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Background: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings., Methods: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients., Results: The median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and pathological complete response across most subgroups favored nivolumab plus chemotherapy over chemotherapy alone. At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did not meet the criterion for significance. Of the patients who underwent randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4% of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group., Conclusions: In patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery. (Funded by Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up., Patients and Methods: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs)., Results: With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61-0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation., Conclusions: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology., Competing Interests: Disclosures SP reports advisory/consultancy roles for AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, IQVIA, Incyte, Janssen, Medscape, MSD, Merck Serono, Merrimack, Novartis, Pharma Mar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, Roche/Genentech, RTP, Sanofi, Seattle Genetics, and Takeda; has received research funding from Amgen, AstraZeneca, Biodesiex, Boehringer Ingelheim, BMS, Clovis, GSK, Illumina, Lilly, MSD, Merck Serono, Mirati, Novartis, Phosplatin Therapeutics, Pfizer, Roche/Genentech, as well as trial investigator roles for Amgen, AstraZeneca, Biodesiex, Boehringer Ingelheim, BMS, Clovis, GSK, Illumina, Lilly, MSD, Merck Serono, Mirati, Novartis, Phosplatin Therapeutics, Pfizer, Roche/Genentech; and has had speaker engagements for AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Illumina, Medscape, MSD, Novartis, PER, Pfizer, PRIME, Roche/Genentech, RTP, Sanofi, and Takeda. AS has received advisory/consultancy roles for AstraZeneca, BMS, MSD, and Roche; speaker engagements and expert testimony for AstraZeneca, BMS, and MSD; has received travel support from AstraZeneca, BMS, MSD, and Roche; and research funding from BMS. RC has received speaker fees from Roche, Pfizer, and BMS; and has participated in advisory boards for Roche, MSD, and Spectrum. YO reports advisory board roles for BMS, MSD, and AstraZeneca. LG reports advisory roles for AstraZeneca, BMS, Boehringer Ingelheim, MSD, Roche, Takeda, AbbVie, Pfizer, and Novartis. TT has received honoraria for advisory board participation, financial support, travel support for conferences, and speaker fees, all from BMS. IM has received non-financial congress support from Pfizer and Roche. SH has participated in advisory boards for Takeda and AstraZeneca. PB reports advisory/consultancy roles for BMS, Takeda, Beigene, AstraZeneca, MSD, Roche, Epizyme, Trizell, and Daiichi Sankyo; and has received research funding from BMS. AKN has received honoraria for consultant/advisory roles for Bayer, PharmAbcine, Trizell, Roche, Boehringer Ingelheim, MSD, Douglas Pharmaceuticals, and Atara Biotherapeutics; received research funding from Douglas Pharmaceuticals and AstraZeneca; and travel support from Boehringer Ingelheim and AstraZeneca. NF has received honoraria from BMS and ONO Pharmaceuticals and reports advisory/consultancy roles and receiving research funding from ONO Pharmaceuticals. AST has received advisory board roles for Ariad, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, EMD Serono, Genentech, Merck, Novartis, Roche, Seattle Genetics, Sellas Life Science, and Takeda; and has received research grants from EMD Serono, Epizyme, Millennium, Polaris, and Seattle Genetics. ASM has received honoraria for advisory roles from AbbVie, AstraZeneca, BMS, Genentech, and Janssen; travel support from AbbVie and Roche; received research funding from Novartis, Verily, Mark Foundation, and NIH; and is a non-remunerated member of the Mesothelioma Applied Research Foundation board. SP has participated in advisory boards for Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Daiichi Sankyo, Guardant Health, Janssen, Lilly, Merck KGaA, Novartis, Roche, and Takeda; and has been a clinical trial investigator for Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Roche, Takeda, Ariad, Celgene, GSK, MSD, Trizell, and Turing Point Therapeutics. XZ, NH, DB, and TS are employees of BMS. TS also has BMS stocks. GZ receives honoraria from AstraZeneca, BMS, and Roche; reports advisory/consultancy roles for AstraZeneca, BMS, Roche, MSD, Da Volterra, and Inventiva; has received travel support from AstraZeneca, BMS, Roche, Boehringer, AbbVie, and Pfizer; and research funding from Roche and Inventiva. MAK has declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)