and homes. For tial approaches to palliative care” and documents/services/health-care-system/reports- of all Canadians including caregivers, example, nurses at the Central West “Fundamental of Palliative Care.” publications/palliative-care/framework-palliative- care-canada/framework-palliative-care-canada. all levels of government, communities, Palliative Care Network, pdf. Published December 2018. Accessed June not-for-profi t organizations, healthcare in partnership with its 3, 2019. 1 2.2 Canadian Institute for Health Information. providers, and the general population. Local Health Integration Access to Palliative Care in Canada. cihi.ca/en/ Despite these eff orts, many challenges Network, led the initia- access-data-and-reports/access-to-palliative-care- persist: tive for identifi cation of in-canada. Published September 2018. Accessed June 3, 2019. • Only 15% of Canadians who die at those patients who would 3.3 Canadian Nurses Association. Joint Position home receive palliative home care benefi t from early pal- Statement – Th e Palliative Approach to Care and services.1 liative care in order to the Role of the Nurse. cna-aiic.ca/-/media/cna/ page-content/pdf-en/the-palliative-approach-to- • People with end-stage cancer are improve the experience care-and-the-role-of-the-nurse_e.pdf?la=en&ha three times more likely to receive pal- of patients and caregivers. sh=E0D799ADB76660EE15D00A7203F862522A liative care compared to patients with Th e partners developed 2776E8. Published June 15, 2015. Accessed June 3, 2019. 2 other life-limiting illnesses. the Early Identifi cation 4.4 Nursing Policy and Innovation Branch. (2017, • Th ere is still a stigma surrounding the and Prognostic Indicator Guide to Advanced Practice Nurses (nurse April). Attending Nurse Practitioners in Long- Term Care Homes - Recruitment and Integration term palliative care, as it is used inter- help healthcare providers identify practitioners and clinical nurse spe- Toolkit. Ottawa: Ministry of Health and Long- changeably with end-of-life care. Th e people who could benefi t from pal- cialists) also provide co-consultation Term Care. Retrieved July 1, 2019, from health. lack of a common defi nition of pallia- liative care. Th e initiative resulted in to patients and healthcare profession- gov.on.ca: http://www.health.gov.on.ca/en/pro/ programs/hhrsd/nursing/docs/2017_NP_LTCH_ tive care, limited resources and fund- an increased percentage of patients als to optimize awareness and avail- Rec_int_toolkit.pdf ing, lack of awareness, and reluctance benefi ting from early palliative care ability of palliative care services. LUNGCANCERNEWS.ORG / DECEMBER 2019 9

5. Yang Z, Yang N, Ou Q, et al. Investigating Expert Perspective from page 7 Pulmonary Hospital, Thoracic Cancer Institute, LUNG CANCER Novel Resistance Mechanisms to Th ird- Tongji University School of Medicine, Shanghai, Generation EGFR Tyrosine Kinase Inhibitor NEWS no NGS approach in oncology has China. Dr. Caicun Zhou is director and profes- Osimertinib in Non-Small Cell Lung Cancer Patients. Clin Canc Res. 2018;24:3097-3107. been approved by NMPA currently. sor of medical oncology, Shanghai Pulmonary 6. Wang Z, Cheng Y, An T, et al. Detection of EDITOR Furthermore, NGS is still costly and Hospital, Thoracic Cancer Institute, Tongji EGFR mutations in plasma circulating tumour Corey J. Langer, MD, FACP time-consuming, requiring approxi- University School of Medicine, Shanghai, China. DNA as a selection criterion for fi rst-line gefi - tinib treatment in patients with advanced lung ASSOCIATE EDITORS mately 2 weeks for results turnaround. References. adenocarcinoma (BENEFIT): a phase 2, single- Fabrice Barlesi, MD, PhD Finally, we agreed with Dr. Oxnard that 1. Siravegna G, Marsoni S, Siena S, et al. arm, multicentre clinical trial. Lancet Resp. Caicun Zhou, MD, PhD some other challenges, including how Integrating liquid biopsies into the management 2018;6:681-690. 7. Zhou Q, Yang JJ, Chen ZH, et al. Serial cfDNA EDITORIAL GROUP MEMBERS best to quantify mutations levels and of cancer. Nat Rev Clin Onc. 2017;14:531-548. 2. Ohashi K, Maruvka YE, Michor F, et al. assessment of response and resistance to EGFR- Edgardo S. Santos Castillero, MD, FACP defi ne meaningful changes of ctDNA Epidermal growth factor receptor tyrosine TKI for patients with EGFR-L858R mutant Marianne Davies, DNP, ACNP, AOCNP for monitoring treatment, must still be kinase inhibitor-resistant disease. J Clin Oncol. lung cancer from a prospective clinical trial. J Janet Freeman-Daily, MS, Eng 2013;31:1070-1080. Hem Onc. 2016;9:86. addressed to ensure reliable treatment 3. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib 8. Feng WN, Gu WQ, Zhao N, et al. Comparison MANAGING EDITOR AND PUBLISHER decisions in the clinical setting. ✦ or Platinum-Pemetrexed in EGFR T790M- of the SuperARMS and Droplet Digital PCR Joy Curzio, Curzio Communications Positive Lung Cancer. N Engl J Med. for Detecting EGFR Mutation in ctDNA From – Fei Zhou, MD, and COPY EDITOR 2017;376:629-640. NSCLC Patients. Trans Onc. 2018;11:542-545. Caicun Zhou, MD, PhD 4. Chen K, Zhou F, Shen W, et al. Novel Mutations 9. Li Y, Xu H, Su S, et al. Clinical validation of a Alana Williams highly sensitive assay to detect EGFR muta- on EGFR Leu792 Potentially Correlate PRODUCTION DIRECTOR to Acquired Resistance to Osimertinib in tions in plasma cell-free DNA from patients About the Authors: Dr. Fei Zhou is in the Doug Byrnes Advanced NSCLC. J Th or Onc. 2017;12:e65-e68. with advanced lung adenocarcinoma. PloS One. Department of Medical Oncology, Shanghai 2017;12:e0183331. GRAPHIC DESIGNER Kelli Schmidt, KSchmidt Designs LLC

