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Background: We report 5-year efficacy and safety outcomes from CheckMate 9LA in patients with metastatic non-small cell lung cancer (mNSCLC) and exploratory analyses in key patient subgroups., Methods: Adults with stage IV/recurrent NSCLC and no sensitizing EGFR/ALK alterations were randomized to receive nivolumab plus ipilimumab with chemotherapy (n = 361) or chemotherapy (n = 358). Outcomes were assessed in all randomized patients and subgroups., Results: With 57.3 months' minimum follow-up, patients continued to derive overall survival (OS) benefit with nivolumab plus ipilimumab with chemotherapy over chemotherapy (HR, 0.73; 95% CI, 0.62-0.85; 5-year OS rates, 18% vs. 11%), regardless of tumor programmed death ligand 1 (PD-L1) expression (PD-L1 < 1%, 22% vs. 8%; PD-L1 ≥ 1%, 18% vs. 11%), histology (squamous, 18% vs. 7%; non-squamous, 19% vs. 12%), or presence of baseline brain metastases (20% vs. 6%). Five-year duration of response (DOR) rates were 19% versus 8% with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, with consistent benefit across subgroups. Patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events had a 5-year OS rate of 37%. Five-year progression-free survival and DOR rates in 5-year survivors were 55% versus 38% and 59% versus 46%, respectively. No new safety signals were observed in 5-year survivors, regardless of the number of ipilimumab doses received., Conclusion: This 5-year update supports the long-term, durable OS benefit and improved 5-year survivorship with nivolumab plus ipilimumab with chemotherapy over chemotherapy in patients with mNSCLC, regardless of tumor PD-L1 expression or histology., Gov Registration: NCT03215706., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Nivolumab plus ipilimumab-based treatment regimens have shown long-term, durable efficacy benefits in patients with metastatic NSCLC. Here we report clinical outcomes from a pooled analysis of patients with metastatic NSCLC and tumor programmed death-ligand 1 (PD-L1) lower than 1% treated with first-line nivolumab plus ipilimumab with or without two cycles of chemotherapy versus up to four cycles of chemotherapy in the randomized phase 3 CheckMate 227 and CheckMate 9LA studies., Methods: Patients were aged 18 years or older and had stage IV or recurrent NSCLC with no sensitizing EGFR/ALK alterations. Assessments included overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety., Results: In patients with tumor PD-L1 lower than 1% in the nivolumab plus ipilimumab with or without chemotherapy (n = 322) versus chemotherapy (n = 315) arms, median OS was 17.4 versus 11.3 months, respectively, (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.54-0.76; 5-y OS rate, 20% versus 7%) at a median follow-up of 73.7 months. The OS benefit was observed across key subgroups, including difficult-to-treat populations such as those with baseline brain metastases (HR = 0.44, 95% CI: 0.26-0.75) or squamous NSCLC (HR = 0.51, 95% CI: 0.36-0.72). In the overall pooled population, the median PFS was 5.4 versus 4.9 months (HR = 0.72, 95% CI: 0.60-0.87; 5-y PFS rate, 9% versus 2%), the objective response rate was 29% versus 22%, and the median duration of response was 18.0 versus 4.6 months. No new safety signals were observed., Conclusion: Nivolumab plus ipilimumab with or without chemotherapy provides a long-term, durable clinical benefit in patients with metastatic NSCLC and tumor PD-L1 lower than 1%, supporting the use of this strategy as a first-line treatment option in this population with high unmet need., Clinical Trial Registrations: NCT02477826, NCT03215706., Competing Interests: Disclosure Dr. Peters reports grants or contracts to her institution from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, and Roche/Genentech; consulting fees to her institution from AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GlaxoSmithKline, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, medtoday, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, PharmaMar, Phosplatin Therapeutics, PER, PeerView, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, and Vaccibody; honoraria to her institution from AiCME, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, Merck Sharp & Dohme, Mirati, Novartis, PeerView, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, and Takeda; support for attending meetings and/or travel paid to her institution from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, and Takeda; and participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genzyme, Gilead, GlaxoSmithKline, Illumina, Incyte, iTeos, Janssen, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, Novocure, PharmaMar, Phosplatin Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, and Vaccibody with fees paid to her institution. Dr. Paz-Ares reports grants or contracts from Merck Sharp & Dohme, AstraZeneca, Pfizer, and Bristol Myers Squibb; consulting fees from Eli Lilly, Merck Sharp & Dohme, Roche, PharmaMar, Merck KGaA (Darmstadt, Germany), AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, Bristol Myers Squibb, Mirati, GlaxoSmithKline, Janssen, Takeda, and Daiichi Sankyo; honoraria from AstraZeneca, Janssen, Merck, and Mirati; and has participated on a Data Safety Monitoring Board or Advisory Board for Altum Sequencing and Genomica. Dr. Reck reports consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Eli Lilly, Mirati, Merck Sharp & Dohme, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Eli Lilly, Mirati, Merck Sharp & Dohme, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; meeting or travel support from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Eli Lilly, Mirati, Merck Sharp & Dohme, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; and