Targeted Combination Therapy Approved for BRAF-mutated Metastatic Colorectal Cancer
The FDA has converted the accelerated approval of encorafenib and cetuximab plus chemotherapy to full approval for first-line treatment of certain colorectal cancers.
The U.S. Food and Drug Administration (FDA) has granted traditional approval to encorafenib (Braftovi) in combination with cetuximab (Erbitux) and fluorouracil-based chemotherapy for the initial treatment of patients with metastatic colorectal cancer harboring a BRAF V600E mutation.
Encorafenib and cetuximab are targeted therapies that block the BRAF and EGFR proteins, respectively, which work in a signaling pathway that stimulates cell proliferation. The BRAF V600E mutation can cause BRAF to signal uncontrollably, contributing to cancer growth. However, blocking the activity of mutated BRAF in colorectal cancer may not be enough to stop tumor growth, as EGFR becomes upregulated and leads to therapy resistance. Simultaneous inhibition of both BRAF and EGFR may therefore shut down the pathway in BRAF-mutated colorectal cancer.
The combination of encorafenib and cetuximab with mFOLFOX6 (a fluorouracil-based combination chemotherapy regimen) for first-line treatment of metastatic colorectal cancer with a BRAF V600E mutation received accelerated approval in 2024.
Conversion to full approval was granted based on updated results from the randomized, active-controlled, open-label, multicenter phase III BREAKWATER clinical trial. In this study, the researchers originally enrolled patients with untreated, BRAF V600E-mutated metastatic colorectal cancer and randomly assigned them (1:1:1) to receive encorafenib plus cetuximab (arm A), encorafenib plus cetuximab and mFOLFOX6 (arm B), or a control regimen of chemotherapy with or without the targeted therapy bevacizumab (Avastin, arm C). Randomization to arm A was stopped early, and another cohort was subsequently added, which received either encorafenib plus cetuximab and FOLFIRI (another fluorouracil-based chemotherapy regimen, arm D) or FOLFIRI with or without bevacizumab (arm E). Treatment in all arms continued until progression, death, or unacceptable toxicity.
While the accelerated approval was granted on the basis of an early analysis of overall response rate (ORR) and duration of response, the conversion to full approval was supported by updated results that demonstrated prolonged survival and disease control.
Median progression-free survival was 12.8 months for arm B and 7.1 months for arm C, corresponding to a 47% reduction in the risk of disease progression or death in patients treated with encorafenib plus cetuximab and mFOLFOX6 compared with those who received the control therapy. Median overall survival was 30.3 months and 15.1 months in arm B and C, respectively, corresponding to a 51% reduction in the risk of death. The updated analysis also included results from the additional cohort, in which ORR was 64% in arm D for patients treated with encorafenib plus cetuximab and FOLFIRI and 39% in arm E for those who received the control treatment.
The prescribing information for cetuximab contains a boxed warning for severe infusion reactions and cardiopulmonary arrest.
The recommended dose for encorafenib is 300 mg given orally once per day in combination with cetuximab and mFOLFOX6 or with cetuximab and FOLFIRI.
Colorectal cancer is a cancer that forms in the large intestine (colon or rectum). Approximately 10% of metastatic colorectal cancers are estimated to harbor the BRAF V600E mutation. According to federal statistics, it was estimated that 154,270 individuals would be diagnosed with colorectal cancer and 52,900 patients would die of the disease in the United States in 2025.
The FDA rendered its decision on February 24, 2026. Check this resource for updated information on all therapeutics regulated by the FDA.