S519 BRAF Mutations Indicate Poor Survival in Metastatic Colorectal Cancer: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Controlled Trials

Introduction: Metastatic colorectal cancer (mCRC) is a leading cause of cancer-related mortality. Among its subtypes, BRAF-mutated mCRC, particularly V600E, is associated with aggressive behavior and poor outcomes. Although anti-VEGF therapies are commonly used in mCRC, their role in the BRAF-mutated population remains uncertain. We aim to evaluate the survival outcomes of BRAF-mutated mCRC patients receiving anti-VEGF therapy compared to those with RAS mutations. Methods: We searched MEDLINE from inception to May 2025 for randomized controlled trials (RCTs) reporting outcomes in BRAF-mutated mCRC treated with anti-VEGF agents. Time-to-event data were extracted from Kaplan-Meier curves, and individual patient data were reconstructed using R. Cox proportional hazards models estimated hazard ratios (HRs) and median overall (OS) and progression-free survival (PFS). Results: Five RCTs were included. In the overall cohort, patients with BRAF-mutant mCRC (n = 171) had significantly worse OS compared to RAS-mutant patients (n = 936) [HR 2.11; 95% CI, 1.78–2.51; P < 0.0001], with a median OS of 10.1 vs 22.5 months. PFS was also inferior [HR 1.49; 95% CI, 1.19–1.87; P = 0.00037; median 5.0 vs 8.0 months]. After maintenance therapy, BRAF-mutant patients (n = 83) had significantly shorter OS [HR 1.78; 95% CI, 1.40–2.27; P < 0.0001], while PFS was similar [HR 0.71; 95% CI, 0.47–1.07; P = 0.12]. For treatment-naive patients receiving initial therapy, BRAF-mutant patients (n = 47) again had significantly worse OS [HR 1.92; 95% CI, 1.39–2.65; P < 0.0001] and PFS [HR 1.97; 95% CI, 1.30–3.00; P = 0.0012] compared to RAS-mutant patients (n = 403). In this subgroup, those treated with FOLFOXIRI (n = 14) had improved median OS (13.5 vs 10.9 months) and PFS (7.2 vs 6.8 months) compared to FOLFIRI (n = 33), though differences were not statistically significant. Conclusion: BRAF-mutant mCRC is associated with significantly worse survival compared to RAS-mutant disease across all treatment phases. These findings emphasize the need for early molecular profiling, consideration of intensified first-line regimens, and prompt initiation of BRAF-targeted strategies upon progression. Limitations include trial heterogeneity and small sample sizes. Modern BRAF-targeted therapies (e.g., encorafenib plus cetuximab) were not represented. Future studies should refine sequencing of triplet chemotherapy versus targeted agents, evaluate maintenance strategies, and explore subclass-specific responses (V600E vs non-V600E).