Abstract
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.
Original language | English (US) |
---|---|
Pages (from-to) | 289-308 |
Number of pages | 20 |
Journal | Journal of Thoracic Oncology |
Volume | 17 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2022 |
Externally published | Yes |
Keywords
- CTLA-4
- First-line
- Immunotherapy
- Metastatic non–small cell lung cancer
- PD-1 checkpoint inhibitor
ASJC Scopus subject areas
- Oncology
- Pulmonary and Respiratory Medicine
Fingerprint
Dive into the research topics of 'First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
In: Journal of Thoracic Oncology, Vol. 17, No. 2, 02.2022, p. 289-308.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC
T2 - 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial
AU - Paz-Ares, Luis G.
AU - Ramalingam, Suresh S.
AU - Ciuleanu, Tudor Eliade
AU - Lee, Jong Seok
AU - Urban, Laszlo
AU - Caro, Reyes Bernabe
AU - Park, Keunchil
AU - Sakai, Hiroshi
AU - Ohe, Yuichiro
AU - Nishio, Makoto
AU - Audigier-Valette, Clarisse
AU - Burgers, Jacobus A.
AU - Pluzanski, Adam
AU - Sangha, Randeep
AU - Gallardo, Carlos
AU - Takeda, Masayuki
AU - Linardou, Helena
AU - Lupinacci, Lorena
AU - Lee, Ki Hyeong
AU - Caserta, Claudia
AU - Provencio, Mariano
AU - Carcereny, Enric
AU - Otterson, Gregory A.
AU - Schenker, Michael
AU - Zurawski, Bogdan
AU - Alexandru, Aurelia
AU - Vergnenegre, Alain
AU - Raimbourg, Judith
AU - Feeney, Kynan
AU - Kim, Sang We
AU - Borghaei, Hossein
AU - O'Byrne, Kenneth John
AU - Hellmann, Matthew D.
AU - Memaj, Arteid
AU - Nathan, Faith Ellen
AU - Bushong, Judith
AU - Tran, Phuong
AU - Brahmer, Julie R.
AU - Reck, Martin
N1 - Funding Information: This study was supported by Bristol Myers Squibb and Ono Pharmaceutical Company Ltd. We thank the patients and families who made this trial possible; the investigators and clinical study teams ( Supplementary Appendix ) who participated in the trial; Lisa Benson of Bristol Myers Squibb for her contributions as trial manager; Ang Li of Bristol Myers Squibb for his contributions as study statistician; Dako, an Agilent Technologies, Inc. company, for collaborative development of the programmed death-ligand 1 immunohistochemistry 28-8 pharmDx assay; and Bristol Myers Squibb and Ono Pharmaceutical Company Ltd. Professional medical writing support was provided by Nick Patterson of Caudex, London, United Kingdom, and was funded by Bristol Myers Squibb. Funding Information: Disclosure: Dr. Paz-Ares reports receiving honoraria from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Celgene, Ipsen, Eli Lilly, Merck Serono, Mirati Therapeutics, Merck Sharp & Dohme, 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 Merck Sharp & Dohme; speaker fees from Bristol Myers Squibb, Eli Lilly, Merck Serono, Merck Sharp & Dohme Oncology, Pfizer, and Roche/Genentech; and travel, accommodation, and expenses from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, and Takeda. Dr. Ramalingam reports receiving advisory/consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, GlaxoSmithKline, Lilly, Merck, Roche/Genentech, Sanofi, and Takeda and research funding from Advaxis, AstraZeneca, Bristol Myers Squibb, EMD Serono, Genmab, GlaxoSmithKline, Merck, Takeda, and Tesaro. Dr. Ciuleanu reports receiving advisory/consulting fees and travel, accommodation, and expenses from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen, Merck Sharp & Dohme, Novartis/GlaxoSmithKline, Pfizer, Roche, Sanofi, and Servier. Dr. J-S. Lee reports receiving advisory/consulting fees from AstraZeneca and Ono Pharmaceutical. Dr. Urban reports receiving travel, accommodation, and expenses from Roche. Dr. Caro reports receiving advisory/consulting fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, and Takeda. Dr. Park reports receiving advisory/consulting fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Johnson and Johnson, Lilly, LOXO, Merck KGaA, Ono Pharmaceutical, and Puma Biotechnology; speaker bureau fees from Boehringer Ingelheim; and research funding from AstraZeneca and Merck Sharp & Dohme