tein gene, NPM, in non-Hodgkin’s lymphoma. Tumor Agnostic Targeted Therapies Conclusion Science. 1994;263(5151):1281-1284. IASLC Lung Cancer News is published bimonthly from page 4 Tumor-agnostic therapeutic strategies 5. Soda M, Choi YL, Enomoto M, et al. by the International Association for the Study represent the true embodiment of a pre- Identifi cation of the transforming EML4-ALK of Lung Cancer (IASLC). IASLC Headquarters is fusion gene in non-small-cell lung cancer. Nature. located at 13100 East Colfax Avenue, Unit 10, entrectinib has signifi cant systemic and cision medicine approach to cancer by 2007;448(7153):561-566. Aurora, CO, 80011, US. intracranial activity in both NTRK and specifi cally targeting biologically relevant 6. Mano H. ALKoma: a cancer subtype with a Purpose and Audience: IASLC Lung Cancer ROS1 fusion–positive NSCLC. pathways, irrespective of old tumor classi- shared target. Cancer Discov. 2012;2(6):495-502. 7. Birchmeier C, Sharma S, Wigler M. Expression News features news about lung cancer fi cation systems. Currently, NTRK fusions and rearrangement of the ROS1 gene in human research, patient care, tobacco control, and Future Potential Tumor- represent the only tumor-agnostic indica- glioblastoma cells. Proc Natl Acad Sci U S A. expert commentary from lung cancer leaders. 987;84(24):9270-9274. The target audience for this publication is Agnostic Targets tion for targeted therapies in cancer, with 8. Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in physicians and other specialists involved in the Th ere are numerous potential tumor- the recent approvals of larotrectinib and ROS1-rearranged non-small-cell lung cancer. N research and treatment of patients with lung agnostic indications on the horizon, entrectinib. Th ese recent successes dem- Engl J Med. 2014;371(21):1963-1971. cancer and other thoracic oncologic disorders. 9. Davies KD, Doebele RC. Molecular pathways: Correspondence: Address correspondence all of which will likely include impor- onstrate the willingness for regulatory ROS1 fusion proteins in cancer. Clin Cancer Res. to Corey J. Langer, MD, FACP, Editor, c/o tant driver oncogenes in lung cancer. agencies to consider novel indications 2013;19(15):4040-4045. [email protected]. RET gene fusions have been identi- and provide a roadmap for future tumor- 10. Pulciani S, Santos E, Lauver AV, et al. Oncogenes in solid human tumours. Nature. Change of Address: Postmaster send address fi ed in lung cancer, papillary thyroid agnostic oncogene targets. Multiple 1982;300(5892):539-542. changes to IASLC Lung Cancer News, c/o IASLC cancer, colorectal cancer, and other opportunities still exist for new tumor- 11. Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic Headquarters, 13100 East Colfax Avenue, Unit tumor types. Th ere are ongoing studies agnostic indications for other oncogenes and drug-sensitive NTRK1 rearrangements in 10, Aurora, CO, 80011, US. lung cancer. Nat Med. 2013;19(11):1469-1472. of selective RET inhibitors for patients in cancer, including ALK, ROS1, RET, 12. Doebele RC, Davis LE, Vaishnavi A, et al. An Subscription: To initiate or cancel a subscrip- with cancers harboring RET fusions FGFR, NRG1, KRAS G12C, and others. Oncogenic NTRK Fusion in a Patient with tion to IASLC Lung Cancer News or to update your Soft -Tissue Sarcoma with Response to the mailing address, please email membership@ including selpercatinib (LOXO-292; The future success of tumor-agnostic Tropomyosin-Related Kinase Inhibitor LOXO- iaslc.org or call +1-720-325-2956. LIBRETTO-001, NCT03157128) strategies will depend on several factors 101. Cancer Discov. 2015;5(10):1049-1057. Advertising: For information on advertis- 13. Vaishnavi A, Le AT, Doebele RC. TRKing down and pralsetinib (BLU-667; ARROW, including the implementation of cross- ing rates or reprints, contact Kevin Dunn, an old oncogene in a new era of targeted therapy. Cunningham Associates, 201-767-4170, NCT03037385). Th e FGFR1-4 inhibitor tumor trial teams to facilitate enrollment Cancer Discov. 2015;5(1):25-34. erdafi tinib was recently FDA approved beyond organ-specifi c tumor sites and, 14. Drilon A, Laetsch TW, Kummar S, et al. [email protected]. All advertising is subject to acceptance by IASLC. IASLC is not respon- for urothelial carcinoma harboring pre- most importantly, the broad deployment Effi cacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. sible for the content of advertising and does specifi ed FGFR alterations including of multiplexed next-generation sequenc- 2018;378(8):731-739. not endorse any advertiser or its products FGFR fusions that have previously been ing panels to identify eligible patients. ✦ 15. Demetri GD, Paz-Ares L, Farago AF, et al. or services. Effi cacy and safety of entrectinib in patients with Disclaimer: The ideas and opinions expressed identifi ed in NSCLC and other cancers. NTRK fusion-positive tumours: Pooled analysis in IASLC Lung Cancer News do not necessarily Erdafi tinib is being evaluated in tumors About the Author: Dr. Doebele is an associ- of STARTRK-2, STARTRK-1, and ALKA-372- refl ect those of the International Association for 001. Ann Oncol. 2018;29. with FGFR fusions, mutations, or ampli- ate professor of medicine at the University of the Study of Lung Cancer. The mention of any 16. Doebele R, Paz-Ares L, Farago AF, et al. Abstract product, service, or therapy in this publication fi cation in the National Cancer Institute Colorado Denver. CT131: Entrectinib in NTRK-fusion positive MATCH study (NCT02465060). KRAS non-small cell lung cancer (NSCLC): Integrated should not be construed as an endorsement, References: and the Association accepts no responsibility G12C mutations, which occur most analysis of patients enrolled in three trials 1. Prahallad A, Sun C, Huang S, et al. (STARTRK-2, STARTRK-1 and ALKA-372-001). for any injury or damage to person or persons frequently in NSCLC but are found in Unresponsiveness of colon cancer to Cancer Res. 2019;79:CT131. arising out of or related to any use of material numerous other malignancies, repre- BRAF(V600E) inhibition through feedback acti- 17. Doebele R, Ahn M, Siena S, et al. OA02.01 contained in this publication or to any errors vation of EGFR. Nature. 2012;483(7387):100-103. or omissions. sent another exciting tumor-agnos- Effi cacy and Safety of Entrectinib in Locally 2. Kopetz S, Grothey A, Van Cutsem E, et al. LBA- Advanced or Metastatic ROS1 Fusion-Positive tic opportunity; recently developed, 006BEACON CRC: a randomized, 3-Arm, phase Non-Small Cell Lung Cancer (NSCLC). J of IASLC MISSION 3 study of encorafenib and cetuximab with or Th oracic Oncol. 2018;13:S321-S322. To embrace the study of the etiology, epidem- mutation specific inhibitors such as without binimetinib vs. choice of either irinote- 18. Fakih M, O’Neil B, Price TJ, et al. Phase 1 study iology, prevention, diagnosis, treatment, and MRTX849 (NCT03785249) and AMG can or FOLFIRI plus cetuximab in BRAF V600E– evaluating the safety, tolerability, pharmacokinet- all other aspects of lung cancer and other mutant metastatic colorectal cancer. Ann Oncol. 510 (NCT03600883), have demon- ics (PK), and effi cacy of AMG 510, a novel small thoracic malignancies; to provide education 2019;30 (Suppl 4): iv137–iv151. strated preliminary antitumor activity molecule KRASG12C inhibitor, in advanced solid and information about lung cancer and other 3. Planchard D, Besse B, Groen HJM, et al. Dabrafenib tumors. J Clin Oncol. 2019;37:3003-3003. 18 thoracic malignancies to IASLC members, to in NSCLC. Finally, gene fusions involv- plus trametinib in patients with previously treated 19. Fernandez-Cuesta L, Plenker D, Osada H, et al. BRAF(V600E)-mutant metastatic non-small cell the medical community at large, and to the ing NRG1 were identifi ed initially in CD74-NRG1 fusions in lung adenocarcinoma. public; to use all available means to eliminate lung cancer: an open-label, multicentre phase 2 Cancer Discov. 2014;4(4):415-422. NSCLC19 but recently have been identi- lung cancer and other thoracic malignancies trial. Lancet Oncol. 2016;17(7):984-993. 20. Jonna S, Feldman RA, Swensen J, et al. Detection as a health threat for the individual patient and fi ed in pancreatic, ovarian, and gallblad- 4. Morris SW, Kirstein MN, Valentine MB, et al. of NRG1 Gene Fusions in Solid Tumors. Clin throughout the world. der cancers, among others.20 Fusion of a kinase gene, ALK, to a nucleolar pro- Cancer Res. 2019 Apr 15. [Epub ahead of print]. 10 IASLC LUNG CANCER NEWS / DECEMBER 2019

