Survival Outcomes in Metastatic Colorectal Cancer Patients with BRAF Mutations Undergoing Targeted Chemotherapy: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: BRAF V600E-mutant metastatic colorectal cancer (mCRC) represents an aggressive molecular subtype associated with poor prognosis and limited response to conventional chemotherapy. Although multiple targeted strategies, including anti-vascular endothelial growth factor (VEGF), anti-epidermal growth factor receptor (EGFR), and BRAF-directed therapies, are used in clinical practice, their comparative effectiveness remains uncertain. We performed a reconstructed individual patient-data (IPD) meta-analysis of randomized controlled trials (RCTs) to evaluate survival outcomes across targeted therapeutic classes in BRAF-mutant mCRC. METHODS: A systematic search of PubMed, Embase, Scopus, and Cochrane databases was conducted through July 2025 to identify RCTs reporting survival outcomes for BRAF-mutant mCRC. Kaplan-Meier curves were digitized and IPD reconstructed using established methods. A one-stage meta-analysis using Cox proportional hazards models was performed to estimate pooled overall survival (OS) and progression-free survival (PFS). Models were adjusted for study-level covariates and clustering, with Bonferroni correction applied for multiple comparisons. RESULTS: Eighteen RCTs comprising 11,931 participants were included. Pooled median OS was 22.3 months for BRAF-directed regimens, 17.1 months for VEGF-targeted therapy, and 10.1 months for EGFR-directed therapy across studies evaluating first-line therapy. Across first-line studies, BRAF inhibitor directed regimen was associated with significantly improved OS compared with EGFR inhibition (HR 0.43, 95% CI 0.31-0.60; P < 0.001) and improved PFS (HR 0.47, 95% CI 0.42-0.53; P < 0.001). VEGF inhibition also demonstrated superior OS compared with EGFR inhibition (HR 0.56, 95% CI 0.38-0.81; p < 0.001). EGFR-directed regimen consistently demonstrated the poorest survival outcomes across analyses. DISCUSSION: In this reconstructed IPD meta-analysis, BRAF-directed therapies were associated with the most favourable survival outcomes, whereas EGFR directed regimen demonstrated limited clinical benefit in BRAF-mutant mCRC. These results highlight the importance of biologically aligned pathway-targeted therapy and provide comparative evidence to inform treatment selection in this aggressive molecular subtype.