Distinct outcome patterns according to RAS and BRAF status in MSI-H/dMMR mCRC treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

BACKGROUND

Immune checkpoint inhibitors (ICIs) are superior to chemotherapy in metastatic colorectal cancer (mCRC) with MSI-H/dMMR. However, whether oncogenic driver alterations contribute to clinically meaningful heterogeneity in outcomes within this immunotherapy-sensitive population remains unclear. We conducted a systematic review and meta-analysis to evaluate the association between RAS and BRAF mutational status and outcomes in ICI-treated MSI-H/dMMR mCRC.

METHODS

A systematic literature search identified studies reporting outcomes of ICI therapy according to RAS and/or BRAF status in MSI-H/dMMR mCRC. Study-level pooled analyses were conducted using random-effects models to estimate odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS).

RESULTS

Nine studies were included, comprising a total of 13 treatment cohorts and 2564 patients were analysed. ORR did not significantly differ across molecular subgroups. Compared with wild-type tumours, RAS-mutated disease was associated with modestly longer PFS (HR 0.81, 95% CI 0.66-0.99), whereas BRAF-mutated tumours showed shorter PFS (HR 1.37, 95% CI 1.11-1.69). Overall survival was significantly worse in BRAF-mutated disease (HR 1.74, 95% CI 1.17-2.59), while no significant OS differences were observed for RAS-mutated tumours. Exploratory analyses suggested that dual checkpoint blockade may increase response rates particularly in BRAF-mutated and molecularly wild-type subgroups.

CONCLUSIONS

Within MSI-H/dMMR mCRC treated with ICIs, molecular subgroups show distinct survival patterns despite similar response rates. BRAF-mutated tumours retain an adverse prognostic impact, whereas RAS-mutated disease may exhibit more durable disease control. These findings support biological stratification within MSI-H/dMMR mCRC and provide a rationale for prospective biomarker-stratified studies of tailored immunotherapy strategies.