has participated on a Data Safety Monitoring Board or Advisory Board for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Eli Lilly, Mirati, Merck Sharp & Dohme, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis. Dr. Carbone reports consulting fees from Arcus Biosciences, Bristol Myers Squibb, Bristol Myers Squibb KK, Boehringer Ingelheim, Curio Science, Daiichi Sankyo, Genentech/Roche, GI Therapeutics (Intellisphere), GlaxoSmithKline, Janssen, Merck, Mirati, Novartis, Novocure, OncoCyte, OncoHost, Roche China, and Seattle Genetics; and has participated on the Advisory Board of Amgen, Arcus Biosciences, AstraZeneca, Merck, Flame Biosciences, Gritstone Oncology, Cantargia (PPD), Daiichi Sankyo, EMD Serono GlaxoSmithKline, Eli Lilly, Regeneron, Sanofi, and Seattle Genetics and the Data Safety Monitoring Board of EORTC, AbbVie, and Eli Lilly. Dr. Brahmer reports grants or contracts to her institution from Bristol Myers Squibb and AstraZeneca; consulting fees from Bristol Myers Squibb, AstraZeneca, Merck, and Regeneron; honoraria from Bristol Myers Squibb; participation in Data Safety Monitoring Board or Advisory Board for Johnson & Johnson, Sanofi, and GlaxoSmithKline; board membership for Society for the Immunotherapy of Cancer (SITC), LUNGevity, Lung Cancer Research Foundation, and Lung Cancer Foundation of America; and medical writing support from Bristol Myers Squibb and Merck. Dr. Borghaei reports research support from Bristol Myers Squibb, Eli Lilly, and Amgen; participation as a consultant or advisory board member for Bristol Myers Squibb, Eli Lilly, Genentech, Pfizer, Merck, EMD Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Amgen, Axiom, PharmaMar, Takeda, Mirati, Daiichi Sankyo, Guardant, Natera, Oncocyte, BeiGene, iTEO, Jazz, Janssen, Puma, BerGenBio, Bayer, Iobiotech, Grid Therapeutics, and RAPT; participation in Data and Safety Monitoring Boards for the University of Pennsylvania CAR T Program, Takeda, Incyte, Novartis, and SpringWorks; employment with Fox Chase Cancer Center; stock options with Sonnet Bio, Inspirna (formerly Rgenix), and Nucleai; honoraria from Amgen, Pfizer, Daiichi Sankyo, and Regeneron; and travel support from Amgen, Bristol Myers Squibb, Merck, Eli Lilly, EMD Serono, Genentech, Regeneron, and Mirati. Dr. Lu reports research support from AstraZeneca, Hutchinson MediPharma, Bristol Myers Squibb, Hengrui Therapeutics, BeiGene, Roche, and Hansoh; consulting fees from AstraZeneca, Hutchinson MediPharma, Simcere Zaiming Pharmaceutical Co., Ltd., Yuhan Corporation, and Zai Lab; honoraria from AstraZeneca, Roche, Hansoh, and Hengrui Therapeutics; participation as an advisor and consultant of AstraZeneca, Yuhan Corporation, and InventisBio Co. Ltd.; participation as an independent director and board member of Innovent Biologics, Inc.; participated as a scientific advisory board member of Simcere Zaiming Pharmaceutical Co., Ltd., Shanghai Fosun Pharmaceutical, and Phanes Therapeutics, Inc.; and stock ownership and other financial or nonfinancial interests. Dr. O’Byrne reports consulting fees from TriStar; honoraria from Astellas, AstraZeneca, Bristol Myers Squibb, Janssen, Merck, Merck Sharp & Dohme, and Roche; travel support from Bayer; participation on a Data Safety Monitoring Board, Advisory Board, or other board or committee for AstraZeneca, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Ipsen, Janssen, Merck Sharp & Dohme, Pfizer, Roche, Takeda, TriStar, and Yuhan; and stock or stock options for Carpe Vitae Pharmaceuticals, DGC Diagnostics, and RepLuca Pharmaceuticals. Dr. John reports consulting fees from Roche, Merck, Merck Sharp & Dohme, Puma, AstraZeneca, Bristol Myers Squibb, Amgen, Gilead, and Specialised Therapeutics; and honoraria from AstraZeneca. Dr. Ciuleanu reports honoraria from Astellas, Janssen, Merck Sharp & Dohme, Merck Serono, Amgen, Roche, Pfizer, Sanofi Genzyme, Servier, Ipsen, AstraZeneca, Eli Lilly, Novartis, Boehringer Ingelheim, and Bristol Myers Squibb; and has participated on a Data Safety Monitoring Board or Advisory Board of Astellas, Janssen, Merck Sharp & Dohme, Merck Serono, Amgen, Roche, Pfizer, Sanofi Genzyme, Servier, Ipsen, AstraZeneca, Eli Lilly, Novartis, Boehringer Ingelheim, and Bristol Myers Squibb. Dr. Schenker has received funding from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Pfizer, GlaxoSmithKline, Roche, Bayer, Astellas, Amgen, Gilead, Tesaro, Clovis, Eli Lilly, Novartis, Regeneron, AbbVie, AstraZeneca, PharmaMar, Mylan, Samsung Pharmaceuticals, Bioven, BeiGene, and Daiichi Sankyo. Dr. Caro reports investigational grants from Roche; honoraria from Roche, Bristol Myers Squibb, Pfizer, Merck Sharp & Dohme, Amgen, Takeda, and AstraZeneca; and participation on a Data Safety Monitoring Board or Advisory Board for Takeda, Roche, Bristol Myers Squibb, and AstraZeneca. Dr. Nishio reports honoraria from Ono Pharmaceuticals, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, AstraZeneca, Merck Sharp & Dohme, AbbVie, Takeda, Pfizer, Boehringer Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen. Dr. Zurawski reports honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, and Roche. Dr. Pluzanski reports consulting fees from Roche and Amgen; honoraria from Bristol Myers Squibb, Roche, Merck Sharp & Dohme, Takeda, Amgen, Pfizer, and Astra; meeting or travel support from Bristol Myers Squibb, Takeda, Merck Sharp & Dohme, and Astra; and participation in Data Safety Monitoring Board or Advisory Board for Takeda, Sanofi, Bristol Myers Squibb, and Merck Sharp & Dohme. Dr. Aoyama is an employee and stockholder of Bristol Myers Squibb. Dr. Tschaika is an employee and stockholder of Bristol Myers Squibb. Dr. Devas is an employee and shareholder of Bristol Myers Squibb. Dr. Grootendorst is an employee and stockholder of Bristol Myers Squibb. