Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142.

Background: In the phase II multicohort CheckMate 142 study, nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at 13.4- and 25.4-month median follow-up (Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779. Overman MJ, Lonardi S, Wong KYM, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: long-term follow-up. J Clin Oncol. 2019;37:635). Here, we present results from the 4-year follow-up of these patients.
Patients and Methods: Patients received nivolumab (3 mg/kg) plus low-dose (1 mg/kg) ipilimumab every 3 weeks (four doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1).
Results: A total of 119 patients were treated; 76% had ≥2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7 months). Median duration of therapy was 24.9 months [95% confidence interval (CI) 15.8-33.2 months]. Investigator-assessed ORR increased from 55% (95% CI 45% to 64%) at 13.4 months to 65% (95% CI 55% to 73%) at 50.9 months with a disease control rate of 81% (95% CI 72% to 87%). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease. Median time to response was 2.8 months (range 1.1-37.1 months), and median duration of response was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 (48%) patients had ongoing responses. Median progression-free survival was not reached [95% CI 38.4 months-not estimable (NE)], and median overall survival was not reached (95% CI NE). Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 13% of patients had any-grade TRAEs leading to discontinuation.
Conclusions: The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. The safety profile was manageable with no new safety signals.
Competing Interests: Disclosure TA reports support for the present manuscript from Bristol Myers Squibb; consulting roles for Bristol Myers Squibb, Gritstone Oncology, GlaxoSmithKline, Merck & Co., Pierre Fabre, Seagen, and Servier; honoraria from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck & Co., Pierre Fabre, Roche/Ventana, Sanofi, and Servier; travel/meetings funding from Bristol Myers Squibb and Roche; and participation in advisory boards for Amgen, Astellas Pharma, Bristol Myers Squibb, Gritstone Oncology, Haliodx, Kaleido Biosciences, Merck & Co., Pierre Fabre, and Servier. SL reports research funding from Amgen, Merck Serono, Bayer, Roche, Eli Lilly, AstraZeneca, and Bristol Myers Squibb; honoraria from Roche, Eli Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, and Amgen; and participation in advisory boards for Amgen, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Servier, and Merck Sharp & Dohme. KYMW reports consulting roles for Merck & Co., Novartis, Ipsen, and Sirtex. FG reports honoraria for speaker/advisory roles from Servier, Eli Lilly, IQVIA, Merck Serono, Amgen, and Bristol Myers Squibb, outside the present work. HJL reports consulting roles for Bayer, Merck & Co., Roche, Bristol Myers Squibb, Merck KGaA, Oncocyte, Fulgent, Jazz Therapeutics, and 3T Bioscience. MAM reports support for the present manuscript from Bristol Myers Squibb; grants from Merck & Co. and Amal; and honoraria from Genentech/Roche. EVC reports participation in advisory boards for AbbVie, Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Halozyme, GlaxoSmithKline, Helsinn, Incyte, Ipsen, Janssen Research, Eli Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabre, Roche, Seattle Genetics, Servier, Sirtex, Terumo, Taiho, TRIGR, and Zymeworks; and research grants from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ipsen, Eli Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, and Servier, paid to his institution. RMD reports personal fees and non-financial support from Pfizer and Janssen; grants from Amgen, Bristol Myers Squibb, and Merck; grants and personal fees from Bayer; non-financial support from Celgene; and personal fees from Clovis. MBS reports support for the present manuscript from Bristol Myers Squibb; grants from AstraZeneca, Alberta Cancer Foundation, Alberta Health Services Strategic Network (Seed Grant Competition), Rexahn, Eli Lilly, Canadian Institutes of Health Research, Bristol Myers Squibb, and Celgene; consulting fees from Ipsen, Bristol Myers Squibb, and Merck & Co.; honoraria from Mylan, Ipsen, Bristol Myers Squibb, and AstraZeneca; support for meetings and travel from Novartis; and holds a patent (number 61/406,856). BN reports support for the present manuscript from Bristol Myers Squibb. SA reports owning stocks and being an employee of Bristol Myers Squibb. AM and MD report being employees of Bristol Myers Squibb. ML reports being an employee of, owning stock in, and being an inventor of patents filed/owned by Bristol Myers Squibb. SK reports consulting or advisory role from Genentech, Merck, Amal Therpeutics, Holy Stone, Novartis, Eli Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, EMD Serono, Redx Pharma, Jacobio, Natera, Repare Therapeutics, Daiichi Sankyo, Lutris, Pfizer, Ipsen, HalioDx, Inivata, GlaxoSmithKline, Jazz Pharmaceuticals, Iylon, Xilis, AbbVie, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotechnology, Bicara Therapeutics, Endeavor BioMedicines, Numab Pharma, Johnson & Johnson/Janssen, Genomic Health, Frontier Medicines, Replimune, and Taiho Pharmaceutical; research funding from Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis, Amgen, Eli Lilly, and Daiichi Sankyo; and stock and other ownership interests from MolecularMatch, Lutris, Iylon, and Frontier Medicines. MJO reports consulting fees from Merck Sharp & Dohme, AbbVie, Agilvax, Takeda, Acrotech Biopharma, and Novartis. All other authors have declared no conflicts of interest. Data sharing BMS policy on data sharing can be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.
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