A Better Treatment for Patients with BRAF V600E–Mutant Colon Cancer

In 2024, the FDA granted fast-track approval for the addition of encorafenib and cetuximab to first-line mFOLFOX6 chemotherapy for patients with BRAF V600E–mutant colon cancer based on the combination's superior response rate over chemotherapy alone in the BREAKWATER trial (NEJM JW Oncol Hematol Mar 26 2025 and Nat Med 2025; 31:901). Investigators now report an update on other endpoints from this industry-sponsored, open-label, randomized, phase 3 trial.

Patients received one of three treatment combinations:

• Encorafenib, cetuximab, and mFOLFOX6 (EC-mFOLFOX6)
• Standard-of-care chemotherapy: 5-FU, capecitabine, oxaliplatin, or irinotecan combination therapy with or without bevacizumab (SOC)
• Encorafenib and cetuximab without chemotherapy (EC); this arm was closed early.

Of 637 patients, 63% had liver metastases, and 48% had three or more sites of metastases.

Key findings for EC-mFOLFOX6 compared with SOC included:

• Median overall survival (OS) was significantly superior (30 months vs. 15 months).
• Median progression-free survival (PFS) showed significant superiority (13 months vs. 7 months).
• Response rate also continued to be superior (66% vs. 37%).

Regarding patients receiving EC, because this arm was discontinued early, statistical analyses were not performed. Nevertheless, the EC patient group had a numerically higher response rate than the SOC group (46%), similar PFS, and a trend toward superior OS (20 months). No new safety signals were observed.