Pfizer Secures Full FDA Approval For BRAFTOVI Regimen Following BREAKWATER Phase 3 Results

Pfizer Inc. announced that the U.S. Food and Drug Administration has granted full approval to BRAFTOVI® (encorafenib) in combination with cetuximab (marketed as ERBITUX®) and fluorouracil-based chemotherapy for the treatment of adult patients with metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation. The approval is supported by data from the global Phase 3 BREAKWATER trial (NCT04607421).

The regimen previously received accelerated approval in December 2024 based on objective response rate (ORR), one of the study’s dual primary endpoints. The conversion to full approval follows confirmation of significant improvements in progression-free survival (PFS) and overall survival (OS) from the Phase 3 portion evaluating BRAFTOVI plus cetuximab and mFOLFOX6. Additional ORR data from Cohort 3, assessing BRAFTOVI with cetuximab and FOLFIRI, also supported the decision.

“This landmark approval, achieved through the robust clinical benefit demonstrated in the BREAKWATER trial, validates that this targeted therapy can impact outcomes for people living with an aggressive, hard-to-treat cancer,” said Aamir Malik, Executive Vice President, Chief U.S. Commercial Officer, Pfizer. “As the only targeted combination regimen shown to deliver a significant improvement in certain outcomes for patients with BRAF V600E‑mutant metastatic colorectal cancer, BRAFTOVI is uniquely positioned to redefine first‑line treatment and establish a new standard of care. This approval reinforces our leadership in bringing differentiated, potentially practice‑changing cancer therapies to patients and healthcare providers who urgently need improved options.”

In the BREAKWATER study, the safety profile of both combination regimens remained consistent with the known safety characteristics of the individual agents, with no new safety signals identified. The most common adverse events (≥25%) with the mFOLFOX6 regimen included peripheral neuropathy, nausea, fatigue, diarrhea, decreased appetite, rash, vomiting, hemorrhage, abdominal pain, arthralgia, pyrexia, and constipation. For the FOLFIRI regimen, common side effects included nausea, diarrhea, fatigue, vomiting, alopecia, constipation, abdominal pain, decreased appetite, and rash.

“This approval gives oncologists confidence to use encorafenib plus cetuximab in combination with fluorouracil-based chemotherapy as a first-line standard of care for patients with BRAF V600E-mutant metastatic colorectal cancer,” said Scott Kopetz, M.D., Ph.D., FACP, Professor and Deputy Chair of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center and co-principal investigator of the BREAKWATER trial. “The BREAKWATER study demonstrated that these targeted combination regimens provided statistically significant benefit, providing the robust evidence we need to make treatment decisions that can meaningfully impact patient outcomes.”

Permanent discontinuation of BRAFTOVI due to adverse reactions occurred in 14% of patients receiving the mFOLFOX6 combination and 9% in the FOLFIRI combination arm. The BRAFTOVI plus mFOLFOX6 regimen is currently under regulatory review in Europe, where Pierre Fabre Laboratories holds exclusive commercialization rights, and has recently received approvals in several additional countries.