A DEEPER DIVE

Rebuilding Choice Architecture for Incurable but Treatable Lung Cancer: Rethinking the Future of Hospice Care in the United States

By Maggie Salinger, MD, MPP, and has occurred within the Veterans Health or aggressive treatment.4 vice rather than solely as a Arif Kamal, MD MBA, MHS, FAAHPM, Administration (VHA). Since 2009, the VHA’s Their design stands out substitute for active anti- FASCO Comprehensive End of Life Care Initiative among other studies on neoplastic treatment. One Hospice is a nationally known interdisciplin- (CELCI) has invited veterans to receive the topic both because risk of generalizing these ary program that provides comfort care for hospice care in conjunction with disease- of its large sample size fi ndings, however, is that the terminally ill. Yet, despite being lauded directed therapies. Through a recent study and its ability to circum- fewer than 20% of veterans for its positive eff ects on both quality of life in JAMA Oncology, Mor and colleagues vent the selection bias received concurrent care in and healthcare costs, hospice continues leveraged this large-scale programmatic inherent in a comparison the highest quintile, and 1-3 to be an under-utilized resource. Fewer shift and the fact that its rollout would of individuals opting into the magnitude of savings than half of Medicare benefi ciaries leverage vary across time and space to perform a or out of hospice. These associated with hospice Dr. Maggie Salinger hospice’s end of life (EoL) services, and, of quasi-experimental examination of CELCI’s strong suits amplify the exposure diminished over those who do, nearly one-third postpone eff ects.4 The study should be applauded signifi cance of their fi nd- time.4 Therefore, it would be comprehensive palliation until death is less not only for its clever design and promis- ings, which show that diffi cult to predict the fi nan- 3 than a week away. The issue of low and ing results, but also for its signifi cant contri- promotion of patient cial outcomes in a broader delayed hospice uptake is linked to unfavor- bution to broader economic, political, and autonomy through pal- Medicare context where able choice architecture in the lead-up to philosophical discussions. liative integration is not concurrent care could enrollment, where simplistic eligibility crite- Using a cohort of more than 13,000 only possible, but also someday become more ria mandate that patients select either dis- patients with newly diagnosed stage IV practical. widely available, including ease-directed therapies or comfort-focused NSCLC at VHAs across the country (years Mor et al.’s analysis in earlier stages of disease. ones—a distinction that has become all the 2006 through 2012), Mor’s team con- revealed that people in Further expansion of con- more obsolete with the evolution of thera- structed a modifi ed diff erence in diff er- high hospice exposure Dr. Arif Kamal current care would likely pies that are better targeted and better ences regression to compare patients with groups received more be accompanied by major tolerated, particularly in lung cancer. Thus, high levels of hospice exposure to those concurrent care (e.g., palliative consult plus policy changes, most notable among them with an eye toward reduced spending and with low levels of exposure according to radiation therapy) and less aggressive care being the possibility of Medicare Advantage improved patient autonomy, policy makers the rate of palliative care consults at each (17.5% vs. 7.4% and 28.3% vs. 35.5% in the (MA) swapping its carve-out model for a have been considering ways to eliminate site. The outcomes they examined in the 6 highest vs. lowest quintiles, respectively). carve-in operation. This move toward a more The quintile with highest exposure was also integrated approach would be advanta- the least expensive, yielding savings on the geous for a variety of reasons, but so too it order of a couple hundred dollars per day.4 might it also have deleterious eff ects. These diff erences in cost were evident As noted above, such policy changes despite the fact that hospital length of stay would aff ord patients and providers greater was similar among quintiles.4 Thus, savings degrees of autonomy and therapeutic fl ex- seemed to come from a hospice-associated ibility. Alongside this ethical benefi t, we reduction in people’s demand for aggres- would expect to see an increase in hospice sive interventions. Framed diff erently, fi nan- uptake because at least some of its pal- cial gains were not predicated on restricted liative services would become available by access to cancer therapies, nor were they default. This would be a signifi cant devia- dependent upon allowance of only one tion from the current status-quo, in which therapeutic modality at a time. patients must opt in to the program, agree Implications for Systemic Change to forgo medical treatment, and have a life expectancy of less than 6 months. The implication for policy makers is that we this false dichotomy between medical and months following diagnosis were per capita Shifting to a carve-in approach would need not marshal patients into silos; we may palliative care at the EoL. costs and patterns of healthcare utiliza- also aff ect the quantity and quality of EoL still be able to provide aff ordable care when Much of the innovation in this space tion, including receipt of concurrent and/ services. Importantly, it would no longer be hospice is off ered as a complementary ser-

References: 1. Kelley AS, Deb P, Du Q, Aldridge Carlson MD, Morrison RS. Hospice enrollment saves money for Medicare and improves care quality across a number of diff erent lengths-of-stay. Health Aff (Millwood). 2013;32(3):552-561. 2. Wright AA, Keating NL, Balboni TA, Matulonis UA, Block SD, Prigerson HG. Place of death: correlations with quality of life of patients with cancer and predictors of bereaved caregivers’ mental health. J Clin Oncol. 2010;28(29):4457-4464. 3. Report to the Congress: Medicare Payment Policy. Medpac. medpac.gov/docs/default-source/reports/mar18_medpac_entirereport_sec.pdf. Published March 2018. Accessed August 31, 2019. 4. Mor V, Wagner TH, Levy C, et al. Association of expanded VA hospice care with aggressive care and cost for veterans with advanced lung cancer. JAMA Oncol. 2019 Jun 1;5(6):810-816. 5. Stevenson DG, Huskamp HA. Integrating Care at the End of Life: Should Medicare Advantage Include Hospice? JAMA. 2014;311(15):1493-1494. LUNGCANCERNEWS.ORG / DECEMBER 2019 11

SUPPORTIVE CARE IN REFERENCE TO: Palliative Care for Patients With Lung Cancer in China Mor V, Wagner TH, Levy C, et al. Association of expanded VA hospice care with aggressive chemotherapy. Regarding psychosocial care has been changed, patients are oft en care and cost for veterans with advanced lung SPOTLIGHT ON cancer. JAMA Oncol. 2019 Jun 1;5(6):810-816. distress, nurses generally provide psy- referred relatively late in the course of PALLIATIVE CARE chosocial care to patients with cancer their disease to a palliative care unit.6 simply because there are no social work- Th is underscores the need to develop By Hui Tan, MPH ers in Chinese hospitals. A recent nurs- training programs for palliative care in the case that hospice enrollees are transi- ing study showed that 38.6% of Chinese China; palliative care education should tioned out of MA plans and into traditional Lung cancer is the most prevalent cancer patients with lung cancer reported a focus not only on physicians and their Medicare. Because integration would and the leading cause of death from relatively high level of psychosocial nurses but also on patients and their heighten MA’s fi nancial responsibility at cancer in China.1 Approximately two- distress during hospitalization.4 Th ere families. ✦

