SynthesisJournal of gastrointestinal cancer2026
First-Line Immunotherapy Versus Chemotherapy in MSI-H/dMMR Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis of Phase III Studies.
Synthesis in Journal of gastrointestinal cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundMetastatic 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.
methodsWe 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.
resultsTwo 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.
conclusionsFirst-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.
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