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy., Methods: Adults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing EGFR/ALK alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting., Results: With a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1<1%, 0.66 (0.50 to 0.86) and ≥1%, 0.74 (0.60 to 0.92)) or histology (squamous, 0.64 (0.48 to 0.84) and non-squamous, 0.80 (0.66 to 0.97)). In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy due to TRAEs (n=61), the 4-year OS rate was 41%. With treatment-switching adjustment for the 36% of patients receiving subsequent immunotherapy in the chemotherapy arm, the estimated HR of nivolumab plus ipilimumab with chemotherapy versus chemotherapy was 0.66 (95% CI 0.55 to 0.80). No new safety signals were observed., Conclusions: In this 4-year update, patients treated with nivolumab plus ipilimumab with chemotherapy continued to have long-term, durable efficacy benefit over chemotherapy regardless of tumor PD-L1 expression and/or histology. A greater estimated relative OS benefit was observed after adjustment for subsequent immunotherapy use in the chemotherapy arm. These results further support nivolumab plus ipilimumab with chemotherapy as a first-line treatment for patients with metastatic/recurrent NSCLC, including those with tumor PD-L1<1% or squamous histology, populations with high unmet needs., Competing Interests: Competing interests: DPC has received consulting fees from Arcus Biosciences, Bristol Myers Squibb, BMS KK, Boehringer Ingelheim, Curio Science, Daiichi Sankyo, Genentech/Roche, GI Therapeutics (Intellisphere), GSK, Janssen, Merck, Mirati, Novartis, Novocure, OncoCyte, OncoHost, Roche China, and Seattle Genetics; and has participated on the advisory board of Amgen, Arcus Biosciences, AstraZeneca, Merck, Flame Biosciences, Gritstone Oncology, Cantargia (PPD), Daiichi Sankyo, EMD Serono GSK, Lilly, Regeneron, Sanofi, and Seattle Genetics and the data safety monitoring board of EORTC, AbbVie, and Lilly. T-EC has received honoraria from Astellas Pharma, Janssen, MSD, Merck Serono, Amgen, Roche, Pfizer, Sanofi Genzyme, Servier, Ipsen, AstraZeneca, Lilly, Novartis, Boehringer Ingelheim, and Bristol Myers Squibb; and has participated on a data safety monitoring board or advisory board of Astellas Pharma, Janssen, MSD, Merck Serono, Amgen, Roche, Pfizer, Sanofi Genzyme, Servier, Ipsen, AstraZeneca, Lilly, Novartis, Boehringer Ingelheim, and Bristol Myers Squibb. MS has received funding from Bristol Myers Squibb, MSD, Merck Serono, Pfizer, GSK, Roche, Bayer, Astellas, Amgen, Gilead, Tesaro, Clovis, Eli Lilly, Novartis, Regeneron, AbbVie, AstraZeneca, PharmaMar, Mylan, Samsung Pharmaceuticals, Bioven, BeiGene, and Daiichi Sankyo. OJ-V has received grants from AstraZeneca Spain, honoraria from Bristol Myers Squibb, Roche/Genentech, MSD Oncology, AstraZeneca/MedImmune, and Takeda; has served as a consultant for Bristol Myers Squibb, Lilly, Takeda, AstraZeneca Spain, and Janssen Oncology, and has received travel support from Takeda, AstraZeneca/MedImmune. NR has received honoraria from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, Hoffmann-La Roche, Janssen, Lilly, MSD, Merck, Pfizer, Symphogen, and Takeda; travel support from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Hoffmann-La Roche, and Takeda; and has participated on a data safety monitoring board or advisory board for Merck and Symphogen. BZ has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GSK, Janssen-Cilag, MSD and Roche. AA has received consulting fees from Boehringer Ingelheim and Roche, provided expert testimony for Bristol Myers Squibb, Novartis, and Sandoz, and received travel support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Roche, and Sanofi. LP-A has received grants or contracts from MSD, AstraZeneca, Pfizer, and Bristol Myers Squibb; consulting fees from Lilly, MSD, Roche, PharmaMar, Merck KGaA (Darmstadt, Germany), AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, Bristol Myers Squibb, Mirati, GSK, Janssen, Takeda, and Daichii Sankyo; honoraria from AstraZeneca, Janssen, Merck, and Mirati; and has participated on a data safety monitoring board or advisory board for Altum Sequencing and Genomica. SL has received consulting fees from AstraZeneca, Boehringer Ingelheim, Hutchinson MediPharma, Simcere, ZaiLab, GenomiCare, Roche, and Hanosh, and honoraria from AstraZeneca, Roche, and Hanosh. TJ has received consulting fees from Roche, Merck, MSD, Puma, AstraZeneca, Bristol Myers Squibb, Amgen, Gilead, and Specialised Therapeutics; and honoraria from AstraZeneca. XZ holds stock in Bristol Myers Squibb. IS has received consulting fees from Bristol Myers Squibb. JRP holds stock in Bristol Myers Squibb. AL holds stock in Bristol Myers Squibb. MR has received consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; travel support from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; and has participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, BeiGene, Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. 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This is a summary of a research article reporting Part A of the CheckMate 914 study (NCT03138512; EudraCT 2016-004502-34). Following surgery to remove renal cell carcinoma (RCC), people with a high risk of the cancer returning received nivolumab plus ipilimumab (adjuvant therapy) or placebo to see if this risk was reduced. The results of this study showed that the risk of RCC returning or death was not changed with adjuvant nivolumab plus ipilimumab treatment compared with placebo. In addition, people treated with nivolumab plus ipilimumab had more side effects compared with people treated with placebo (89% versus 57%)., (© 2023. The Author(s).)

