ONCOLOGY FDA Updates Highlighting the Latest Cancer Treatments

Pembrolizumab for Advanced Esophageal “Patients at this stage of prostate cancer typically don’t have symp- Squamous Cell Cancer toms of the disease. The overarching goals of treatment in this setting The FDA approved for patients with recurrent, locally are to delay the spread of prostate cancer and limit the burdensome advanced, or metastatic squamous cell carcinoma of the esophagus side effects of therapy,” said Matthew Smith, MD, PhD, Director of (ESCC) whose tumors express PD-L1 (combined positive score [CPS] the Genitourinary Malignancies Program at Massachusetts General ≥10), as determined by an FDA-approved test, with disease progres- Hospital Cancer Center. “This approval marks an important new op- sion after one or more prior lines of systemic therapy. tion for the prostate cancer community.” The FDA also approved a new use for the PD-L1 IHC 22C3 phar- In the ARAMIS trial, both arms showed a 9 percent discontinua- mDx as a companion diagnostic device for selecting patients for tion rate due to adverse reactions. The most frequent adverse reactions the above indication. requiring discontinuation in patients who received darolutamide in- Efficacy was investigated in two clinical trials, KEYNOTE-181 cluded cardiac failure (0.4%) and death (0.4%). Adverse reactions oc- (NCT02564263) and KEYNOTE-180 (NCT02559687). KEYNOTE-181 curring more frequently in the darolutamide arm (≥2% over placebo) was a randomized, open-label, active-controlled trial that enrolled were fatigue (16% vs. 11%), pain in extremity (6% vs. 3%), and rash 628 patients with recurrent locally advanced or metastatic esophageal (3% vs. 1%). Darolutamide was not studied in women and there is a cancer who progressed on or after one prior line of systemic treat- warning and precaution for embryo-fetal toxicity. ment for advanced or metastatic disease. Patients were randomized Overall survival (OS) and time to pain progression were additional (1:1) to receive either pembrolizumab 200 mg intravenously (IV) secondary efficacy endpoints. OS data were not yet mature at the time of every 3 weeks or the investigator’s choice of the following regimens: final MFS analysis. The MFS result was supported by a delay in time to paclitaxel 80-100 mg/m2 IV on days 1, 8, and 15 of every 4-week cycle; pain progression, defined as at least a 2-point worsening from baseline docetaxel 75 mg/m2 IV every 3 weeks; or irinotecan 180 mg/m2 IV ev- of the pain score on Brief Pain Inventory-Short Form or initiation of ery 2 weeks (control arm). Randomization was stratified by geographic opioids, in patients treated with darolutamide as compared to placebo. region and histologic subtype (squamous vs. adenocarcinoma). PD-L1 Pain progression was reported in 28 percent of all patients on study. status was determined using the PD-L1 IHC 22C3 pharmDx kit. The primary efficacy outcome measure of KEYNOTE-181 was FDA Accepts IND Application for huMNC2- overall survival (OS) in patients with ESCC, patients with tumors CAR44 T Cells to Treat Solid Tumors expressing PD-L1 CPS ≥10, and all randomized patients. Additional The FDA has approved an IND application to conduct clinical trials efficacy outcome measures were progression-free survival, overall re- with huMNC2-CAR44, an autologous CAR T-cell therapy for solid sponse rate (ORR), and response duration. The hazard ratio for OS in tumors. huMNC2-CAR44 targets MUC1* (muk one star), a cleaved patients with ESCC whose tumors expressed PD-L1 CPS ≥10 was 0.64 form of MUC1 present on over 75 percent of solid tumor cancer cells. (95% CI: 0.46, 0.90). Median OS was 10.3 months (95% CI: 7.0, 13.5) Unlike the normal full-length MUC1, MUC1* is a potent growth and 6.7 months (95% CI: 4.8, 8.6) in the pembrolizumab and control factor receptor that is rendered constitutively active when onco-em-

arms, respectively. bryonic growth factor NME7ABbinds to and dimerizes its truncated KEYNOTE-180 was a single-arm, open-label trial that enrolled extracellular domain. 121 patients with locally advanced or metastatic esophageal cancer The chimeric antigen receptor (CAR) technology genetically en- who progressed on or after at least 2 prior systemic treatments for gineers the patient’s own immune cells to recognize and kill specific advanced disease. With the exception of the number of prior lines of types of cancer cells. The homing device on the CAR is an antibody treatment, the eligibility criteria were similar to and the dosage regi- that can distinguish the tumor-associated cleavage product, MUC1*, men identical to KEYNOTE-181. from the normal, full-length MUC1. Previous attempts to make can- The major efficacy outcome measures of KEYNOTE-180 were ORR cer therapeutics that target MUC1 have failed because they have tar- and response duration. In the 35 patients with ESCC expressing PD-L1 geted the a portion of full-length MUC1, which on tumor cells is CPS ≥10, ORR was 20 percent (95% CI: 8, 37) and response durations