FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation
Regulatory approval: On Dec 20, 2024, the FDA granted accelerated approval to encorafenib with cetuximab and mFOLFOX6 for patients with metastatic colorectal cancer harboring a BRAF V600E mutation, as detected by an FDA-approved test. The decision was based on confirmed objective response rate and duration of response from the ongoing, active-controlled BREAKWATER trial. Progression-free survival and overall survival analyses are planned as post-marketing confirmatory evidence.
FDA accelerated approval (Dec 20, 2024)
The US FDA granted accelerated approval to encorafenib (Braftovi) in combination with cetuximab and mFOLFOX6 for metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test.
Evidence base: BREAKWATER (NCT04607421)
Approval was supported by BREAKWATER, an active-controlled, open-label, multicenter trial in treatment-naïve BRAF V600E–positive mCRC (mutation detected by the Qiagen therascreen BRAF V600E RGQ PCR kit). The trial initially randomized patients 1:1:1 to (1) encorafenib+cetuximab, (2) encorafenib+cetuximab+mFOLFOX6, or (3) control chemotherapy regimens (mFOLFOX6/FOLFOXIRI/CAPOX) with or without bevacizumab; it was later amended to 1:1 randomization between encorafenib+cetuximab+mFOLFOX6 and control.
Primary efficacy endpoint: confirmed ORR by blinded independent central review in the first 110 patients per arm.
- ORR: 61% (95% CI, 52–70) vs 40% (95% CI, 31–49)
- Median DoR: 13.9 months (95% CI, 8.5–NE) vs 11.1 months (95% CI, 6.7–12.7)
Confirmatory evidence: ongoing evaluation of PFS and OS will serve as post-marketing confirmation.
Safety and dosing (from FDA summary)
Common adverse reactions (≥25%): peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, pyrexia. Common grade 3/4 lab abnormalities (≥20%): increased lipase, decreased neutrophil count.
Recommended encorafenib dose: 300 mg orally once daily with cetuximab and mFOLFOX6 until progression or unacceptable toxicity.
Review notes: conducted under Project Orbis (with Health Canada collaboration) and used RTOR; priority review granted.