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Ref Type Journal Article
PMID (29355075)
Authors Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, Morse MA, Van Cutsem E, McDermott R, Hill A, Sawyer MB, Hendlisz A, Neyns B, Svrcek M, Moss RA, Ledeine JM, Cao ZA, Kamble S, Kopetz S, André T
Title Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer.
Journal Vol Issue Date Pages Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 36 8 2018 Mar 10 773-779 J Clin Oncol
URL
Abstract Text Purpose Nivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported. Patients and Methods Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR. Results Of 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free survival rates were 76% (9 months) and 71% (12 months); respective OS rates were 87% and 85%. Statistically significant and clinically meaningful improvements were observed in patient-reported outcomes, including functioning, symptoms, and quality of life. Grade 3 to 4 treatment-related adverse events (AEs) occurred in 32% of patients and were manageable. Patients (13%) who discontinued treatment because of study drug-related AEs had an ORR (63%) consistent with that of the overall population. Conclusion Nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes. Indirect comparisons suggest combination therapy provides improved efficacy relative to anti-programmed death-1 monotherapy and has a favorable benefit-risk profile. Nivolumab plus ipilimumab provides a promising new treatment option for patients with dMMR/MSI-H mCRC.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MSH6 negative colorectal cancer sensitive Ipilimumab + Nivolumab FDA approved Actionable In a Phase II (CheckMate 142) trial that supported FDA approval, Opdivo (nivolumab) and Yervoy (ipilimumab) combination treatment resulted in an objective response rate of 54.6% (65/119, 4 complete response, 61 partial response) and disease control over 12 weeks in 80% of patients with microsatellite instability-high (MSI-H) or DNA mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) metastatic colorectal cancer (PMID: 29355075; NCT02060188). detail... detail... 29355075
MLH1 negative colorectal cancer sensitive Ipilimumab + Nivolumab FDA approved Actionable In a Phase II (CheckMate 142) trial that supported FDA approval, Opdivo (nivolumab) and Yervoy (ipilimumab) combination treatment resulted in an objective response rate of 54.6% (65/119, 4 complete response, 61 partial response) and disease control over 12 weeks in 80% of patients with microsatellite instability-high (MSI-H) or DNA mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) metastatic colorectal cancer (PMID: 29355075; NCT02060188). detail... 29355075 detail...