Introduction: In CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years' minimum follow-up., Methods: Treatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only)., Results: Overall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months' minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43-0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66-0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed., Conclusions: With all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including BRCA1/2 alterations, can sensitize cancer cells to poly (ADP-ribose) polymerase inhibition, which may improve outcomes in treatment-naïve mCRPC when combined with androgen receptor signaling inhibition., Methods: MAGNITUDE (ClinicalTrials.gov identifier: NCT03748641) is a phase III, randomized, double-blinded study that evaluates niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in patients with (HRR+, n = 423) or without (HRR-, n = 247) HRR-associated gene alterations, as prospectively determined by tissue/plasma-based assays. Patients were assigned 1:1 to receive niraparib + AAP or placebo + AAP. The primary end point, radiographic progression-free survival (rPFS) assessed by central review, was evaluated first in the BRCA1/2 subgroup and then in the full HRR+ cohort, with secondary end points analyzed for the full HRR+ cohort if rPFS was statistically significant. A futility analysis was preplanned in the HRR- cohort., Results: Median rPFS in the BRCA1/2 subgroup was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.6 v 10.9 months; hazard ratio [HR], 0.53; 95% CI, 0.36 to 0.79; P = .001). In the overall HRR+ cohort, rPFS was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.5 v 13.7 months; HR, 0.73; 95% CI, 0.56 to 0.96; P = .022). These findings were supported by improvement in the secondary end points of time to symptomatic progression and time to initiation of cytotoxic chemotherapy. In the HRR- cohort, futility was declared per the prespecified criteria. Treatment with niraparib + AAP was tolerable, with anemia and hypertension as the most reported grade ≥ 3 adverse events., Conclusion: Combination treatment with niraparib + AAP significantly lengthened rPFS in patients with HRR+ mCRPC compared with standard-of-care AAP., [Media: see text].

Background: The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown., Methods: In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization., Results: Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P = 0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing., Conclusions: Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: CheckMate 651 (ClinicalTrials.gov identifier: NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance) in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN)., Methods: Patients without prior systemic therapy for R/M SCCHN were randomly assigned 1:1 to nivolumab plus ipilimumab or EXTREME. Primary end points were overall survival (OS) in the all randomly assigned and programmed death-ligand 1 combined positive score (CPS) ≥ 20 populations. Secondary end points included OS in the programmed death-ligand 1 CPS ≥ 1 population, and progression-free survival, objective response rate, and duration of response in the all randomly assigned and CPS ≥ 20 populations., Results: Among 947 patients randomly assigned, 38.3% had CPS ≥ 20. There were no statistically significant differences in OS with nivolumab plus ipilimumab versus EXTREME in the all randomly assigned (median: 13.9 v 13.5 months; hazard ratio [HR], 0.95; 97.9% CI, 0.80 to 1.13; P = .4951) and CPS ≥ 20 (median: 17.6 v 14.6 months; HR, 0.78; 97.51% CI, 0.59 to 1.03; P = .0469) populations. In patients with CPS ≥ 1, the median OS was 15.7 versus 13.2 months (HR, 0.82; 95% CI, 0.69 to 0.97). Among patients with CPS ≥ 20, the median progression-free survival was 5.4 months (nivolumab plus ipilimumab) versus 7.0 months (EXTREME), objective response rate was 34.1% versus 36.0%, and median duration of response was 32.6 versus 7.0 months. Grade 3/4 treatment-related adverse events occurred in 28.2% of patients treated with nivolumab plus ipilimumab versus 70.7% treated with EXTREME., Conclusion: CheckMate 651 did not meet its primary end points of OS in the all randomly assigned or CPS ≥ 20 populations. Nivolumab plus ipilimumab showed a favorable safety profile compared with EXTREME. There continues to be a need for new therapies in patients with R/M SCCHN.

Background: In CheckMate 9LA (NCT03215706), first-line nivolumab plus ipilimumab with chemotherapy (2 cycles) significantly improved overall survival versus chemotherapy (4 cycles) in patients with metastatic non-small cell lung cancer and no known sensitising epidermal growth factor receptor/anaplastic lymphoma kinase alterations. We present exploratory patient-reported outcomes (PROs; minimum follow-up, 2 years)., Methods: In patients (N = 719) randomised 1:1 to nivolumab plus ipilimumab with chemotherapy or chemotherapy alone, disease-related symptom burden and health-related quality of life were assessed using the Lung Cancer Symptom Scale (LCSS) and 3-level EQ-5D (EQ-5D-3L). Treatment-phase changes in LCSS average symptom burden index (ASBI), LCSS three-item global index (3-IGI) and EQ-5D-3L visual analogue scale (VAS) and utility index (UI) over time were analysed descriptively and using mixed-effect model repeated measures. Time-to-deterioration/improvement analyses were conducted., Results: Treatment-phase PRO questionnaire completion rates were >80%. Mean treatment-phase changes showed no deterioration from baseline in both arms for LCSS ASBI/3-IGI and EQ-5D-3L VAS/UI; however, minimally important differences were not met. Mixed-effect model repeated measures analyses showed overall reduction in symptom burden from baseline for both arms; changes from baseline for LCSS 3-IGI and EQ-5D-3L VAS/UI were numerically improved with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, but minimally important differences were not met. Nivolumab plus ipilimumab with chemotherapy delayed time-to-definitive-deterioration versus chemotherapy (LCSS ASBI: hazard ratio, 0.62 [95% confidence interval, 0.45-0.87]); results were similar