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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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First-Line Immunotherapy Versus Chemotherapy in MSI-H/dMMR Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis of Phase III Studies

  • 期刊论文

  • 发表日期：

    2026年7月20日

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  • Wala Ben Kridis,
  • Afef Khanfir

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.