cleaved, then shed and released form the cancer cell surface. ranged from 4.2 to 25.1+ months, with 71 percent (five patients) hav- ing responses of 6 months or longer and 57 percent (three patients) FDA Approves First Therapy for Rare Joint having responses of 12 months or longer. Tumor Adverse reactions in patients with esophageal cancer were similar The FDA granted approval to pexidartinib capsules for the treatment to those in 2,799 patients with melanoma or NSCLC treated with sin- of adult patients with symptomatic tenosynovial giant cell tumor gle-agent pembrolizumab. Common adverse reactions reported in at (TGCT) associated with severe morbidity or functional limitations least 20 percent of patients receiving pembrolizumab include fatigue, and not responsive to improvement with surgery. musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, “TGCT can cause debilitating symptoms for patients such as pain, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. stiffness and limitation of movement. The tumor can significantly af- The recommended pembrolizumab dose for esophageal cancer is fect a patient’s quality of life and cause severe disability,” said Richard 200 mg every 3 weeks. Pazdur, MD, Director of the FDA’s Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products Darolutamide for Non-Metastatic in the FDA’s Center for Drug Evaluation and Research. “Surgery is the Castration-Resistant Prostate Cancer primary treatment option, but some patients are not eligible for sur- The FDA approved darolutamide, an androgen receptor inhibitor, gery, and tumors can recur, even after the procedure. Today’s approval for the treatment of patients with non-metastatic castration-resistant is the first FDA-approved therapy to treat this rare disease.” prostate cancer (nmCRPC). The approval is based on the phase III TGCT is a rare tumor that affects the synovium and tendon sheaths. ARAMIS trial evaluating darolutamide plus androgen deprivation The tumor is rarely malignant but causes the synovium and tendon therapy (ADT), which demonstrated a highly significant improve- sheaths to thicken and overgrow, causing damage to surrounding tissue. ment in the primary efficacy endpoint of metastasis-free survival The approval of pexidartinib was based on the results of a multi- (MFS), with a median of 40.4 months versus 18.4 months for placebo center international clinical trial of 120 patients, 59 of whom received plus ADT (p<0.0001). Darolutamide was approved under the FDA’s placebo. The primary efficacy endpoint was the overall response rate designation, which is reserved for medicines that may (ORR) analyzed after 25 weeks of treatment. The clinical trial dem- provide significant improvements in the safety or effectiveness of the onstrated a statistically significant improvement in ORR in patients treatment for serious conditions. Continued on page 29

28 Oncology Times September 5, 2019 for a minimum of 12 months following the pexidartinib Risk Evaluation and contraception during treatment with FDA Updates the initial response maintained their re- Mitigation Strategy (REMS) Program. pexidartinib. Women who are pregnant continued from page 28 sponse for 12 or more months. Common side effects for patients tak- or breastfeeding should not take pexi- The prescribing information for ing pexidartinib were increased lactate dartinib because it may cause harm to pexidartinib includes a Boxed Warning dehydrogenase, increased aspartate ami- a developing fetus or newborn baby. who received pexidartinib, with an ORR to advise health care professionals and notransferase, loss of hair color, increased Pexidartinib must be dispensed with a of 38 percent, compared to no responses patients about the risk of serious and alanine aminotransferase, and increased patient Medication Guide that describes in patients who received placebo. The potentially fatal liver injury. Health care cholesterol. Additional side effects in- important information about the drug’s complete response rate was 15 percent professionals should monitor liver tests cluded neutropenia, increased alkaline uses and risks. and the partial response rate was 23 per- prior to beginning treatment and at spec- phosphatase, decreased lymphocytes, eye The FDA granted this application cent. A total of 22 out of 23 responders ified intervals during treatment. If liver edema, decreased hemoglobin, rash, dys- Breakthrough Therapy designation and who had been followed for a minimum tests become abnormal, pexidartinib may geusia, and decreased phosphate. Priority Review designation. Pexidartinib of 6 months following the initial re- need to be withheld, the dose reduced, The FDA advises health care profes- also received Orphan Drug designation, sponse maintained their response for 6 or permanently discontinued, depend- sionals to tell females of reproductive which provides incentives to assist and or more months, and a total of 13 out ing on the severity of the liver injury. age and males with a female partner of encourage the development of drugs for of 13 responders who had been followed Pexidartinib is available only through reproductive potential to use effective rare diseases. OT