across PRO measures., Conclusions: At 2-year minimum follow-up, first-line nivolumab plus ipilimumab with chemotherapy reduced the risk of definitive deterioration in disease-related symptom burden and health-related quality of life versus chemotherapy and maintained QoL in patients with metastatic non-small cell lung cancer., Clinical Trial Registration: ClinicalTrials.gov Identifier, NCT03215706., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Effective adjuvant therapy for patients with resected localised renal cell carcinoma represents an unmet need, with surveillance being the standard of care. We report results from part A of a phase 3, randomised trial that aimed to assess the efficacy and safety of adjuvant nivolumab plus ipilimumab versus placebo., Methods: The double-blind, randomised, phase 3 CheckMate 914 trial enrolled patients with localised clear cell renal cell carcinoma who were at high risk of relapse after radical or partial nephrectomy between 4-12 weeks before random assignment. Part A, reported herein, was done in 145 hospitals and cancer centres across 20 countries. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks for 12 doses plus ipilimumab (1 mg/kg) intravenously every 6 weeks for four doses, or matching placebo, via an interactive response technology system. The expected treatment period was 24 weeks, and treatment could be continued until week 36, allowing for treatment delays. Randomisation was stratified by TNM stage and nephrectomy (partial vs radical). The primary endpoint was disease-free survival according to masked independent central review; safety was a secondary endpoint. Disease-free survival was analysed in all randomly assigned patients (intention-to-treat population); exposure, safety, and tolerability were analysed in all patients who received at least one dose of study drug (all-treated population). This study is registered with ClinicalTrials.gov, NCT03138512., Findings: Between Aug 28, 2017, and March 16, 2021, 816 patients were randomly assigned to receive either adjuvant nivolumab plus ipilimumab (405 patients) or placebo (411 patients). 580 (71%) of 816 patients were male and 236 (29%) patients were female. With a median follow-up of 37·0 months (IQR 31·3-43·7), median disease-free survival was not reached in the nivolumab plus ipilimumab group and was 50·7 months (95% CI 48·1 to not estimable) in the placebo group (hazard ratio 0·92, 95% CI 0·71-1·19; p=0·53). The number of events required for the planned overall survival interim analysis was not reached at the time of the data cutoff, and only 61 events occurred (33 in the nivolumab plus ipilimumab group and 28 in the placebo group). 155 (38%) of 404 patients who received nivolumab plus ipilimumab and 42 (10%) of 407 patients who received placebo had grade 3-5 adverse events. All-cause adverse events of any grade led to discontinuation of nivolumab plus ipilimumab in 129 (32%) of 404 treated patients and of placebo in nine (2%) of 407 treated patients. Four deaths were attributed to treatment with nivolumab plus ipilimumab and no deaths were attributed to treatment with placebo., Interpretation: Adjuvant therapy with nivolumab plus ipilimumab did not improve disease-free survival versus placebo in patients with localised renal cell carcinoma at high risk of recurrence after nephrectomy. Our study results do not support this regimen for the adjuvant treatment of renal cell carcinoma., Funding: Bristol Myers Squibb and Ono Pharmaceutical., Competing Interests: Declaration of interests RJM reports clinical trial support (institutional) from Bristol Myers Squibb (BMS) for this manuscript; advisory board fees from AstraZeneca, AVEO, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer; and fees (institutional) for coordinating principal investigator from AVEO, BMS, Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer. VG reports medical writing and processing charges from BMS for this manuscript, research grants (institutional) from BMS, Ipsen, MSD, and Pfizer; speakers' bureau fees from Astellas, AstraZeneca, BMS, Eisai, Ipsen, Janssen-Cilag, Merck Serono, MSD, Nanobiotix, Novartis, Ono Pharmaceutical, Pfizer, and Roche; advisory board fees from Apogepha, BMS, Debiopharm, Eisai, EUSA, MSD, Nanobiotix, Oncorena, PCI Biotech, Pfizer, Roche, and Merck Serono; leadership roles (unpaid) with AIO and Das Lebenshaus for patient advocacy; stock options from AstraZeneca, BMS, MSD, and Seattle Genetics; steering committee membership for BMS, Eisai, Ipsen, and Novartis; and being trial chair for PharmaMar. YT reports research grants from Chugai and Ono Pharmaceutical; speakers' bureau fees from Astellas, BMS, Merck, and Ono Pharmaceutical; and advisory board fees from Eisai, Ono Pharmaceutical, and MSD. SB reports research grants from Novartis; speakers' bureau fees from BMS, Ipsen, MSD, and Novartis; payment for expert testimony from MSD, BMS, Ipsen, and Pfizer; advisory board fees from BMS, Ipsen, MSD, Novartis, and Pfizer; fees (institutional) for being a coordinating principal investigator from BMS and Ipsen; and being a member of AIOM and Meet-URO group. PB reports research grants from BMS, Ipsen, MSD, Pfizer, Merck, AstraZeneca, and Janssen-Cilag; consulting fees from BMS, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas, Amgen, and Gilead; honoraria from BMS, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas, Seagen, Novartis, and AAA; travel expense support from Pfizer, Merck, BMS, and Ipsen; and advisory board fees from Merck and Pfizer. JCG reports medical writing support from BMS for this manuscript; research grants (institutional) from BeiGene; honoraria from MSD and GlaxoSmithKline; travel expense support from AstraZeneca; advisory board fees from BMS, GlaxoSmithKline, MSD, Eisai, Janssen, and AstraZeneca; stock options from ICON Cancer Centres; meeting chair fees from Ipsen; and local principal investigator fees from BMS. J-BL reports consulting fees from BMS, Merck, Sanofi, Paladin, Pfizer, Novartis, Knights Pharmacy, Verity, and AbbVie; speakers' bureau fees from Tersera and Tolmar; advisory board fees from BMS, Knights Pharmacy, and Verity; being a local principal investigator for BMS; and being a