Technology. Dr. Sakai reports receving research funding from AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Merck KGaA, Merck Sharp & Dohme K.K., Ono Pharmaceutical, and Taiho Pharmaceutical and speaker bureau fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb Japan, Chugai Pharma, Merck Sharp & Dohme K.K., Ono Pharmaceutical, and Taiho Pharmaceutical. Dr. Ohe reports receiving advisory/consulting fees from Amgen, AstraZeneca, Celltrion, Chugai Pharmaceutical, Kyorin, Lilly Japan, Novartis, Ono Pharmaceutical, and Takeda; honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb Japan, Celltrion, Chugai Pharmaceutical, Kyorin, Kyowa Kim, Lilly Japan, Merck Sharp & Dohme, Nippon Kayaki, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda; and research funding from AstraZeneca, Bristol Myers Squibb Japan, Chugai Pharmaceutical, Janssen, Kissei Pharmaceutical, Kyorin, Lilly Japan, LOXO, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda. Dr. Nishio reports receiving advisory/consulting fees from AbbVie, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, and Teijin Pharma; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Janssen, Lilly, Merck, Merck Sharp & Dohme, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda; and research funding from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Janssen, Lilly, Merck, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda. Dr. Audigier-Valette reports receiving advisory/consulting fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Eli Lilly, Novartis, Pfizer, and Roche. Dr. Burgers reports receiving advisory/consulting fees from Roche and research funding from Merck Sharp & Dohme. Dr. Pluzanski reports receiving expert testimony fees from Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, and Roche; speaker bureau fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche; and travel, accommodations, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and Merck Sharp & Dohme. Dr. Sangha reports receiving advisory/consulting fees from AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and Takeda and honoraria from AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and Takeda. Dr. Gallardo reports receiving advisory/consulting fees from AstraZeneca and Merck Sharp & Dohme; expert testimony from AstraZeneca and Novartis; honoraria from AstraZeneca, Merck Sharp & Dohme, Novartis, and Roche; and travel, accommodations, and expenses from Merck Sharp & Dohme and Roche. Dr. Takeda reports receiving personal fees from AstraZeneca K.K., Bristol Myers Squibb, Chugai Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma K.K., and Ono Pharmaceutical. Dr. Linardou reports receiving advisory fees from Amgen, AstraZeneca, Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pfizer, and Roche and expert testimony fees and speaker bureau fees from AstraZeneca. Dr. K. H. Lee reports receiving advisory fees from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, and Pfizer. Dr. Provencio reports receiving fees for expert testimony from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, and Takeda and honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, and Takeda. Dr. Otterson reports receiving advisory/consulting fees from AstraZeneca, Bristol Myers Squibb, and Turning Point; data safety committee fees from Novocure; and research funding from Astellas, AstraZeneca, Bristol Myers Squibb, Genentech, Merck, and Pfizer. Dr. Schenker reports receiving research funding from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Clovis, Gilead Sciences, GlaxoSmithKline, Lilly, Merck Sharp & Dohme, Novartis, Pfizer/EMD Serono, Regeneron, Roche, and Tesaro and travel, accommodations, and expenses from Bristol Myers Squibb. Dr. Zurawski reports receiving research funding from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, and Roche. Dr. Alexandru reports receiving advisory/consulting fees for Boehringer Ingelheim Pharmaceuticals Inc. and Roche; expert testimony fees for AstraZeneca, Boehringer Ingelheim Pharmaceuticals Inc., Bristol Myers Squibb, Pfizer, Roche, and