the EoL, its contracted payers would fold thirds of patients with lung cancer die are few nursing models, nursing clinical within 2 years due to advanced disease guidelines, and nurse training resources About the Author: Hui Tan is a nurse man- hospice-related costs into their capitated (stage IIIB and IV) at time of diagnosis. available for managing psychosocial dis- ager in the Department of Thoracic Neoplasm payment plans. Replacing the current per Many patients with lung cancer experi- tress in China, so implementing univer- Chemotherapy, Hunan Cancer Hospital, the diem basis of payment would alleviate ence multiple physical symptoms, includ- sal psychosocial distress screening is still Affi liated Hospital of Xiangya School of Medicine, concerns about the duration of hospice ing fatigue, shortness of breath, pain, premature. 4,5 Central South University, China, and is a visiting care and instead direct attention to its appetite loss, insomnia, nausea, and dry scholar at the Yale University School of Nursing. 5 cough.2 Multiple studies have demon- Words Matter quality. However, the associated need for References: payers to recalculate risk scores would be strated that better patient outcomes are Another barrier to palliative care is the 1. Chen W, Zheng R, Baade PD, et al. Cancer associated with palliative care. However, stigma associated with end of life. Death Statistics in China, 2015. CA Cancer J Clin. complicated by the fact that any change compared to Western countries, palliative and dying is a major taboo in Chinese 2016;66(2):115-132. 2. Hong QY, Wu GM, Qian GS, et al. Prevention in the choice architecture for hospice 3 care is extremely limited in China. culture. When “palliative care” was fi rst and Management of Lung Cancer in China. enrollment would bring with it a change Th ere are only a few comprehensive introduced in China, the name “Lin Cancer. 2015;121:3080-3088. in the demand for its palliative services, 㸦Ѥ㓸යᘰ㸧 3. Yin ZY, Li JX, Ma K, et al. Development of palliative care programs or units at Zhong Guan Huai ” was Palliative Care in China: A Tale of Th ree Cities. the extent and cost of which would be Chinese tertiary hospitals in large cities. used, which translates to “terminal care.” Oncologist. 2017;22(11):1362-1367. For example, at Hunan Cancer Hospital, Understandably, this term is regarded by 4. Tan H, Davis M, McCorkle R, et al. Th e preva- diffi cult to estimate. lence and related factors associated with psy- the interdisciplinary lung cancer care patients, families, and healthcare profes- There is also general uncertainty chosocial distress among 420 hospitalized lung team (including oncology nurses) and sionals as unlucky and constitutes a major cancer patients in China: A case study. Eur J about which hospice interventions reap palliative unit deliver palliative radia- impediment to referral. Recognizing Cancer Care (Engl). 2019;28(4):e13046. the most benefi t. As a result, policymak- 5. Chen SJ, Tan H, Chen YY, et al. Th e fi ve tion therapy, chemotherapy, and surgery, this challenge, Dr. Li adopted the term steps of psychosocial distress manage- ers have no clear guidance for how to go targeted therapy, and pain control for “Gu Xi Guan Huai㸦ጡᜥයᘰ㸧,” which ment for cancer patients in the US and its enlightenment to China. Chinese Nursing about streamlining a program that, his- patients with advanced lung cancer. In means “care to alleviate suff ering.” Th is Management.2018;10:118-121. torically, has been so adept at tailoring its addition, Chinese medicine, acupunc- name is now widely used in China along 6. Gu XL, Cheng WW, Chen ML, et al. Timing of ture, and massage play an important role with another name, “Huan He Yi Liao, referral to inpatient palliative care services for care. And although it is true that Mor et al.’s advanced cancer patients and earlier referral pre- in palliative care because they improve 㕃࿴་⯇ ” which has a similar mean- study implies we can have our cake and dictors in mainland China. Palliat Support Care. quality of life and reduce side eff ects of ing. Even though the term for palliative 2016;14(5):503-509. eat it too, we know that some traditional elements of hospice are actually going to be cost ineffi cient in the eyes of insurance ADVOCACY AND SURVIVORSHIP payers. As an example, carve-in plans are unlikely to off er year-long bereavement A Balancing Act: Managing Patients’ Expectations support to family members of decedents. By Leah Lawrence In the article, the chief executive offi cer ism professionals, including those spe- The potential for mismatch between of Accelerated Evolution Biotechnologies cializing in health news, were laid off ,2 the socially determined value of an ini- Many patients newly diagnosed with Ltd. said that, based on the results of a Ms. Freeman-Daily noted. tiative and its economically calculated lung cancer have diffi culty navigating recent study, the company would be able “I would like to see the press become worth extends far beyond the topic of the world of cancer when unexpectedly to off er a “complete cure for cancer” much more aware of the impact they hospice redesign. But because death is a and unwillingly thrust into it. In addition within a year’s time. However, only by can have on people,” Ms. Freeman-Daily destiny we all share and an event of great to understanding their diagnosis, prog- scrolling to the last paragraph of the arti- added. “Th ey should not be using the nosis, and treatment options, patients cle could a reader see that the company word ‘cure’ in a headline or the article import to all cultures, perhaps this par- are also bombarded with an abundance had just completed a mouse experiment when it is not yet proven.” ticular policy issue could bring unity to a of information on the internet, direct- testing the new approach. Another recent headline read, divided Congress and serve as a roadmap to-consumer advertising of new cancer “Th ere are so many people desperate “Terminally-Ill British Mother, 40, Who for navigating other philosophical com- therapies, and headlines in the media for hope that they may see a headline Kept Her Lung Cancer Secret From Her plexities in the healthcare reformation of touting miracle cures. talking about a ‘cure’ without reading the Young Daughter Shocks Medics Aft er the United States. ✦ “It can be overwhelming,” said Janet body of the article, and share it on social Tumour Shrinks by 75% Following Freeman-Daily, a lung cancer survivor media,” Ms. Freeman-Daily said. “More Alternative Treatment in Mexico.”3 In the and patient advocate. people see it and do the same thing. It can article, the woman credits the alternative About the Authors: Dr. Salinger is an inter- Ms. Freeman-Daily was particularly be dangerous.” therapies for shrinking her tumor. Th ese nal medicine doctor and resident at Duke University Hospital, Internal Medicine taken aback in January 2019, when other Th e seductive headline teasing a cure- included treatments focused on heat, Residency Program. Dr. Kamal is an associ- patients with lung cancer began contact- all for cancer led to myriad other news light, and laser therapies, according to ate professor of Medicine and an associate ing her aft er seeing a headline written and social media outlets picking up the the article, including hyperbaric oxygen professor in Population Health Sciences at by the Jerusalem Post that read “A Cure story. Th e timing of this was particularly therapy, coff ee enemas, saunas, and infra- Duke Cancer Institute. For Cancer? Israeli Scientists May Have tragic because in the week prior to the red lamp therapy. Only by scrolling far Found One.”1 article’s publication, hundreds of journal- continued on page 13 12 IASLC LUNG CANCER NEWS / DECEMBER 2019

