Overview

• The phase III BREAKWATER trial enrolled 637 untreated patients with BRAF V600E mutation-positive metastatic colorectal cancer and compared the encorafenib-cetuximab-mFOLFOX6 combination to standard chemotherapy
• Triplet treatment reduced the risk of death by 51% and lowered the risk of disease progression by 47% relative to control regimens
• Median overall survival reached 30.3 months with the triplet therapy versus 15.1 months with standard care, and median progression-free survival improved to 12.8 months from 7.1 months
• The FDA granted accelerated approval for the regimen in December 2024 based on early response data and PFS findings, paving the way for its adoption as frontline therapy
• Although higher rates of grade 3–4 adverse events such as neutropenia, anemia and peripheral neuropathy were observed, investigators deemed the safety profile manageable