Multinational phase 3 trial of encorafenib with cetuximab and chemotherapy for previously untreated BRAF-mutant metastatic colorectal cancer

The multinational phase 3 BREAKWATER trial included patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer (mCRC). Patients were randomized to encorafenib plus cetuximab (EC), EC plus mFOLFOX6, or standard of care (SOC). Results of the EC plus mFOLFOX6 group (n=236) compared with the SOC group (n=243) have now been published. Data for the coprimary endpoint of progression-free survival were not yet mature. For the coprimary endpoint objective response rate, there was a significant and clinically relevant improvement with EC plus mFOLFOX6 versus SOC (60.9% versus 40.0%; OR 2.433; p=0.0008) with median duration of response 13.9 versus 11.1 months and improved response rates in all predefined subgroups. At the first interim analysis of overall survival the hazard ratio with EC plus mFOLFOX6 versus SOC was 0.47 (95% CI 0.166-1.322). Serious adverse event rates were 37.7% versus 34.6%; with safety profiles consistent with those known for each agent. The authors conclude that BREAKWATER demonstrated a significantly improved response rate that was durable for first-line EC plus mFOLFOX6 versus SOC in patients with BRAF V600E-mutant mCRC.