DIAGNOSTICDI ONCOLOGY PD-L1 in Cytology Specimens

By Anjali Saqi, MD, MBA; Deepali Jain, MD, 3. Which PD-L1 assays can be used on 6. What are the advantages of cytology mum tumor cell/tissue requirements. FIAC; Lukas Bubendorf, MD; Keith Kerr, cytology preparations? specimens? Small specimens may suff er from low MB, ChB, MRCPath, FRCPath, FRCP(Ed); All assays have been tested on cytology First and foremost, cytology specimens yield and insuffi cient cellularity follow- and Andre Moreira, MD, PhD specimens. Akin to testing on their his- represent a signifi cant proportion of lung ing tissue allocation for various tests set tology counterparts, cytology specimens cancer specimens and, therefore, provide forth by guidelines for advanced-stage Lung cancer is a leading cause of can- with assays 22C3, 28-8, and SP263 are greater access to patients for potential lung adenocarcinomas. When inter- cer-related deaths worldwide. In the similar, whereas SP142 and 73-10 dem- systemic therapy options. Second, the preting PD-L1 results, diff erentiating 21st century, there have been two sig- onstrate relatively lower and higher back-and-forth or fanning tissue-disrup- between relatively small tumor cells nifi cant developments in the systemic sensitivities, respectively, for tumor cell tive motion of FNA acquisition is advan- without signifi cant nuclear pleomor- management of lung cancers. Th e fi rst staining. tageous for sampling a broader area than phism and macrophages, especially when was the introduction of tyrosine kinase is feasible with a relatively localized sam- both are similar in size and singly dis- inhibitors (TKIs) reserved for patients 4. What types of cytology specimens pling with a biopsy. Similarly, eff usions persed, can be challenging. Some PD-L1 with confi rmed driver mutations. Th e can be stained with PD-L1? and BALs can detect cells from diff erent assays require tabulation of immune second, as well as the most recent, is PD-L1 testing is feasible on all cytology areas. Th ese sampling modalities may cells; there is poor reliability on histol- the incorporation of immune check- preparations, including fi ne needle aspi- capture tumor heterogeneity. ogy specimens. Moreover, in a limited REPORTS FROM THE IASLC PATHOLOGY COMMITTEE PATHOLOGY IASLC THE FROM REPORTS point inhibitors as a standard of care rations (FNAs) and exfoliative specimens An advantage specifi c to cell blocks sample, assessing whether immune cells in the armamentarium. Th ere are mul- (i.e., eff usions, bronchoalveolar lavages is preservation of some degree of archi- are associated with the tumor or not may tiple immune checkpoint inhibitors, [BAL], brushings) used in the diagnosis tecture. Th is is particularly helpful for not be feasible and should be evaluated and each has its respective predictive and staging of lung cancer. matching and localizing cells of inter- only in the context of sufficient and PD-L1 immunohistochemical (IHC) est on serial slides, identifi cation of cell intact tissue fragments. biomarker test—companion or com- 5. Which cytology preparations have membrane staining, as well as provid- Th ere are drawbacks unique to cytol- plementary—that interrogates patient been evaluated for PD-L1? ing histological cues for those without ogy specimen subtypes other than for- eligibility. Most published PD-L1 studies on cytol- formal training or limited exposure to malin-fi xed paraffi n embedded (FFPE) Although promising data have ogy specimens, including as part of the interpreting cytology. cell blocks, including cell blocks with continued to expand indications for Blueprint Phase 2, have been performed ethanol pre-fi xation, smears, and LBC. immune checkpoint inhibitors, enroll- on cell blocks. Although concordant with 7. What are potential drawbacks of First, on smears and LBC, membranous ment into clinical trials is frequently matched histology specimens and prom- cytology specimens? staining may be less pronounced, and the restricted to those with biopsy/histology ising, there are limited data on the use of Several limitations apply to all small distinction between membranous and specimens. Th is criterion aff ects clini- Papanicolaou-stained slides (i.e., smears specimens (small biopsy and cytology) cytoplasmic staining could be blurred cal adoption and may cause question and liquid-based cytology [LBC]) rela- rather than specifi cally to cytology. Most and compromised by overlapping cells. over the validity of testing on cytology tive to cell blocks. predictive assays frequently have mini- Also, non-FFPE preparations require samples, which comprise a signifi cant proportion and are oft en the only avail- Table. PD-L1 in Cytology able specimens upon which lung cancer Specimen Concordance Matched Year Study Assay(s) N Diagnoses Preparation Fixation diagnoses are rendered. We believe that type(s) with FFPE specimens cytology-type samples, when prepared 2017 Skov et al. 28-8 86 pairs ADCA SQCA EBUS FNA Cell blocks Formalin 85% - 95% Matched appropriately, are valid material for 22C3 NSCLC Other EUS-FNA histology clinical PD-L1 testing. Eff usion In an eff ort to address the shortcom- 2017 Heymann 22C3 214 ADCA SQCA EBUS FNA Cell blocks Formalin 91% In 23 matched et al. NSCLC Eff usion specimens ings and lack of data, several studies 2018 Ilie et al. ASL48 70 pairs ADCA SQCA BAL Eff usion Cell blocks Formalin NovaPrep 90% Matched across diff erent laboratories and coun- 22C3 LBC histology tries have examined PD-L1 testing on 2018 Jain et al. SP263 26 pairs ADCA SQCA Brushing LBC CytoRich Red 88% Matched cytology specimens, including as part of Washing (Papanicolaou-stained) histology the Blueprint Phase 2 Project that com- 2018 Russell- EIL3N 56 pairs ADCA SQCA FNA Eff usion Cell blocks Formalin Moderate to Matched pared staining of fi ve PD-L1 IHC assays Goldman et al. NSCLC Small Brushing Rinse high histology cell Other on clinical samples.1-12 Th ese studies have 2018 Wang et al. 22C3 1419 ADCA SQCA EBUS FNA EUS Cell blocks Formalin Methanol / addressed several questions, which are NSCLC Eff usion BAL Ethanol summarized here. 2018 Noll et al. 22C3 41 pairs ADCA SQCA EBUS FNA Smears Alcohol 97% 82% Matched 1. Can cytology specimens be used for NSCLC Cell blocks (Papanicolaou-stained) histology PD-L1 testing? 2019 Hernandez 22C3 52 pairs ADCA SQCA EBUS FNA Cell blocks Formalin 67% Matched Th e overall consensus is that cytology et al. NSCLC Eff usion histology specimens are suitable for PD-L1 testing. Brushing 2019 Torous et al. 22C3 232 ADCA SQCA EBUS FNA Cell blocks CytoLyt NSCLC Eff usion 2. Are results of PD-L1 cytology speci- Washing BAL mens equivalent to those of surgical 2019 Lozano et al. 22C3 113 pairs NSCLC EBUS FNA Smears Alcohol 97.30% Matched cell biopsies and resections? EUS-FNA (Papanicolaou-stained) block and Results of PD-L1 testing on cytology histology specimens are highly concordant with 2019 Gagne et al. 22C3 1249 ADCA SQCA Cell blocks Ethanol Formalin NSCLC those of histology specimens, includ- ADSQ Other ing among squamous cell carcinomas, Abbreviations: ADCA, adenocarcinoma; SQCA, squamous cell carcinoma; NSCLC, non–small cell lung cancer; FNA, fi ne needle aspiration; EBUS, endobronchial ultra- adenocarcinomas, and NSCLCs. sound–guided FNA; EUS, endoscopic ultrasound–guided FNA; BAL, bronchoalveolar lavage; LBC, liquid-based cytology; FFPE, formalin fi xed paraffi n embedded. LUNGCANCERNEWS.ORG / DECEMBER 2019 13

MEETING HIGHLIGHTS First-Ever IASLC School of Nursing Held at Latin American Lung Cancer Regional Meeting in Mexico City

