BRAF V600E and survival benefit of anti-EGFR monoclonal antibody (mAb) therapy for metastatic colorectal cancer (mCRC): A meta-analysis

Background: BRAF V600E mutation is a known marker of poor prognosis for individuals with mCRC. However, whether it is also a predictive marker of the efficacy of anti-EGFR mAb therapy is uncertain. Methods: A systematic review and random-effects meta-analysis of RCTs was undertaken to evaluate the effect of BRAF V600E on the progression-free survival (PFS) and overall survival (OS) benefit of anti-EGFR mAb therapy for mCRC. Treatment effect was reported as a hazard ratio (HR) with 95% confidence interval (CI). Results: Six RCTs (n = 4295) met the inclusion criteria for assessment of OS, while 7 RCTs (n = 4609) met the inclusion criteria for assessment of PFS. Of the 2497 participants with RAS WT tumors across the 7 RCT substudies, 261 (10.5%) were BRAF mutant. For both OS and PFS, the HR point estimates for RAS WT / BRAF V600E tumors were situated midway between those of RAS WT / BRAF WT tumors and RAS mutant tumors. However, the reduction in efficacy (RAS WT / BRAF V600E vs RAS WT / BRAF WT) was not statistically significant (P = 0.57 and P = 0.18 for OS and PFS, respectively). For PFS, but not OS, the HR for the RAS WT / BRAF V600E tumors significantly different from RAS mutant tumors (P = 0.02). Conclusions: There is currently insufficient evidence to definitively claim that BRAF V600E is a negative predictive marker of anti-EGFR mAb benefit in RAS WT mCRC. Despite including data from 7 large RCTs comprising > 4000 participants, a larger sample size is required for adequate power to distinguish clinically meaningful differences.