RESULTS from an international Phase III clinical trial presented at the 2025 ASCO Annual Meeting evaluate a treatment regimen combining encorafenib and cetuximab with mFOLFOX6 chemotherapy in patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer (mCRC). According to the BREAKWATER study, the combination was associated with longer overall survival and progression-free survival compared to the standard-of-care chemotherapy with or without bevacizumab.
The study enrolled 637 patients with a median age of approximately 60 years. The trial initially included three arms: encorafenib and cetuximab alone (158 patients), encorafenib and cetuximab with mFOLFOX6 (236 patients), and standard chemotherapy with or without bevacizumab (243 patients). Based on early findings showing improved objective response rates, enrollment to the encorafenib/cetuximab monotherapy arm was closed through a protocol amendment.
In the combination arm including mFOLFOX6, the median overall survival was 30.3 months. This compared to 19.5 months in the encorafenib/cetuximab alone group and 15.1 months in the control group. Progression-free survival was reported as 12.8 months, 6.8 months, and 7.1 months, respectively.
The objective response rate was 65.7% in the encorafenib/cetuximab with mFOLFOX6 arm, compared with 45.6% in the encorafenib/cetuximab alone group and 37.4% in the control arm. Patients in the triplet combination arm had a 51% lower risk of death and a 47% lower risk of disease progression compared with those in the control group.
Treatment-related serious adverse events occurred in 30% of patients receiving encorafenib and cetuximab alone, 46% in the triplet group, and 39% in the control arm. Common adverse events included nausea, anemia, and diarrhea.
Researchers plan to continue investigating encorafenib and cetuximab in combination with an alternative chemotherapy backbone, FOLFIRI.
Reference:
American Society of Clinical Oncology (ASCO). Combination of Encorafenib and Cetuximab With Chemotherapy Helps Some Patients With Advanced Colorectal Cancer Live Longer. May 30, 2025. Available at: https://asco1.sharefile.com/share/view/6ee8af44187f42b3/fod471b5-6c79-44e5-babd-39022782c4e4. Last accessed: 1 June 2025.
