First-Line Encorafenib and Cetuximab in BRAF V600E–Mutant Colon Cancer

In December 2024, the U.S. FDA granted accelerated approval for the combination of encorafenib and cetuximab (EC) with mFOLFOX6 (oxaliplatin, leucovorin, and 5-FU) for first-line treatment of BRAF-mutant colorectal cancer, based on the results of the industry-sponsored, phase 3 BREAKWATER trial. Now, investigators have published results of this trial, which featured dual primary endpoints of objective response rate (ORR) and progression-free survival (PFS).

A total of 479 patients with previously untreated metastatic colorectal cancer with a BRAF V600E mutation were randomized to receive either EC with mFOLFOX6 or standard-of-care chemotherapy. Eighty percent had primary colon cancer, and 61% had right-sided tumors; 52% had prior complete or partial primary tumor resection, and 63% had hepatic metastases. Patients receiving EC and mFOLFOX6 had a significantly greater ORR than those receiving chemotherapy alone (60.9% vs. 40%; odds ratio, 2.4) and a significantly longer median duration of response (13.9 vs. 11.1 months). Data on PFS were not mature at the time of publication, but an interim analysis of overall survival suggested a benefit with EC (hazard ratio, 0.47), although it did not reach statistical significance. Rates of grade 3/4 treatment-related adverse events were higher with EC than with chemotherapy alone (69.7% vs. 53.9%). No new safety signals were observed.