Fig. 1. PD-L1 Staining (Cell Block): Fig. 2. PD-L1 Staining (Cell Block): By Enza Esposito Nguyen, DNP coverage for specialty groups Staining Present in Adenocarcinoma Staining Present in Macrophages within the organization. The IASLC held its Th is year, three schools ninth Latin American were offered: IASLC Lung Cancer (LALCA) School of Thoracic regional meeting in Oncology, IASLC Mexico City this past School of Pathology, October. Interest in this and for the fi rst time, meeting has grown consis- IASLC School of Nursing tently, with more than 800 Dr. Enza Esposito Nguyen (SON). Th e proposal for the Figures courtesy of Dr. John Crapanzano attendees participating this SON was conceived by Luis year. Each year, pre-conference schools Raez, MD, FACP, FCCP, and Christian additional rigorous validation and pos- References: are off ered to provide in-depth content continued on page 15 sible modifi cations of protocols and 1. Heymann JJ, Bulman WA, Swinarski D, et al. PD-L1 expression in non-small cell lung car- workfl ows, which may result in subop- cinoma: Comparison among cytology, small timal adoption by laboratories. biopsy, and surgical resection specimens. Cancer Managing Patients’ Expectations it is hard for them to discern what is Cytopathol. 2017;125(12):896-907. from page 11 bonafi de from what is hyped,” Dr. Langer 2. Skov BG, Skov T. Paired Comparison 8. Which type of cytology preparation of PD-L1 Expression on Cytologic and said. “Giving a balanced perspective on should be used for PD-L1 staining? Histologic Specimens From Malignancies down in the story is it revealed that she some of this research doesn’t make good in the Lung Assessed With PD-L1 IHC FFPE cell blocks are currently the 28-8pharmDx and PD-L1 IHC 22C3pharmDx. had been placed on targeted therapy with TV, but it is what is necessary.” recommended cytology preparations Appl Immunohistochem Mol Morphol. alectinib prior to traveling to Mexico. for PD-L1 testing based on the great- 2017;25(7):453-459. “Th e media plays a huge role in respon- Where to Turn 3. Ilie M, Ngo-Mai M, Long-Mira E, et al. Using est available data, including part of 22C3 Anti-PD-L1 Antibody Concentrate on sibly reporting these stories because any To help patients weed through all of the the Blueprint Phase 2 comparability Biopsy and Cytology Samples from Non-small person interviewing her should point available information on lung cancer, Dr. study. Moreover, use of a standardized Cell Lung Cancer Patients. J Vis Exp. 2018(139). out that she was also on conventional Langer oft en points them to patient advo- 4. Jain D, Sukumar S, Mohan A, Iyer VK. method that closely parallels histology Programmed death-ligand 1 immunoexpression therapy and at least ask her if she thinks cacy groups or reliable online sources of provides initiative to integrate cytol- in matched biopsy and liquid-based cytology that might have anything to do with her information. ogy into clinical trials, perform inter- samples of advanced stage non-small cell lung impressive results,” said Corey J. Langer, Ms. Freeman-Daily will oft en suggest carcinomas. Cytopathology. 2018;29(6):550-557. laboratory comparisons and outcomes 5. Noll B, Wang WL, Gong Y, et al. Programmed MD, director of Th oracic Oncology and that patients visit LCSMChat.com to fi nd analyses, digitally scan/evaluate slides death ligand 1 testing in non-small cell lung professor of Medicine at Perelman Center sources for trusted lung cancer informa- carcinoma cytology cell block and aspirate 4 without a z-axis, and incorporate other smear preparations. Cancer Cytopathol. for Advanced Medicine, University of tion. eff orts frequently restricted to histology 2018;126(5):342-352. Pennsylvania, and Editor of the IASLC When discussing the hype of some specimens. 6. Russell-Goldman E, Kravets S, Dahlberg SE, Lung Cancer News. media articles, Ms. Freeman-Daily said Sholl LM, Vivero M. Cytologic-histologic cor- relation of programmed death-ligand 1 immu- that she has been accused of “trying to kill 9. What are possible future directions? nohistochemistry in lung carcinomas. Cancer Closer to Home hope,” but wanted to clarify that killing Dual/multiplex staining that high- Cytopathol. 2018;126(4):253-263. Dr. Langer said that managing patient hope is not her intention at all. 7. Torous VF, Rangachari D, Gallant BP, Shea lights and differentiates the tumor M, Costa DB, VanderLaan PA. PD-L1 testing expectations can also be diffi cult when “I want to help patients with stage IV cells and macrophages can potentially using the clone 22C3 pharmDx kit for selection discussing direct-to-consumer advertising lung cancer understand that there is no of patients with non-small cell lung cancer to aid in a more accurate assessment. The receive immune checkpoint inhibitor therapy: of evidence-based treatments that patients cure and that no one therapy is going to role of digital analysis and automated are cytology cell blocks a viable option? J Am have seen on television or in magazines. work for everybody,” Ms. Freeman-Daily scoring requires further exploration. Soc Cytopathol. 2018;7(3):133-141. “Commercials for some of these newer explained. “I encourage patients to work 8. Tsao MS, Kerr KM, Kockx M, et al. PD-L1 Most importantly, incorporation of Immunohistochemistry Comparability Study drugs, particularly marketing for Merck’s with their physicians to choose the treat- FFPE cell blocks into clinical trials is in Real-Life Clinical Samples: Results of Keytruda and Bristol Myers Squibb’s ment that is backed by evidence and that essential. ✦ Blueprint Phase 2 Project. J Th orac Oncol. Opdivo, give patients a lot of hope,” Dr. will provide the best possible outcome.” ✦ 2018;13(9):1302-1311. 9. Wang H, Agulnik J, Kasymjanova G, et al. Langer said. “Th ey oft en depict actors References: Cytology cell blocks are suitable for immuno- About the Authors: Dr. Saqi is a professor in the as patients who look a lot happier and 1. Jaff e-Hoff man M. A Cure For Cancer? Israeli histochemical testing for PD-L1 in lung cancer. Department of Pathology and Cell Biology at healthier than a lot of my patients.” Scientists May Have Found One. Th e Jerusalem Ann Oncol. 2018;29(6):1417-1422. Post. jpost.com/HEALTH-SCIENCE/A-cure- Columbia University Medical Center. Dr. Jain 10. Gagne A, Wang E, Bastien N, et al. Impact of According to Dr. Langer, these com- for-cancer-Israeli-scientists-say-they-think-they- Specimen Characteristics on PD-L1 Testing is an additional professor in the Department mercials sometimes create unrealistic found-one-578939. Published January 28, 2019. in Non-Small Cell Lung Cancer: Validation of Accessed April 20, 2019. of Pathology at All India Institute of Medical the IASLC PD-L1 Testing Recommendations. expectations with patients or imply that 2. Allsop J. A Brutal Week for American Journalism. J Th orac Oncol. 2019. S1556-0864(19)33186- Sciences, New Delhi, India. Prof. Bubendorf is these drugs are destined to work better Columbia Journalism Review. cjr.org/the_media_ 33187. a professor of Pathology at University Hospital than other approaches. today/layoff s_huff post_buzzfeed_gannett.php. 11. Hernandez A, Brandler TC, Zhou F, Moreira Published January 28, 2019. Accessed April 20, Basel, Switzerland. Prof. Kerr is a consultant AL, Schatz-Siemers N, Simsir A. Assessment “Th ese commercials sometimes obli- 2019. of Programmed Death-Ligand 1 (PD-L1) pathologist in the Department of Pathology, gate me to bring patients down from an 3. Nikolic I. Terminally-Ill British Mother, 40, Who Immunohistochemical Expression on Cytology Aberdeen University Medical School and emotional high, and that is never good,” Kept Her Lung Cancer Secret From Her Young Specimens in Non-Small Cell Lung Carcinoma. Daughter Shocks Medics Aft er Tumour Shrinks Aberdeen Royal Infi rmary, UK. Prof. Moreira is a Am J Clin Pathol. 2019;151(4):403-415. he said. “It can create an adversarial rela- by 75% Following Alternative Treatment in 12. Lozano MD, Abengozar-Muela M, Echeveste JI, professor of Pathology at New York University tionship between the patient and the Mexico. DailyMail.com. dailymail.co.uk/news/ et al. Programmed death-ligand 1 expression on article-6842297/Terminally-ill-British-mother- Langone Medical Center, where he also direct Pap-stained cytology smears from non- caregiver.” 40-shocks-medics-tumour-shrinks-75.html. serves as director of Surgical Pathology and small cell lung cancer: Comparison with cell In some cases, Dr. Langer has even Published March 23, 2019. Accessed April 20, blocks and surgical resection specimens. Cancer CardioThoracic Pathology service and direc- had patients come in begging for these 2019. Cytopathol. 2019;127(7):470-480. tor of the Center of Biorepository Research and drugs without even realizing that they are 4. LCSMChat. Where to Find Trusted Lung Cancer Info. lcsmchat.com/lung-cancer-resources/where- Development. already being treated with them. to-fi nd-trusted-online-info-about-lung-cancer. “Patients are getting bombarded, and Accessed April 20, 2019. 14 IASLC LUNG CANCER NEWS / DECEMBER 2019 CORNER

