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Background: Patients with relapsed or refractory multiple myeloma (RRMM) who have exhausted lenalidomide benefits require improved therapies. The 3-cohort phase 2 MM-014 trial (NCT01946477) explored pomalidomide in early lines of treatment for lenalidomide-exposed RRMM. In cohort B, pomalidomide plus daratumumab and dexamethasone (DPd) showed promising efficacy (median follow-up 28.4 months), as previously reported. Here, we report final overall survival (OS) in cohort B., Methods: Patients aged ≥ 18 years were treated in 28-day cycles: pomalidomide 4 mg orally daily from days 1 to 21; daratumumab 16 mg/kg intravenously on days 1, 8, 15, and 22 (cycles 1-2), days 1 and 15 (cycles 3-6), and day 1 (cycle ≥ 7); and dexamethasone 40 mg (age ≤ 75 years) or 20 mg (age > 75 years) orally on days 1, 8, 15, and 22. The primary endpoint was ORR. OS and safety were secondary endpoints., Results: Among 112 patients enrolled, 85 (75.9%) had lenalidomide-refractory disease and 27 (24.1%) had lenalidomide-relapsed disease. At a median follow-up of 41.9 months (range, 0.4-73.1), median OS was 56.7 months (95% confidence interval, 46.5-not reached). Treatment-emergent adverse events related to, and leading to discontinuation of, pomalidomide, dexamethasone, or daratumumab occurred in 7 (6.3%), 9 (8.0%), and 6 (5.4%) patients, respectively., Conclusion: With long-term follow-up, our results show favorable OS with DPd. The safety profile was consistent with previous reports, with no new safety signals identified. IMiD agent-based therapy can still be considered in patients with RRMM who experience progressive disease on or after lenalidomide., Competing Interests: Disclosure N.J.B. declares research funding from Bristol Myers Squibb (BMS); honoraria from AbbVie, Amgen, BMS/Celgene, Forus, Genentech, GlaxoSmithKline (GSK), Janssen, Karyopharm, Pfizer, Sanofi, and Takeda; and payment for expert testimony from BMS/Celgene, Karyopharm, and Pfizer. C.S. declares no competing financial interests. D.R. declares research funding from BMS; consulting fees from Amgen, BMS, and Janssen; honoraria from Amgen, BMS, GSK, Sanofi, and Takeda; payment for expert testimony from BMS and Janssen; and board membership with Canadian Myeloma Research Network (CMRG; Chief Medical Officer). M.S. declares payment for expert testimony from BMS, Gilead/Kite, Janssen, Novartis, Pfizer, and Sanofi; and participation on a data safety monitoring or advisory board with Janssen. J.M. declares consulting fees from BeiGene and Pharmacyclics; and participation on a data safety monitoring or advisory board with BeiGene. J.G.B. declares research funding from 2seventy bio, AbbVie, Acetylon, Amgen, BMS/Celgene, bluebird bio, C4 Therapeutics, CARsgen, Cartesian, Celularity, CRISPR, EMD Serono, Fate, Genentech, GSK, Ichnos, Incyte, Janssen, Karyopharm, Lilly, Novartis, Poseida, Sanofi, Takeda, and Teva; and consulting fees from bluebird bio, BMS/Celgene, CRISPR, Janssen, Kite, Legend, Roche, Secura, and Takeda. J.S. declares honoraria from BMS, Janssen, Pfizer, and Sanofi. G.J.S. declares research funding from AbbVie, Actinium, Actuate, Agios, AltruBio, Amgen, Aptevo, Arog, Astellas, AVM Bio, BioMea, Biopath, Biosight, BMS/Celgene, Celator, Cellectis, Celularity, Cogent, Constellation, Daiichi Sankyo, Deciphera, Delta-Fly, Fate, Forma, FujiFilm, Gamida, Genentech/Roche, Geron, Gilead/Kite, Glycomimetics, Immunogene, Incyte, Janssen, Jazz, Karyopharm, Kiadis, Kronos Bio, Kura, Loxo, Marker, Mateon, Novartis, Onconova, Ono-UK, Orca, Pfizer, PrECOG, Regimmune, Samus, Sangamo, Sellas, Stemline, Syros, Takeda, Tolero, and Trovagene; consulting fees from BMS/Celgene, Curios, and Daiichi Sankyo; honoraria from AbbVie, Agios, Amgen, Astellas, AstraZeneca, AVM Biotech, BMS, Celgene, Gamida, Gilead, GSK, Incyte, Karyopharm, Novartis, Ono, and Stemline; participation on a data safety monitoring or advisory board with Agios, Amgen, AstraZeneca, AVM Biotech, BMS, Gamida, Gilead, GSK, Incyte, Novartis, and Ono; and stock or stock options with Amgen, BMS, and Janssen/Johnson & Johnson. S.G. declares consulting fees from AstraZeneca, BMS, Kite, and Sanofi; and honoraria from Kite and Seagen. K.S. declares research funding from BMS; and honoraria from Amgen, BMS, and Sanofi. C.S.S. declares no competing financial interests. M.A-R. declares honoraria from BMS, Eisai, and Merck Sharp Dohme. M.B. declares no competing financial interests. D.Q. declares no competing financial interests. G.F. declares honoraria from Amgen, BMS, and Sanofi. H.L. declares employment and stock/stock options with BMS. C.G. declares employment and equity ownership with BMS. P.S. declares employment with BMS. D.S. declares research funding from BMS; consulting fees from BMS, Janssen, and Karyopharm; honoraria from BMS and Janssen; participation on a data safety monitoring or advisory board with BMS; and stock or stock options with COTA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort., Patients and Methods: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1., Results: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis., Conclusions: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients., Competing Interests: Disclosure IM reports consultancy fees from AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, EMD Serono, F-Star, Genmab, Gossamer Bio, Lilly, Merck Sharp & Dohme, Numab, PharmaMar, Roche, Tusk Therapeutics, Highlight Therapeutics, Alligator Bioscience, Genentech, CatalYm GmbH, BioLineRx, Boston Pharma, Janssen, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., and Monopteros Therapeutics; honoraria from Alligator Biosciences, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Lilly, Roche/Genentech, Tusk Therapeutics, Moderna, and CatalYm GmbH; travel support from Bristol Myers Squibb, Incyte, Merck Sharp & Dohme, and Roche/Genentech; and research grants from Alligator Biosciences, Bristol Myers Squibb, AstraZeneca, Genmab, Pfizer, and Roche/Genentech. TY reports consultancy fees from AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme Oncology. YKK reports consulting fees from ALX Oncology, Amgen, Blueprint, Bristol Myers Squibb, Daehwa, MacroGenics, Merck, Novartis, Roche, Surface Oncology, and Zymeworks. TYK is the founder of IMBdx, Inc. and has received research funds from Bayer Korea. AS reports consulting role at Bayer, Bristol Myers Squibb, Eisai, Gilead Sciences, Incyte, Merck Sharp & Dohme, Pfizer, Sanofi, and Servier; and speakers’ bureau participation for AbbVie, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eisai, Gilead Sciences, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Servier, and Takeda. BS reports consultancy fees from Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Eisai, Eli Lilly, Incyte, Ipsen, Novartis, Roche, Sirtex Medical, Terumo; speaker fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Incyte, Ipsen, Roche, Sirtex Medical, and Terumo; and research grants (to institution) from Bristol Myers Squibb and Sirtex Medical. MK reports consultancy fees from Chugai, Roche, Eisai, and AstraZeneca; speaker fees from Eli Lilly, Bayer, Eisai, Chugai, Takeda, and AstraZeneca; research grants (to institution) from Taiho, Otsuka, EA Pharma, AbbVie, Eisai, Chugai, GE Healthcare, and Ono Pharmaceutical Company. AM reports consulting role at Bayer, Eisai, Merck Sharp & Dohme, Roche, and Sirtex Medical; and speakers’ bureau participation for Bayer, Boston Biologics, Eisai, Merck Sharp & Dohme. FT reports consultancy role for Ipsen, Eisai, and Roche. JK reports consultancy fees from AstraZeneca, Ibsen, Taiho, and Hoffman-La Roche; and research support from AstraZeneca, Merck, Ibsen, and Roche. ARH reports consulting role at Eisai, Genentech/Roche, and Merck; speakers’ bureau participation for Bristol Myers Squibb, Eisai, and Exelixis; and research grants from Genentech and Merck. BER reports research grants from AstraZeneca, Bristol Myers Squibb, EUSA Pharmaceuticals, Exelixis, Merck, Novartis, and Xencor; consulting fees from AstraZeneca, Bristol Myers Squibb, Deciphera, Ipsen, NeoGenomics, Roche, and Seagen; and advisory role at Exelixis. HYL reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb/Medarex, Eisai, and