Background
Phase II single-arm multi-cohort trial. 119 patients with dMMR/MSI-H metastatic colorectal cancer who received ≥2 prior lines (including fluoropyrimidine, oxaliplatin, and irinotecan). Evaluated combined nivolumab + ipilimumab checkpoint blockade in the chemotherapy-refractory dMMR/MSI-H mCRC population.
Interventions and follow up
Regimen: Nivolumab 3 mg/kg IV q2wk + ipilimumab 1 mg/kg IV q6wk until progression or unacceptable toxicity
Design: Single cohort; no comparator. Historical chemotherapy response rates in this heavily pretreated population served as reference
Primary endpoint: Investigator-assessed objective response rate (ORR) per RECIST 1.1
Median follow-up: 13.4 months
Design: Single cohort; no comparator. Historical chemotherapy response rates in this heavily pretreated population served as reference
Primary endpoint: Investigator-assessed objective response rate (ORR) per RECIST 1.1
Median follow-up: 13.4 months
Results
ORR: 55% (95% CI 45–64%)
CR rate: 3%
Disease control rate (DCR): 80%
12-month PFS rate: 71%
12-month OS rate: 85%
Duration of response: not reached at median follow-up
CR rate: 3%
Disease control rate (DCR): 80%
12-month PFS rate: 71%
12-month OS rate: 85%
Duration of response: not reached at median follow-up
Adverse events
Grade ≥3 treatment-related AEs: 32%
Most common grade ≥3: lipase increased 7%, diarrhea/colitis 5%, fatigue 5%, ALT increased 4%
Immune-mediated AEs (any grade): 47%; discontinuation due to toxicity 13%
Most common grade ≥3: lipase increased 7%, diarrhea/colitis 5%, fatigue 5%, ALT increased 4%
Immune-mediated AEs (any grade): 47%; discontinuation due to toxicity 13%
Conclusions
Nivolumab + ipilimumab produced an ORR of 55% in heavily pretreated dMMR/MSI-H mCRC — a landmark result where chemotherapy response rates are typically <10%. Disease control at 12 months was 71% for PFS and 85% for OS, establishing dual checkpoint blockade as a practice-changing option in this biomarker-selected disease.
Key Limitations
Single-arm phase II design without randomized comparator limits direct attribution; however, historical chemotherapy ORR in this setting is <5%, making interpretation clear. Exclusively dMMR/MSI-H population (∼4–5% of all mCRC). Long-term DFS/OS durability not yet characterized at primary analysis. No biomarker predictor of response within the dMMR subgroup identified. Grade ≥3 toxicity of 32% is higher than single-agent anti-PD-1 in this setting.
Clinical Context
CheckMate 142 led to FDA approval of nivolumab + ipilimumab for dMMR/MSI-H mCRC in May 2018, the first dual checkpoint combination approval in CRC. The combination was subsequently evaluated as first-line therapy in CheckMate 8HW (phase III), where it demonstrated superiority over chemotherapy for PFS. ESMO-MCBS score: 5 (maximum).