Dr. Richard Pazdur Discusses Project Facilitate and the Expanded-Access Program

In June 2019, the U.S. Food and Drug Administration (FDA) Oncology Center of Q: Th e FDA has also published new guidance on broadening cancer trial eli- Excellence launched Project Facilitate, a call center that assists oncology healthcare gibility. How many patients are expected to be aff ected by that guidance, and professionals with the submission process involved in obtaining unapproved thera- will it reduce the need for Expanded Access? pies for individual patients with cancer via the Expanded Access program.1 Richard A: Th e fi rst option for patients for whom available treatments have been exhausted Pazdur, MD, director of the FDA Oncology Center of Excellence fi elded questions is to enroll in a clinical trial. However, in clinical trials testing treatments for from the IASLC Lung Cancer News on the impetus behind this pilot project as cancer, some eligibility criteria have become commonly accepted over time or well as its potential benefi ts to patients and the broader cancer care community. used as a template across trials without a clear scientifi c or clinical rationale or justifi cation. In other cases, eligibility criteria can be deliberately restrictive, even Q: What is Expanded Access? though it is not clinically merited. A: Expanded Access is a potential pathway for a patient with an immediately In March 2019, the FDA published four draft guidances and one fi nal guidance life-threatening or serious disease or condition to gain access to investigational regarding cancer trial eligibility criteria.2 Th ese guidances provide recommenda- therapies for treatment outside of clinical trials when there are no comparable or tions on how sponsors could safely and eff ectively broaden the criteria for the satisfactory alternative therapy options available. In those cases in which patients inclusion of certain patient populations in clinical trials, when appropriate, for do not fi t the trial requirements or live too far from a trial site, healthcare profes- pediatric patients and patients with HIV, Hepatitis B and C Virus Infections, brain sionals can request permission from the FDA to treat a patient with an investi- metastases, prior or concurrent malignancies, or organ dysfunction. It is too early gational medical product through Expanded Access. to tell how many patients will be aff ected, but we hope that our recommendations will help to shift the design of oncology clinical trials to be more representative Q: What is Project Facilitate, and what gap is it intended to address? How will of the patients who may ultimately benefi t from novel treatments. the program’s success be determined? In cases in which patients do not fi t the trial requirements or live too far from A: Navigating the Expanded Access process can be complex, particularly for a trial site, healthcare professionals can request permission from the FDA to treat oncologists who don’t have experience working with clinical trials or these types a patient with an investigational medical product through Expanded Access.3 of requests. Project Facilitate is a call center that is a single point of contact where FDA oncology staff help oncology healthcare providers through the process to Q: Are there benefi ts to the FDA and the greater research community to having submit an Expanded Access request for an individual patient. Experienced FDA a program like Project Facilitate, apart from improving access for individual oncology staff support oncologists and other healthcare professionals with their patients? questions, assist in fi lling out the appropriate paperwork, and act as a facilitator A: Th e pilot program includes a central offi ce for oncology requests so that the FDA for the process. As with all Expanded Access requests, the drug manufacturer can follow up on individual requests and gather data, such as how many patients has the right to approve or disapprove the physician’s request. We will also need received the investigational medical products and if not, why the requests were to determine if oncology healthcare providers are using Project Facilitate. Th ere denied. Th e FDA will use these data to determine how the process is benefi ting are several factors that will be used to evaluate the program, including use of the patients and healthcare professionals. In addition, the data could assist in encour- call center as represented by the number of calls to Project Facilitate. aging sponsors to open clinical trials to study drugs for additional indications. ✦ References: Q: If Project Facilitate is deemed successful, are there plans to expand the 1. FDA announces Project Facilitate to assist physicians seeking access to unapproved therapies program? for patients with cancer. U.S. Food and Drug Administration. www.fda.gov/news-events/press- announcements/fda-announces-project-facilitate-assist-physicians-seeking-access-unapproved- A: Th e FDA has been working to improve the Expanded Access framework, includ- therapies-patients?utm_campaign=060319_PR_FDA%20announces%20Project%20Facilitate&utm_ ing the development of an updated and more streamlined application form. Project medium=email&utm_source=Eloqua. Published June 3, 2019. Accessed September 21, 2019. 2. FDA In Brief: FDA takes new steps to broaden patient participation in cancer clinical trials, advanc- Facilitate is part of our continued commitment to Expanded Access, and we hope ing policies to promote inclusion of pediatric patients and patients with medical conditions that can that the pilot program will simplify the process for oncology healthcare providers occur alongside cancer. U.S. Food and Drug Administration. www.fda.gov/news-events/fda-brief/fda- and will ultimately benefi t patients. As Project Facilitate is a pilot program, it is too brief-fda-takes-new-steps-broaden-patient-participation-cancer-clinical-trials-advancing. Published March 12, 2019. Accessed September 21, 2019. early to determine if the program will be expanded to areas outside of oncology. 3. Expanded Access. U.S. Food and Drug Administration. www.fda.gov/news-events/public-health-focus/ expanded-access. Updated May 6, 2019. Accessed September 21, 2019. Names and News Jeff rey Bradley, MD, FASTRO, is the ported by the National Cancer Institute) of Radiation Oncology at the University gator of the Master Lung Protocol Study. new executive vice chairman of the since 2010, a role he will continue. of Pennsylvania. Dr. Hahn specializes in Department of lung cancer and sarcoma. Alice Shaw, MD, has joined Novartis Radiation Oncology Stephen M. Hahn, MD, FASTRO, has as the vice president, global head of at Winship been nominated to be the next com- Vassiliki Papadimitrakopoulou, MD, Translational Cancer Institute of missioner of the has left The University of Texas MD Clinical Oncology. Emory University. U.S. Food and Drug Anderson Cancer Previously, Dr. Previously Dr. Administration by Center, where Shaw was the direc- Bradley was the S. President Trump. she was a profes- tor of Thoracic Lee Kling Endowed If approved by the sor of medicine in Oncology and the Professor of Radiation Oncology, clinical Senate, Dr. Hahn the Department Paula O’Keeffe director of the Kling Proton Center, and will vacate his posi- of Thoracic/ Endowed Chair in chief of the Radiation Oncology Th oracic tion as chief execu- Head and Neck Thoracic Oncology at Massachusetts Cancer Service at Washington University tive offi cer of Th e University of Texas MD Medical Oncology, General Hospital, as well as a professor of School of Medicine in St. Louis. Dr. Anderson Cancer Center, which he has to join Pfizer Oncology as the medicine at Harvard Medical School. Dr. Bradley has served as the Lung Cancer held since 2017. He is also the Gilbert Clinical Development Leader. Dr. Shaw’s research in ALK and ROS1 rear- Committee Chairman for NRG Oncology H. Fletcher Memorial Distinguished Papadimitrakopoulou is also a member rangements in NSCLC and in targeted- (the largest of the four adult National Chair and professor of radiation oncol- of the FDA’s Oncologic Drugs Advisory therapy resistance has led to novel treat- Clinical Trials Network Groups sup- ogy there. Previously, he was the chair Committee and was co-principal investi- ment strategies. ✦ LUNGCANCERNEWS.ORG / DECEMBER 2019 15