Sanofi; speaker bureau fees for Bristol Myers Squibb, Novartis, and Sandoz; and travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim Pharmaceuticals Inc., Bristol Myers Squibb, Pfizer, Roche, and Sanofi. Dr. Vergnenegre reports receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Hoffman Laroche, Merck Sharp & Dohme/Merck, and Pierre Fabre Oncologie. Feeney reports receiving research funding from Bristol Myers Squibb and speaker bureau fees from Bristol Myers Squibb. Borghaei reports receiving advisory/consulting fees from AbbVie, Amgen, AstraZeneca, BioNTech AG, Boehringer Ingelheim, Bristol Myers Squibb, Cantargia AB, Celgene, Eli Lilly, EMD Serono, Genentech, Genmab, HUYA Bioscience International, Merck, Novartis, Nuclaei, Pfizer, PharmaMar, Regeneron, Rgenix, Sonnet, Takeda, and Trovagene; honoraria from Amgen, Axiom Biotechnologies, Bristol Myers Squibb, Celgene, Eli Lilly, and Pfizer; research funding from Bristol Myers Squibb, Celgene, Eli Lilly, Merck, and Millennium; stock ownership in Nuclaei, Rgenix, and Sonnet; travel, accommodations, and expenses from Amgen, Bristol Myers Squibb, Celgene, Clovis Oncology, Eli Lilly, Genentech, Merck, and Novartis; and others from Incyte and University of Pennsylvania. Dr. O'Byrne is a board member for Carpe Vitae Pharmaceuticals; reports receiving advisory/consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen-Cilag, Merck Sharp & Dohme, Natera, Novartis, Pfizer, Roche/Genentech, Teva, and TriStar; receiving speakers bureau fees from Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen-Cilag, Merck Sharp & Dohme, Mundipharma, Pfizer, and Roche/Genentech; receiving travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche/Genentech; and being a shareholder at Carpe Vitae Pharmaceuticals and RepLuca Pharmaceuticals. Dr. Hellmann reports receiving advisory/consulting fees from Achilles, Arcus, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Eli Lilly, Janssen, Immunani, Instil Bio, Mana Therapeutics, Merck, Mitrati, Natera, Nektar, Pact Pharma, Regeneron, Roche/Genentech, Shattuck Labs, and Syndax; receiving research funding from Bristol Myers Squibb; and having stock ownership in Arcus, Factorial, Immunani, and Shattuck Labs. Mr. Memaj is an employee of and has stock ownership in Bristol Myers Squibb. Dr. Nathan is an employee of Bristol Myers Squibb and reports having stock ownership in AstraZeneca, Eli Lilly, Gilead Sciences, and Johnson & Johnson. Ms. Bushong is an employee of and has stock ownership in Bristol Myers Squibb. Dr. Tran is an employee of and has stock ownership in Bristol Myers Squibb. Dr. Brahmer reports receiving advisory/consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Genentech, GlaxoSmithKline, Merck, Regeneron, and Sanofi; honoraria from Roche/Genentech; research funding from AstraZeneca, Bristol Myers Squibb, RAPT Therapeutics, Revolution, Roche/Genentech, and Spectrum Pharmaceuticals; travel, accommodations, and expenses from Bristol Myers Squibb and Roche/Genentech; and other from Janssen Oncology. Dr. Reck reports advisory/consulting fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Mirati Therapeutics, Merck Sharp & Dohme Oncology, Novartis, Pfizer, Roche/Genentech, and Samsung Bioepis and speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Merck Serono, Mirati Therapeutics, Merck Sharp & Dohme Oncology, Novartis, Pfizer, and Roche/Genentech. The remaining authors declare no conflict of interest. Publisher Copyright: © 2021 International Association for the Study of Lung Cancer
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
KW - CTLA-4
KW - First-line
KW - Immunotherapy
KW - Metastatic non–small cell lung cancer
KW - PD-1 checkpoint inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85119665843&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85119665843&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2021.09.010
DO - 10.1016/j.jtho.2021.09.010
M3 - Article
C2 - 34648948
AN - SCOPUS:85119665843
SN - 1556-0864
VL - 17
SP - 289
EP - 308
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 2
ER -