학술논문
Four-year clinical update and treatment switching-adjusted outcomes with first-line nivolumab plus ipilimumab with chemotherapy for metastatic non-small cell lung cancer in the CheckMate 9LA randomized trial.
Document Type
Academic Journal
Author
Carbone DP; Division of Medical Oncology and the Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA david.carbone@osumc.edu.; Ciuleanu TE; Department of Medical Oncology, Institutul Oncologic Prof Dr Ion Chiricută and University of Medicine and Pharmacy Iuliu Haţieganu, Cluj-Napoca, Romania.; Schenker M; Department of Medical Oncology, SF Nectarie Oncology Center, Craiova, Romania.; Cobo M; Department of Medical Oncology, Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, Málaga, Spain.; Bordenave S; L'institut du Thorax, Nantes, France.; Juan-Vidal O; Department of Medical Oncology, Hospital Universitario La Fe, Valencia, Spain.; Menezes J; Department of Oncology, Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil.; Reinmuth N; Department of Oncology, Asklepios Lung Clinic, German Center for Lung Research, Munich-Gauting, Germany.; Richardet E; Department of Clinical Oncology, IONC Instituto Oncológico de Córdoba, Córdoba, Argentina.; Cheng Y; Department of Oncology, Jilin Cancer Hospital, Changchun, Jilin, China.; Mizutani H; Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan.; Felip E; Medical Oncology Service, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; Zurawski B; Chemotherapy Department, Ambulatorium Chemioterapii, Bydgoszcz, Poland.; Alexandru A; Department of Oncology, Institute of Oncology Prof Dr Alexandru Trestioreanu Bucha, Bucharest, Romania.; Paz-Ares L; Medical Oncology Department, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain.; Lu S; Department of Medical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai JiaoTong University, Shanghai, China.; John T; Medical Oncology Department, Austin Hospital, Heidelberg, Victoria, Australia.; Zhang X; Global Drug Development, Oncology Clinical Development, Bristol Myers Squibb, Princeton, New Jersey, USA.; Mahmood J; Global Drug Development, Oncology Clinical Development, Bristol Myers Squibb, Princeton, New Jersey, USA.; Hu N; Global Biometrics and Data Sciences, Bristol Myers Squibb, Princeton, New Jersey, USA.; De T; Parexel, Billerica, Massachusetts, USA.; Santi I; Parexel, Billerica, Massachusetts, USA.; Penrod JR; Global Drug Development, Oncology Clinical Development, Bristol Myers Squibb, Princeton, New Jersey, USA.; Yuan Y; Global Drug Development, Oncology Clinical Development, Bristol Myers Squibb, Princeton, New Jersey, USA.; Lee A; Global Drug Development, Oncology Clinical Development, Bristol Myers Squibb, Princeton, New Jersey, USA.; Reck M; Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, Lung Clinic, Grosshansdorf, Germany.
Source
Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE
Subject
Language
English
Abstract
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. See rights and permissions. Published by BMJ.)
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. See rights and permissions. Published by BMJ.)