First-Line Immunotherapy Versus Chemotherapy in MSI-H/dMMR Metastatic Colorectal Cancer: A Systematic Review and...

Metastatic colorectal cancer (mCRC) with microsatellite instability-high or mismatch repair deficiency (MSI-H/dMMR) demonstrates limited responsiveness to conventional cytotoxic chemotherapy but increased susceptibility to immune checkpoint inhibition. Although randomized phase III trials have shown superiority of immune checkpoint inhibitors (ICIs) in the first-line setting, a comprehensive synthesis of survival outcomes across key molecular and clinical subgroups remains warranted.

We conducted a systematic review and meta-analysis of randomized, open-label, phase III trials comparing first-line ICI-based therapy with standard chemotherapy in MSI-H/dMMR mCRC. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses evaluated outcomes according to BRAF mutation status, KRAS/NRAS mutation status, and primary tumor location. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using random-effects models. Safety outcomes were analyzed using Mantel-Haenszel fixed-effect models. Statistical heterogeneity was assessed using the I² statistic.

Two phase III trials (KEYNOTE-177 and CheckMate-8HW), including more than 600 patients, were eligible. ICI-based therapy significantly improved PFS compared with chemotherapy (pooled HR 0.61; 95% CI, 0.51-0.73; I²=0%) and demonstrated a significant OS benefit (pooled HR 0.77; 95% CI, 0.63-0.94; I²=0%). Immunotherapy was associated with lower rates of overall and grade ≥ 3 adverse events, despite more frequent immune-related toxicities.

First-line ICI-based therapy provides significant and consistent survival benefits across BRAF-mutated and wild-type tumors, KRAS/NRAS-mutated and wild-type disease, and both right- and left-sided primary tumors, supporting its role as the standard of care for MSI-H/dMMR mCRC.