ADVOCACY AND SURVIVORSHIP STARS Patient Research Advocate Training Program Seeks Patients and Caregivers

By Adam Mohrbacher well as several activities that are exclusive for STARS participants. Patients with lung cancer and their care- “I fi rmly believe that research advo- givers are becoming more empowered cacy is a community endeavor. Th at’s and knowledgeable than ever. As a result, what the STARS program helped lung cancer now has a growing group of accomplish,” said Upal Basu Roy, MPH, patients who have lived long enough to PhD, vice president of research for the become advocates for their disease. Some LUNGevity Foundation, who also served are evolving into research advocates— as a mentor for STARS inaugural year. volunteers with a personal connection to “Not only [does it] train future patient cancer who are passionate about helping research advocates, but [it] also cre- translate research fi ndings into mean- ates a long-lasting community that can ingful outcomes for patients and their From left to right, back to front: Caleb Egwuenu, Lillian Leigh, Shelly Engfer- co-learn and co-evolve, with the goal families. Lung cancer research advocates Triebenbach, Kim MacIntosh, Sue McCullough, Laura Greco, Jill Hamer-Wilson, of ensuring that lung cancer research provide the perspective of the collective Jill Feldman, Dusty Donaldson, and Dr. Upal Basu Roy. incorporates the patient voice.” lung cancer patient community in order Preparation for the second year of to help research focus on the questions realities of lung cancer research. In the municate with the public or their lung STARS is now well underway, with the most important to patients and to create program, PRAs work with mentors cancer community during November’s application period scheduled to open in studies that will extend lives and improve (experienced research advocates) and annual Lung Cancer Awareness Month early February 2020. Healthcare profes- quality of life for people who have lung receive training to increase their scien- event. Finally, both mentors and PRAs sionals are encouraged to recommend the cancer. However, learning the complex tifi c literacy and ability to provide accu- attend the IASLC World Conference on program to any established patient with mechanisms of action regarding diff er- rate scientifi c translation to their patient- Lung Cancer (WCLC), which will be lung cancer or caregiver advocate look- ent cancer therapies and details of clinical caregiver communities. Additionally, the held in Singapore in 2020. At WCLC, ing to increase their scientifi c capabilities trial design can be a steep learning curve program equips its participants to con- they attend relevant presentations geared and advocacy. for many patients, even those who are nect and communicate with lung cancer toward enhancing their knowledge of To apply to the STARS program, visit strongly motivated. researchers and research agencies in lung cancer research and treatments as www.iaslc.org/stars. ✦ Over the past year, the IASLC launched order to bring the patient perspective to a new program designed to further studies and policy. It involves a 6-month empower aspiring patient research advo- commitment on the part of both mentors cates (PRAs) called STARS: Supportive and PRAs, culminating in each PRA pre- Training for Advocates in Research and senting on a scientifi c focus topic to the Science. STARS aims to train, develop, rest of the STARS cohort. PRAs also must and nurture lung cancer patient research develop a plan for how they intend to use Submit your abstract advocates (PRAs) in the science and the skills acquired during STARS to com- by 14 January 2020

First-Ever IASLC School of Nursing Panama, and Brazil pre-registered. Th ere from page 13 was such enthusiasm for the SON that a and make a difference total of 75 attendees were present, includ- in lung cancer Rolfo, MD, PhD, MBA, who recognized ing several medical oncologists and tho- the signifi cant contribution of nurses racic surgeons who joined the SON to to the care of patients with lung cancer bring back information to the nurses through the trajectory of their illness. with whom they work. Nursing partici- Th ey also recognized that there was a gap pants appreciated the extent to which in specialty education for nurses. they shared common issues relating to As the event chair, I worked closely the care of patients with complex cases with local nursing delegates to assess the of lung cancer, incorporation of pallia- educational needs of thoracic nurses and tive care early in the continuum of care, identify regional nursing experts to pres- and management of the diverse family GENEVA SWITZERLAND ent. Th e program was developed to pro- unit. In addition, nurses from each of 15-18 APRIL 2020 vide an overview and updates on nurses’ the countries represented shared similar roles in clinical trials, access to care, lung experiences in barriers to care delivery Submit your abstract to the ELCC 2020, where you will have the chance to interact cancer staging, biomarker testing, lung and gaps in access to care. All participants with top experts in the ﬁeld and network with cancer screening programs, survivorship, expressed interest in opportunities to par- oncology stakeholders to discuss challenges and opportunities in the lung cancer arena. and nutrition. Case-based presentations ticipate in ongoing webinars and regional provided an opportunity for nurses to meetings to support their practice. IMPORTANT DEADLINES discuss the care of patients in the post- The next IASLC regional meeting 14 January 2020 Abstract submission operative setting and in those receiving is scheduled for November 2021 in 5 February 2020 Early registration chemotherapy, targeted therapies, or Montevideo, Uruguay, with the goal of 10 March 2020 Late-breaking abstracts radiation therapy; pain and symptom off ering the second LALCA-SON. Th is 25 March 2020 Late registration management; management of immune- SON program can serve as a model for mediated adverse side eff ects; and stigma other regional meeting around the globe Organisers Partners of palliative care. to support and develop the practice of elcc2020.org Approximately 40 nurses from Mexico, thoracic nursing worldwide. ✦ FIGHTING CANCER at 150,000 cycles per second

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References: 1. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine. Effect of Tumor Treating Fields (TTFields) (150kHz) concurrent with standard of care therapies for treatment of stage 4 non-small cell lung cancer (NSCLC) following platinum failure (LUNAR). NCT02973789. https:// clinicaltrials.gov/ct2/show/NCT02973789. Updated January 17, 2019. Accessed January 23, 2019. 2. Gutin PH, Wong ET. Noninvasive application of alternating electric fields in glioblastoma: a fourth cancer treatment modality. Am Soc Clin Oncol Educ Book. 2012:126-131. 3. Kirson ED, Dbalý V, Tovarys F, et al. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007:104(24):10152-10157. 4. Gera N, Yang A, Holtzman TS, Lee SX, Wong ET, Swanson KD. Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit. PLOS ONE. 2015.10(5):e0125269. doi:10.1371/journal.pone.0125269. 5. Novocure Data on File. NovocureTrial.com. LUNAR. 2018. This is an investigational trial. TTFields has not been approved by the US FDA for treatment of NSCLC. ©2019 Novocure. All rights reserved. Novocure is a registered trademark of Novocure. SRC-258