member of AUA, Canadian Uro-Oncology Group, and Canadian Urological Association. LA reports research grants (institutional) from BMS, consulting fees (institutional) from BMS, Ipsen, Roche, Novartis, Pfizer, Astellas Pharma, Merck, MSD, AstraZeneca, Janssen, and Eisai; and travel support from BMS and MSD. SG reports advisory board fees from AVEO, Bayer, BMS, Corvus, Eisai, EMD Serono, Exelixis, Merck, Pfizer, QED Therapeutics, Sanofi/Genzyme, and Seattle Genetics; and non-financial interests from Agensys, Aravive, AVEO, Bayer, BMS, Calithera, Corvus, Eisai, Exelixis, Gilead, Merck, Novartis, Pfizer, Seattle Genetics, and Surface Oncology. BSh reports research grants (institutional) from Allogene and Rebiotix; royalties from Up to Date; consulting fees from Veracyte and Merck; speakers' bureau fees from Merck; advisory board fees from Genentech, Merck, and Johnson & Johnson; and board leadership fees from the National Cancer Institute PDQ. JSo reports consulting fees from Apexigen, Jazz Pharmaceuticals, and Iovance Biotherapeutics; and honoraria from Apexigen, Jazz Pharmaceuticals, and Iovance Biotherapeutics. MS reports support from BMS for this manuscript; grants from Pfizer, GlaxoSmithKline, AVEO, BMS, Novartis, Bayer, Roche/Genentech, Immatics, Wilex, Ipsen, Exelixis, and Eisai; consulting fees from Pfizer, GlaxoSmithKline, Novartis, Bayer, Roche AVEO, EUSA Pharma, Astellas, Ipsen, Exelixis, Peloton Therapeutics, Eisai, BMS, MSD, and Apogepha; and travel support from Pfizer, EUSA Pharma, Ipsen, Eisai, BMS, MSD, and Apogepha. BSi, JSp, and AC are employed by and have stock ownership in BMS. AB reports research grants from Pfizer, advisory board fees from the International Kidney Cancer Coalition and the Kidney Cancer Association; and being a local principal investigator and steering committee member for BMS and Roche/Genentech. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: We characterized the safety of first-line nivolumab plus ipilimumab (NIVO+IPI) in a large patient population with metastatic NSCLC and efficacy outcomes after NIVO+IPI discontinuation owing to treatment-related adverse events (TRAEs)., Methods: We pooled data from three first-line NIVO+IPI studies (NIVO, 3 mg/kg or 240 mg every 2 wk; IPI, 1 mg/kg every 6 wk) in metastatic NSCLC (CheckMate 227 part 1, CheckMate 817 cohort A, CheckMate 568 part 1). Safety end points included TRAEs and immune-mediated adverse events (IMAEs) in the pooled population and patients aged 75 years or older., Results: In the pooled population (N = 1255), any-grade TRAEs occurred in 78% of the patients, grade 3 or 4 TRAEs in 34%, and discontinuation of any regimen component owing to TRAEs in 21%. The most frequent TRAE and IMAE were diarrhea (20%; grade 3 or 4, 2%) and rash (17%; grade 3 or 4, 3%), respectively. The most common grade 3 or 4 IMAEs were hepatitis (5%) and diarrhea/colitis and pneumonitis (4% each). Pneumonitis was the most common cause of treatment-related death (5 of 16). Safety in patients aged 75 years or older (n = 174) was generally similar to the overall population, but discontinuation of any regimen component owing to TRAEs was more common (29%). In patients discontinuing NIVO+IPI owing to TRAEs (n = 225), 3-year overall survival was 50% (95% confidence interval: 42.6-56.0), and 42% (31.2-52.4) of 130 responders remained in response 2 years after discontinuation., Conclusions: First-line NIVO+IPI was well tolerated in this large population with metastatic NSCLC and in patients aged 75 years or older. Discontinuation owing to TRAEs did not reduce long-term survival., (Copyright © 2022. Published by Elsevier Inc.)

Background: Prostate cancer has a multifaceted treatment pattern. Evidence is lacking for optimal treatment sequences for metastatic castration-resistant prostate cancer (mCRPC)., Objective: To increase the understanding of real-world treatment pathways and outcomes in patients with mCRPC., Design Setting and Participants: A prospective, noninterventional, real-world analysis of 3003 patients with mCRPC in the Prostate Cancer Registry (PCR; NCT02236637) from June 14, 2013 to July 9, 2018 was conducted., Intervention: Patients received first- and second-line hormonal treatment and chemotherapy as follows: abiraterone acetate plus prednisone (abiraterone)-docetaxel (ABI-DOCE), abiraterone-enzalutamide (ABI-ENZA), abiraterone-radium-223 (ABI-RAD), docetaxel-abiraterone (DOCE-ABI), docetaxel-cabazitaxel (DOCE-CABA), docetaxel-enzalutamide (DOCE-ENZA), and enzalutamide-docetaxel (ENZA-DOCE)., Outcome Measurements and Statistical Analysis: Baseline patient characteristics, quality of life, mCRPC treatments, and efficacy outcomes (progression and survival) were presented descriptively., Results and Limitations: Data from 727 patients were eligible for the analysis (ABI-DOCE n  = 178, ABI-ENZA n  = 99, ABI-RAD n  = 27, DOCE-ABI n  = 191, DOCE-CABA n  = 74, DOCE-ENZA n  = 116, and ENZA-DOCE n  = 42). Demographics and disease characteristics among patients between different sequences varied greatly. Most patients who started on abiraterone or enzalutamide stopped therapy because of disease progression. No randomisation to allow treatment/sequence comparisons limited this observational study., Conclusions: The real-world PCR data complement clinical trial data, reflecting more highly selected patient populations than seen in routine clinical practice. Baseline characteristics play a role in mCRPC first-line treatment selection, but other factors, such as treatment availability, have an impact. Efficacy observations are limited and should be interpreted with caution., Patient Summary: Baseline characteristics appear to have a role in the first-line treatment selection of metastatic castration-resistant prostate cancer in the real-world setting. First-line abiraterone acetate plus prednisone seems to be the preferred treatment option for older patients and those with lower Gleason scores, first-line docetaxel for younger patients and those with more advanced disease, and first-line enzalutamide for patients with fewer metastases and more favourable performance status. The benefit to patients from these observations remains unknown., (© 2022 The Authors.)