MSD Oncology; consulting role at AstraZeneca, Bayer, Bristol Myers Squibb, and Eisai; and speakers’ bureau participation for Bayer. SS, JY, JN, and MT report being employees of and owning stock in Bristol Myers Squibb. CH reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Ono Pharmaceuticals, Eisai, Ipsen, Merck Sharp & Dohme, Novartis, PharmaEngine, Roche, and TTY Biopharm. ABEK reports consultancy fees from ABL Bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Eisai, Exelixis, Gilead Sciences, Merck, Pieris Pharmaceuticals, QED Therapeutics, Qurient, Roche, Senti Biosciences, Servier, and Tallac Therapeutics; honoraria from ABL Bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Eisai, Exelixis, EMD Serono, Gilead Sciences, Merck, Roche/Genentech, QED Therapeutics, Qurient, Roche, Senti Biosciences, Servier, and Tallac Therapeutics; and research grants from AstraZeneca, Astex Pharmaceuticals, and Fulgent Genetics. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To investigate the safety and efficacy of nivolumab plus cabozantinib with or without ipilimumab in patients with advanced hepatocellular carcinoma., Methods: In cohort 6 of the multicohort, open-label, phase I/II CheckMate 040 study, patients who were treatment-naive, sorafenib-intolerant, or had progressed on sorafenib were randomly assigned 1:1 to nivolumab 240 mg once every 2 weeks plus cabozantinib 40 mg once daily (doublet arm); or nivolumab 3 mg/kg every 2 weeks plus cabozantinib 40 mg once daily with ipilimumab 1 mg/kg once every 6 weeks (triplet arm). Primary objectives were safety and tolerability, objective response rate, and duration of response by investigator assessment per RECIST v1.1. Secondary objectives included progression-free survival (by blinded independent central review) and overall survival., Results: Seventy-one patients were randomly assigned: 36 to the doublet arm and 35 to the triplet arm. After 32.0-month median follow-up, objective response rate (95% CI) was 17% (6 to 33) and 29% (15 to 46) in the doublet and triplet arms, respectively. Median (95% CI) duration of response was 8.3 (6.9 to not estimable) months in the doublet arm and not reached (0.0 to not estimable) in the triplet arm. Median progression-free survival was 5.1 and 4.3 months, and median overall survival was 20.2 and 22.1 months for the doublet and triplet arms, respectively. Grade 3-4 treatment-related adverse events occurred in 50% and 74% of patients and treatment-related adverse events leading to discontinuation were reported for 11% and 23% in the doublet and triplet arms, respectively. There were no treatment-related deaths in either arm., Conclusion: Nivolumab plus cabozantinib with or without ipilimumab showed encouraging preliminary antitumor activity and had consistent safety profiles with those established for the individual drugs in patients with advanced hepatocellular carcinoma.

Patients with relapsed/refractory multiple myeloma (RRMM) need proven subsequent therapies after early-line lenalidomide treatment failure. The phase 2 MM-014 trial (NCT01946477) investigated pomalidomide, dexamethasone, and daratumumab after 1 to 2 prior treatment lines (62.5%, 1 prior line) in patients with RRMM and prior lenalidomide (75.0%, lenalidomide refractory). With a median follow-up of 28.4 months, overall response rate was 77.7% (52.7% achieved very good partial response or better) and median progression-free survival was 30.8 months. For patients with lenalidomide-refractory disease, these outcomes were 76.2%, 47.6%, and 23.7 months, respectively. No new safety signals were observed; 64.3% experienced grade 3/4 neutropenia. Health-related quality of life was preserved or trended toward improvement through 12 treatment cycles. Pomalidomide, dexamethasone, and daratumumab given immediately after early-line lenalidomide-based treatment continues to demonstrate safety and efficacy, supporting pomalidomide-dexamethasone as a foundation of combination therapy in RRMM and providing evidence that the immunomodulatory agent class delivers benefit after lenalidomide treatment failure.

