The U.S. Food and Drug Administration has granted full approval to Pfizer’s BRAFTOVI (encorafenib) in combination with cetuximab and fluorouracil-based chemotherapy for the first-line treatment of adults with metastatic colorectal cancer (mCRC) harbouring a BRAF V600E mutation.
With this decision, the BRAFTOVI regimen becomes the only approved targeted therapy specifically indicated for previously untreated BRAF V600E-mutant metastatic colorectal cancer, an aggressive subtype associated with poor prognosis.
The approval is based on results from the global Phase 3 BREAKWATER trial (NCT04607421). In the pivotal Phase 3 portion evaluating BRAFTOVI plus cetuximab and mFOLFOX6, the combination demonstrated a 51% reduction in the risk of death and a 47% reduction in the risk of disease progression or death compared with chemotherapy alone, with or without bevacizumab. The study met its dual primary endpoints, showing statistically significant improvements in progression-free survival, along with a meaningful benefit in overall survival.
BRAFTOVI in combination with cetuximab and mFOLFOX6 had previously received accelerated approval in December 2024 based on objective response rate data. The conversion to full approval reflects confirmatory evidence of improved progression-free and overall survival from the Phase 3 trial segment. Additional objective response data from Cohort 3 of the BREAKWATER study, which evaluated BRAFTOVI with cetuximab and FOLFIRI, also supported the expanded indication.
The updated label provides flexibility for clinicians to use BRAFTOVI in combination with cetuximab and different fluorouracil-based chemotherapy backbones, including mFOLFOX6 and FOLFIRI, allowing treatment to be tailored to patient needs.
In the BREAKWATER study, the safety profile of the BRAFTOVI-based combinations was consistent with the known profiles of the individual agents, and no new safety signals were identified. In the mFOLFOX6 arm, the most common adverse events occurring in at least 25% of patients included peripheral neuropathy, nausea, fatigue, diarrhoea, decreased appetite, rash, vomiting, haemorrhage, abdominal pain, arthralgia, pyrexia and constipation. In the FOLFIRI arm, common side effects included nausea, diarrhoea, fatigue, vomiting, alopecia, constipation, abdominal pain, decreased appetite and rash.
Permanent discontinuation of BRAFTOVI due to adverse reactions occurred in 14% of patients receiving the mFOLFOX6-based combination and in 9% of those receiving the FOLFIRI-based regimen. Rates of chemotherapy discontinuation due to side effects were comparable between the BRAFTOVI combination arm and the chemotherapy control arm.
The BRAFTOVI combination regimen with mFOLFOX6 is currently under regulatory review in Europe, where Pierre Fabre Laboratories holds exclusive commercialisation rights, and has already received approval in several other countries.
The full approval marks a significant expansion of targeted treatment options in first-line metastatic colorectal cancer and reinforces the role of molecular testing in guiding therapy for patients with BRAF V600E-mutant disease.
