Pfizer’s BRAFTOVI® Combo Boosts Survival in Phase 3 BREAKWATER Trial
Pfizer Inc. (NYSE: PFE) has announced promising results from the Phase 3 BREAKWATER study of BRAFTOVI® (encorafenib) in combination with cetuximab (marketed as ERBITUX®) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for patients with metastatic colorectal cancer (mCRC) harboring the BRAF V600E mutation. The trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), one of its dual primary endpoints. This was assessed through a blinded independent central review (BICR), with patients receiving the BRAFTOVI combination regimen showing better results compared to those treated with chemotherapy alone or with bevacizumab. Additionally, the BRAFTOVI combination regimen also showed a significant improvement in overall survival (OS), a key secondary endpoint of the study.
Roger Dansey, M.D., Chief Oncology Officer at Pfizer, expressed excitement about the results, noting that they offer a potential game-changing treatment for a patient population that has long faced limited treatment options and poor outcomes. “The BRAFTOVI regimen is emerging as a new standard of care as the first targeted therapy approved for use as early as first-line for patients with mCRC with a BRAF V600E mutation,” Dr. Dansey said. He added that Pfizer looks forward to discussing the data with global health authorities to expedite the availability of this treatment to more patients.
The BRAFTOVI combination regimen received accelerated approval from the U.S. Food and Drug Administration (FDA) in December 2024 for treatment-naïve patients with BRAF V600E-mutant mCRC, based on a statistically significant and clinically meaningful improvement in confirmed objective response rate (ORR), which was one of the trial’s primary endpoints. These ORR results were shared at the 2025 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI) and published in Nature Medicine in January 2025.
At the time of the ORR analysis, the safety profile of the BRAFTOVI combination with cetuximab and mFOLFOX6 remained consistent with the known safety profiles of each agent. No new safety concerns were identified. Detailed results from this analysis are expected to be presented at a future medical conference.
The approval of the BRAFTOVI combination regimen was among the first to be conducted under the FDA’s Project FrontRunner, which aims to support the development and approval of new cancer therapies for advanced or metastatic diseases. Pfizer plans to share these results with the FDA to potentially support full approval for BRAFTOVI in combination with cetuximab and mFOLFOX6 for patients with mCRC harboring a BRAF V600E mutation. Discussions are also ongoing with regulatory authorities worldwide to support additional license applications for the regimen.
About the BREAKWATER Study
BREAKWATER is a Phase 3, randomized, active-controlled, open-label, multicenter trial that involved patients with previously untreated BRAF V600E-mutant metastatic CRC. Patients were randomized to receive either BRAFTOVI 300 mg orally once daily combined with cetuximab (discontinued after 158 patients were randomized), BRAFTOVI 300 mg orally once daily with cetuximab and mFOLFOX6 (236 patients), or chemotherapy regimens (mFOLFOX6, FOLFOXIRI, or CAPOX) with or without bevacizumab (243 patients) in the control arm. The primary endpoints for the trial were ORR and PFS, with OS serving as a key secondary endpoint.
Colorectal Cancer (CRC) Overview
Colorectal cancer is the third most common cancer worldwide, with an estimated 1.8 million new cases diagnosed in 2022. It is the second leading cause of cancer-related deaths globally, and the lifetime risk of developing CRC is approximately 1 in 24 for men and 1 in 26 for women. In the United States, about 154,270 people are expected to be diagnosed with CRC in 2025, with an estimated 53,000 deaths from the disease each year. Approximately 20% of people diagnosed with CRC have metastatic disease, making treatment more challenging, and up to half of patients with localized disease will eventually develop metastases.
The BRAF V600E mutation occurs in 8-12% of mCRC cases and is associated with a poorer prognosis. Patients with this mutation face a risk of mortality more than twice as high as those without the mutation. Prior to the approval of BRAFTOVI, no biomarker-driven therapies were specifically approved for treatment-naïve patients with BRAF V600E-mutant mCRC.
About BRAFTOVI® (Encorafenib)
BRAFTOVI is an oral small molecule kinase inhibitor that targets the BRAF V600E mutation, which plays a critical role in activating the MAPK signaling pathway (RAS-RAF-MEK-ERK) in certain cancers, including CRC. The drug is marketed by Pfizer in the U.S., Canada, Latin America, the Middle East, and Africa, with Ono Pharmaceutical Co., Ltd. holding rights for Japan and South Korea, Medison for Israel, and Pierre Fabre Laboratories for other global markets, including Europe and Asia (excluding Japan and South Korea).