Background & Aims: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status., Methods: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0., Results: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC., Conclusions: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC., Lay Summary: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population., Clinical Trial Number: NCT01658878., Competing Interests: Conflict of interest MK reports receiving personal fees from Bristol Myers Squibb, Bayer, Eisai, MSD, and Ono Pharmaceutical Co., Ltd., and receiving grants from Eisai, Otsuka, Taiho Pharmaceutical, EA Pharma, Takeda, AbbVie, and Gilead Sciences. AM reports receiving personal fees from Bayer, BTG, and Bristol Myers Squibb and receiving grants and other funding from Bayer. AS reports receiving personal fees from Bristol Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Takeda, Roche, AbbVie, Amgen, Celgene, ArQule, Lilly, Sandoz, and Novartis. IM reports receiving personal fees from Alligator Bioscience, Bristol Myers Squibb, EMD Serono, F-Star Biotechnology, Genmab, Roche, Bayer, MSD, Numab, Lilly, AstraZeneca/MedImmune, Incyte, and Tusk Therapeutics and receiving grants from Pfizer, Alligator Bioscience, Bristol Myers Squibb, and Roche. SP reports receiving personal fees from Celgene, Novartis, Eisai, Bristol Myers Squibb, Shire, and Sirtex Medical; receiving grants from Bristol Myers Squibb; and receiving non-financial support from Bristol Myers Squibb, Amgen, and Merck. ABE reports receiving personal fees from CytomX Therapeutics, Bristol Myers Squibb, Bayer, Eisai, Roche/Genentech, EMD Serono, Exelixis, Pieris Pharmaceuticals, Agenus, and Merck and receiving grants from AstraZeneca, Merck, and Astex Pharmaceuticals. RK reports receiving research funding from Bristol Myers Squibb, Eisai, Ono Pharmaceutical Co., Ltd., MSD KK, AstraZeneca plc, EA Pharma Co., Ltd, Takeda Pharmaceutical Company Limited, CHUGAI Pharmaceutical Co, LTD and honoraria from MSD, Mitsubishi Tanabe Pharma Corporation, Shionogi & Co., Ltd, GE Healthcare Japan, Daiichi Sankyo Company, Limited. BE reports receiving personal fees from Bayer, Lexicon, RTI Health Solutions, BTG, Loxo, Merrimack, and Bristol Myers Squibb; receiving grants from AVEO, Boston Biomedical, Bristol Myers Squibb, Cleave Biosciences, Five Prime Therapeutics, Genentech, Hoosier Cancer Research Network, ICON Clinical Research, Merck, Novartis, Pfizer, PPD, Taiho Pharmaceutical, Xencor, and AstraZeneca/MedImmune; and receiving other funding from Exelixis and ERYTECH Pharma. YI reports receiving personal fees from Gilead Sciences Inc, AbbVie Inc, Merck Sharp & Dohme, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd., funding from Takeda Pharmaceutical Company Limited, EA Pharma Co, Ltd, Eisai Co Ltd, AbbVie Inc, Merck Sharp & Dohme, Bayer Yakuhin Ltd, Bristol Myers Squibb, Astellas Pharma Inc, Nissan Chemical Industries, Ltd, FUJIREBIO Inc, Ono Pharmaceutical Co., Ltd., Gilead Sciences Inc, and Nichinichi Pharmaceutical Co Ltd. MR reports receiving personal fees from Bayer, Bristol Myers Squibb, AstraZeneca, Ipsen, Lilly, BTG, and Roche; receiving grants from Bayer and Lilly; and receiving non-financial support from Bayer and Bristol Myers Squibb. YS reports receiving personal fees from Bristol Myers Squibb; and receiving other funding from Bristol Myers Squibb and Sanofi. JN reports receiving personal fees and other funding from Bristol Myers Squibb. JA reports receiving personal fees and other funding from Bristol Myers Squibb. TW reports receiving personal fees, grants, and other funding from Bristol Myers Squibb. BS has served in a consulting or advisory role for Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, TERUMO, H3 Biomedicine, Ipsen, Lilly, and Roche; has served on speakers’ bureaus for Bayer, Bristol Myers Squibb, Sirtex Medical, TERUMO, and Ipsen; and has received research funding from Bristol Myers Squibb and Sirtex Medical. ACG, MA, KN, FD, and OC report no disclosures. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1-21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.

Importance: Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy., Objective: To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib., Design, Setting, and Participants: CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C)., Interventions: Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C)., Main Outcomes and Measures: Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1)., Results: Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis)., Conclusions and Relevance: In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study., Trial Registration: ClinicalTrials.gov Identifier: NCT01658878.