longer follow-up and CLL-specific real- with . Further investigation re- CLL (N Engl J Med 2018;379(26):2517- BTK INHIBITORS world data will be needed to validate these garding the safety and activity of zanu- 2528). More selective and less toxic BTKi, continued from page 8 findings. brutinib in patients intolerant (but not such as and , refractory) to ibrutinib or in individuals may be more suitable for the treatment Zanubrutinib-Based with significant comorbid health condi- of individuals with relevant comorbid All patients were treated with ≥1 Combinations in CLL tions is warranted. In addition, in light conditions, the latter being very com- dose of oral zanubrutinib at doses of Given its lack of influence on ADCC, of its lack of activity on ITK, its combi- mon in patients affected by CLL, as the 40 to 320 mg once daily, and almost all (Haematologica 2019 Jan 24) the com- nation with anti-CD20 monoclonal an- median age at the time of diagnosis is 72 received either 320 mg daily or 160 mg bination of zanubrutinib and obinu- tibodies may produce deeper and more years (Br J Haematol 2017;178(3):394- twice daily. Median age was 64 years, 68 tuzumab has been investigated in a durable responses than that observed 402). Ongoing trials investigating the percent of patients were men, 15 per- multicenter phase Ib trial, includ- with ibrutinib-based combinations. safety and efficacy of these agents in cent were aged ≥ 75 years and 91 per- ing 20 patients with treatment-naïve combination with anti-CD20 monoclo- cent had relapsed or refractory disease. and 25 patients with relapsed refrac- Conclusions & Future nal antibodies and other targeted agents, After a median exposure to zanubruti- tory CLL (Blood 2017;130(Suppl Directions such as , may result in deeper nib of 13 months and a median relative 1):1745-1745; Hematological Oncology The introduction of ibrutinib has revo- responses and potentially eradication of dose intensity of 99 percent across all 2017;35(S2):113-113; ICML 2019). The lutionized the treatment of patients with minimal residual disease. OT studies, 38 percent of patients discon- only grade > 3 toxicities observed in > tinued treatment: 25 percent because of 5 percent of patients were neutropenia progressive disease (most from DLBCL (31%), pneumonia (8.9%), and throm- and other NHL), 9 percent because of bocytopenia (6.7%). There were no cases adverse events. of major hemorrhage or atrial fibrilla- Ninety-seven percent of patients tion/flutter. The ORR for TN and R/R reported adverse events, but primar- CLL/SLL was 100 percent (20/20) and ily grade 1-2; the most common grade 92 percent (23/25), CR rates 30 percent ≥ 3 adverse events were neutrophil 6/20) and 28 percent (7/25), and 1-year count decreased (14%), anemia (8%), PFS rate 100 percent and 92 percent, neutropenia (7%), pneumonia (4%), and 2-year PFS rate 95 percent and 83 platelet count decreased (4%), lung in- percent, respectively. Larger studies and fection (4%), and hypertension (3%). extended follow-up will better define the Serious adverse events were reported durability of these high response rates in 36 percent of patients and were over time. treatment-related in 12 percent; the A phase II study adding venetoclax most common serious adverse events to this combination in patients with were pneumonia (5%), lung infection previously untreated CLL is ongoing (3%), urinary tract infection (2%), fe- (NCT03824483). In addition, a phase ver (2%), cellulitis (1%), pleural effu- III randomized trial comparing the ef- sion (1%), and anemia (1%); the only ficacy of single agent zanubrutinib to treatment-related serious adverse event chemoimmunotherapy in patients with reported in >1 percent of patients was treatment-naïve CLL (BGB-3111-304; pneumonia (2%). NCT03336333), and a phase III random- Adverse events of interest were infre- ized trial comparing the efficacy of single quent. Atrial fibrillation occurred in 1.9 agent zanubrutinib to single agent ibru- percent of patients, in 77 percent of cases tinib in patients with relapsed/refrac- within the first 12 months of treatment, tory CLL are ongoing (BGB-3111-305; and mostly in individuals with predis- NCT03734016). posing risk factors (such as prior atrial Zanubrutinib has recently received fibrillation, hypertension or concomitant FDA breakthrough designation for the infection). Major hemorrhage was ob- treatment of patients with relapsed served in 2.5 percent of patients, all with mantle cell . Ongoing ran- predisposing risk factors, such as gastro- domized phase III trials will help under- intestinal disease, trauma, or concomi- standing whether the pre-clinical data of tant use of anticoagulants. While these higher potency will translate into greater represent very encouraging safety data, clinical efficacy as compared to that seen oncology-times.com 29