Comparative efficacy and safety of second- and later-line BRAF-targeted regimens in BRAF V600E–mutant metastatic colorectal cancer: A systematic review and network meta-analysis

Background: BRAF V600E mutations occur in approximately 8 to 12% of metastatic colorectal cancer (mCRC) cases and define an aggressive phenotype with poor prognosis. While the BEACON CRC trial established encorafenib-based combinations as effective second-line options, direct head-to-head comparisons among available BRAF-targeted regimens are lacking. This network meta-analysis (NMA) compared the relative efficacy and safety of second- and later-line BRAF-targeted regimens in BRAF V600E–mutant mCRC. Methods: PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov were searched from inception through January 2026. Eligible studies enrolled adult patients with BRAF V600E–mutant mCRC receiving second- or later-line BRAF-targeted therapy and reported time-to-event survival outcomes. A frequentist NMA was conducted under a random-effects model using the netmeta package in R. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled for progression-free survival (PFS) and overall survival (OS). Where HRs were unavailable, individual patient data were reconstructed from Kaplan–Meier curves using the Guyot method. Treatment ranking used P-scores, with irinotecan plus cetuximab as the reference comparator. Results: Four trials enrolling 922 patients across 9 treatment arms were included. All 4 experimental regimens demonstrated significant PFS benefit over irinotecan plus cetuximab. Encorafenib plus cetuximab plus alpelisib ranked highest for PFS (HR 0.33, 95% CI 0.15–0.71; P-score 0.789), followed by encorafenib plus binimetinib plus cetuximab (EBC; HR 0.38, 95% CI 0.29–0.49), encorafenib plus cetuximab (EC; HR 0.40, 95% CI 0.31–0.50), and vemurafenib plus irinotecan plus cetuximab (HR 0.50, 95% CI 0.32–0.77). For OS, only EBC (HR 0.52, 95% CI 0.39–0.69) and EC (HR 0.59, 95% CI 0.46–0.76) achieved statistically significant benefits. No significant difference was detected between EBC and EC on either endpoint. No between-study heterogeneity was detected (I 2 = 0%). In the exploratory safety network, encorafenib plus cetuximab was the only encorafenib-based regimen associated with significantly fewer grade ≥ 3 adverse events than irinotecan plus cetuximab (odds ratio 0.67, 95% CI 0.47–0.96). Conclusion: These findings position encorafenib-based therapy, and encorafenib plus cetuximab in particular, as the reference standard for previously treated BRAF V600E–mutant mCRC, while underscoring that the incremental value of more intensive regimens must be weighed against tolerability and confirmed in adequately powered trials.