Introduction: In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up., Methods: Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who discontinued nivolumab plus ipilimumab due to treatment-related AEs (TRAEs)., Results: After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65-0.90) and PD-L1 less than 1% (0.64; 0.51-0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 ≥1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemotherapy was rash; most immune-mediated AEs (except endocrine events) occurred within 6 months from start of treatment and resolved within 3 months after, mainly with systemic corticosteroids. Patients who discontinued nivolumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all randomized population., Conclusions: At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Gatipotuzumab is a humanized monoclonal antibody recognizing the carbohydrate-induced epitope of the tumor-associated mucin-1 (TA-MUC1). This study aimed to evaluate the efficacy and safety of switch maintenance therapy with gatipotuzumab in patients with TA-MUC1-positive recurrent ovarian, fallopian tube, or primary high-grade serous peritoneal cancer., Patients and Methods: In this double-blind, randomized, placebo-controlled, phase II trial, patients with at least stable disease (SD) following chemotherapy were randomized 2:1 to receive intravenous gatipotuzumab (500 mg followed by 1700 mg 1 week later) or placebo every 3 weeks until tumor progression or unacceptable toxicity occurred. Stratification factors were the number of prior chemotherapy lines (2 versus 3-5), response versus SD after the most recent chemotherapy, and progression-free survival (PFS) <6 versus 6-12 months following the prior therapy. Primary endpoint was PFS according to modified immune-related RECIST 1.1 response criteria. Secondary endpoints were PFS at 6 months, safety, overall response rate, CA-125 progression, overall survival, quality of life, and pharmacokinetics., Results: Overall, 216 patients were randomized to gatipotuzumab (n  =  151) or placebo (n  =  65). Median PFS with gatipotuzumab was 3.5 months as compared with 3.5 months with placebo (hazard ratio 0.96, 95% confidence interval 0.69-1.33, P  =  0.80). No advantage for gatipotuzumab over placebo was seen in the secondary efficacy endpoints or in any stratified subgroups. Gatipotuzumab was well tolerated, with mild to moderate infusion-related reactions being the most common adverse events., Conclusions: Gatipotuzumab switch maintenance therapy does not improve outcome in TA-MUC1-positive ovarian cancer patients., Trial Registration: ClinicalTrials.govNCT01899599; https://clinicaltrials.gov/ct2/show/NCT01899599., Competing Interests: Disclosure JL reports institutional research grant from AstraZeneca and MSD/Merck; serves on the steering group and advisory board of Pfizer; serves on the advisory board and provides lectures for AstraZeneca, Artios Pharma; GSK, MSD, Clovis Oncology, Eisai, and Neopharm; is a VBL Therapeutics Chair; is on the IDMC for Regeneron; is the Vice President of ESGO; and an editor of the ESMO Gynaecological Clinical Practice Guidelines; FR reports honoraria from GSK and MSD; is on the speakers bureau for GSK and MSD; reports travel, accommodations, expenses paid by GSK, MSD, and PharmaMar. UDG reports consultant fees from Janssen, Astellas Pharma, Sanofi, Bayer, Pfizer, BMS, Novartis, Ipsen, and Merck. JAA reports honoraria from Astellas Pharma and Pfizer; consulting or advisory role for Pfizer, Astellas Pharma, Janssen-Cilag, MSD, Bristol-Myers Squibb, EUSA Pharma, Merck, and AstraZeneca; and research funding from Bristol-Myers Squibb (institution); MRM reports grants from GSK, Pfizer, AstraZeneca, and Clovis; CC is on the advisory boards of Boehringer Ingelheim, Novartis, Pfizer, and Merck; reports lecture fees from AstraZeneca, BMS, Bayer, Ipsen, Astellas, MSD, and Sandoz; reports travel grants from Alvogen, Merck, and Boehringer Ingelheim; and reports educational grants from AstraZeneca. ACH reports grants or contracts from PharmaMar, AstraZeneca, Lilly, Eisai, and Tesaro/GSK; reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, PharmaMar, AstraZeneca, Lilly, Tesaro/GSK, and Deciphera; reports support for attending meetings and/or travel from PharmaMar, Roche, Lilly, GSK/Tesaro, and Merck; and reports participation on a data safety monitoring board or advisory board of PharmaMar, Roche, Merk, Lilly, Eisai, and Karyopharm; NC reports advisory and consultancy role for Roche, PharmaMar, AstraZeneca, MSD/Merk, Clovis Oncology, Tesaro, GSK, Novartis, Pfizer, Takeda, BIOCAD, Immunogen, Mersana, Eisai, and OncXerna MH reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK and Clovis Oncology; reports participation on a data safety monitoring board or advisory board of Amgen, GSK, and Clovis Oncology; reports receipt of equipment, materials, drugs, medical writing, gifts, or other services from Clovis Oncology, BMS, and Merck educational grants for clinical trials. AJ is employee at Premier Research, the CRO conducting the study. IA-F, AZ, and HB are employees or consultants at Glycotope, the sponsor of the study. In addition, HB owns stock or stock option of Glycotope. JS reports grants or contracts from Roche, GSK, AstraZeneca, Clovis, MSD, Merck, and Eisai; and participation in advisory boards at Roche, GSK, AstraZeneca, Clovis, MSD, Merck, Eisai as well as a Congress Leadership President at NOGGO. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA trial with a 2-year minimum follow-up., Patients and Methods: Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs., Results: With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months [hazard ratio 0.72 (95% confidence interval 0.61-0.86)]; 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation., Conclusions: With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer., Competing Interests: Disclosure MR reports advisory/consulting fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Mirati Therapeutics, MSD Oncology, Novartis, Pfizer, Roche/Genentech, and Samsung Bioepis; speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Merck Serono, Mirati Therapeutics, MSD Oncology, Novartis, Pfizer, and Roche/Genentech. TEC reports advisory/consulting fees and travel, accommodation, and expenses from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen, Merck Sharp & Dohme (MSD), Novartis/GlaxoSmithKline, Pfizer, Roche, Sanofi, and Servier. MS reports research funding from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Clovis, Eli Lilly, Gilead Sciences, GlaxoSmithKline, MSD, Novartis, Pfizer/EMD Serono, Regeneron, Roche, and Tesaro; travel, accommodation, and expenses from Bristol Myers Squibb. BZ reports research funding from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen-Cilag, MSD, and Roche. JB reports advisory/consulting fees and honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Roche, and Servier; travel, accommodation, and expenses from AstraZeneca