Optimal First-Line Immunotherapy for MSI-H/dMMR Metastatic Colorectal Cancer: Evidence, Gaps, and Clinical Decision-Making.

Microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) has emerged as a model for biomarker-driven immunotherapy. Yet the optimal positioning of pembrolizumab, nivolumab, and nivolumab plus ipilimumab in routine practice remains unsettled. This narrative review examines landmark and contemporary evidence from KEYNOTE-164, KEYNOTE-177, CheckMate 142, CheckMate 8HW, and the COMMIT trial, together with high-quality non-randomized cohort studies and ongoing trial data. Pembrolizumab is the most mature first-line single-agent standard, with superior progression-free and overall survival versus chemotherapy and a well-characterized long-term safety profile.

Nivolumab plus ipilimumab provides the strongest evidence for intensified dual checkpoint blockade and has demonstrated superiority over both chemotherapy and nivolumab monotherapy in randomized trials, but at the cost of substantially higher immune-related toxicity and treatment discontinuation rates. The COMMIT trial suggests a role for chemo-immunotherapy combinations, though sample size and early closure limit interpretation. Key factors influencing treatment selection include disease burden, metastatic pattern, performance status, biomarker confidence, and ability to manage immune-related adverse events. In the absence of a direct head-to-head comparison between pembrolizumab and nivolumab plus ipilimumab, treatment selection must integrate evidence strength, toxicity profile, patient fitness, and biologic context.

Ongoing trials, including SEAMARK and the overall survival analysis of CheckMate 8HW, will further refine optimal first-line strategy.