On February 24, 2026, the FDA granted traditional approval to encorafenib (Braftovi) in combination with cetuximab and fluorouracil-based chemotherapy for the treatment of adults with metastatic colorectal cancer (CRC) harboring a BRAF V600E mutation, as determined by an FDA-authorized test. This follows the accelerated approval of encorafenib with cetuximab and mFOLFOX6 for the same indication in 2024.
The approval was based on the phase 3 BREAKWATER trial (NCT04607421), which evaluated efficacy in treatment-naive patients with BRAF V600E–mutated metastatic CRC. The mutation was confirmed using the Qiagen “therascreen BRAF V600E RGQ PCR Kit.” Initial randomization was 1:1:1 across 3 treatment arms:
- Arm A: Encorafenib with cetuximab
- Arm B: Encorafenib with cetuximab and mFOLFOX6
- Arm C: mFOLFOX6, FOLFOXIRI, or CAPOX, each with or without bevacizumab
Later, the trial focused on comparing arm B (experimental) and arm C (control) and introduced cohort 3, which compared arm D (encorafenib, cetuximab, and FOLFIRI) and arm E (FOLFIRI, with or without bevacizumab).
For the phase 3 population, key efficacy measures included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Among 236 patients in arm B and 243 in arm C, median PFS was 12.8 months in arm B versus 7.1 months in arm C (hazard ratio [HR], 0.53; P<.0001). Median OS was 30.3 months in arm B compared with 15.1 months in arm C (HR, 0.49; P<.0001). ORR was higher in arm B (61%) than in arm C (40%; P=.0008).
In cohort 3, ORR was 64% in arm D compared with 39% in arm E (P=.0011).
The prescribing information includes warnings for new primary malignancies, tumor promotion in BRAF wild-type tumors, cardiomyopathy, hepatotoxicity, hemorrhage, uveitis, QT prolongation, and embryo-fetal toxicity.
The recommended dose of encorafenib is 300 mg (four 75-mg capsules) orally once daily with cetuximab, combined with either mFOLFOX6 or FOLFIRI, until disease progression or unacceptable toxicity.
Source
- FDA grants traditional approval to encorafenib for metastatic colorectal cancer with a BRAF V600E mutation. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-encorafenib-metastatic- colorectal-cancer-braf-v600e-mutation