and Roche. EF reports advisory fees from AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Blue Print Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Medical Trends, Merck KGaA, MSD, Novartis, Peptomyc, Pfizer, Puma Biotechnology, Regeneron, Roche, Sanofi Genzyme, Syneos Health, Takeda; independent board member of Grifols; research funding from Grant for Oncology Innovation and Fundación Merck Salud; speaker fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Medscape, MSD, Novartis, PeerVoice, Pfizer, Prime Oncology, Roche, Springer, Takeda, Touch Medical, and CME Outfitters. OJV reports advisory/consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, Lilly, MSD, Roche/Genetech, and Takeda; honoraria from AstraZeneca/MedImmune, Bristol Myers Squibb, MSD Oncology, and Roche/Genentech; research funding from AstraZeneca Spain; speaker fees from Roche/Genentech; travel, accommodation, and expenses from Boehringer Ingelheim, Bristol Myers Squibb, MSD, and Roche/Genentech. AA reports advisory/consulting fees from Boehringer Ingelheim Pharmaceuticals Inc and Roche; expert testimony fees for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Roche, and Sanofi; speaker fees from Bristol Myers Squibb, Novartis, and Sandoz; travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Roche, and Sanofi. HS reports research funding from AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Merck KGaA, MSD K.K, Ono Pharmaceutical, and Taiho Pharmaceutical; speaker fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb Japan, Chugai Pharma, MSD K.K, Ono Pharmaceutical, and Taiho Pharmaceutical. FR reports consulting and speaker fees from Novartis; travel, accommodation, and expenses from Roche. PJS reports non-financial support from AstraZeneca, Bristol Myers Squibb, MSD, and Roche; personal fees from AstraZeneca, Bristol Myers Squibb, Novartis, and Roche; research funding from AstraZeneca, Bristol Myers Squibb, Novartis, MSD, and Roche. CM reports advisory and speaker fees from AstraZeneca, Bristol Myers Squibb, and MSD. MP reports advisory fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; research funding from AstraZeneca, Boehringer Ingelheim, Chugai, Roche, and Takeda; speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, MSD, Pfizer, Roche, and Takeda; travel support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, MSD, Pfizer, Roche, and Takeda. AS reports expert testimony fees from AstraZeneca/MedImmune, Bristol Myers Squibb, MSD Oncology, and Roche; research funding from Bristol Myers Squibb; speaker fees from AstraZeneca/MedImmune; travel, accommodation, and expenses from AstraZeneca/MedImmune, Bristol Myers Squibb, MSD Oncology, and Roche. SL reports advisory/consulting fees from AstraZeneca, Boehringer Ingelheim, Hutchison MediPharma, Roche, and Simcere; research funding from AstraZeneca, Bristol Myers Squibb, Hutchison MediPharma, Heng Rui, and Roche; speaker fees from AstraZeneca, Hanseng, and Roche. LPA reports honoraria from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Celgene, Ipsen, Eli Lilly, Merck Serono, Mirati Therapeutics, MSD, Novartis, Pfizer, PharmaMar, Roche/Genentech, Sanofi, Servier, and Takeda; leadership fees from Genomica and ALTUM Sequencing; research funding from AstraZeneca, Bristol Myers Squibb, Kura Oncology, PharmaMar, and MSD; speaker fees from Bristol Myers Squibb, Eli Lilly, Merck Serono, MSD Oncology, Pfizer, Roche/Genentech; travel, accommodation, and expenses from AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Roche, and Takeda. DPC reports advisory/consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Bristol Myers Squibb Japan, Curio Science, Daiichi Sankyo, Eli Lilly, EMD Serono, Flame Biosciences, G1 Therapeutics (Intellisphere), Geneplus, GlaxoSmithKline, Gloria Biosciences, Incyte, Inivata, Inovio Pharmaceutical, Janssen, Johnson & Johnson, Kyowa Hakko Kirin, Loxo, Merck, Merck KGaA, MSD, Novartis, Novocure, Oncocyte, OncoHost, Pfizer, Piper Sandler, Roche/Genentech, Sanofi, and Takeda; employment with James Cancer Center; honoraria from AstraZeneca and Nexus Pharmaceutical; research funding from Bristol Myers Squibb. AM is an employee of and has stock ownership in Bristol Myers Squibb. SM is an employee of and has stock ownership in Bristol Myers Squibb; was employed as a contractor by Sanofi (Rangam Consultants Inc); reports travel, accommodation, and expenses from Bristol Myers Squibb. XZ is an employee of Bristol Myers Squibb. PT is an employee of and has stock ownership in Bristol Myers Squibb. TJ reports advisory/consulting fees from AstraZeneca, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol Myers Squibb, Ignyta, Merck KGaA, MSD Oncology, Novartis, Pfizer, and Roche/Genentech; honoraria from AstraZeneca/MedImmune, Bristol Myers Squibb, MSD Oncology, and Roche/Genentech; travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, and Roche. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: In CheckMate 227 (NCT02477826), patients with treatment-naive stage IV or recurrent NSCLC and 1% or greater tumor programmed death ligand 1 expression had significantly improved overall survival with nivolumab plus ipilimumab versus chemotherapy. We present the patient-reported outcomes (PROs)., Methods: Patients (N = 1189) were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy. PROs were exploratory. Changes in Lung Cancer Symptom Scale (LCSS) average symptom burden index, LCSS 3-item global index, EQ-5D visual analog scale (VAS), and EQ-5D utility index were analyzed descriptively. Mixed-effect model repeated measures and time-to-first deterioration and improvement analyses were conducted., Results: PRO completion rates were generally greater than 80%. On-treatment improvements from baseline in LCSS measures of symptom burden and global health status with nivolumab plus ipilimumab generally met or exceeded the minimal important difference (smallest clinically meaningful change) from weeks 24 and 30, respectively; improvements with chemotherapy generally remained below the minimal important difference. Mean on-treatment EQ-5D VAS scores for both treatments approached the U.K. population norm at week 24, remaining so throughout the treatment period. Mixed-effect model repeated measures analyses revealed numerically greater improvements from baseline with nivolumab plus ipilimumab versus chemotherapy across LCSS average symptom burden index and 3-item global index, and EQ-5D VAS and utility index. Nivolumab plus ipilimumab had delayed time-to-first deterioration (hazard ratio [95% confidence interval] 0.74 [0.56 to 0.98]) and a trend for more rapid time-to-first improvement (1.24 [0.98 to 1.59]) versus chemotherapy., Conclusions: Nivolumab plus ipilimumab revealed delayed deterioration and numerical improvement in symptoms and health-related quality of life versus chemotherapy in patients with advanced NSCLC and 1% or greater programmed death ligand 1 expression., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)