Survival Pfizer Inc. announced positive topline results from the phase 3 BREAKWATER study, evaluating Braftovi (encorafenib) in combination with cetuximab (Erbitux) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for metastatic colorectal cancer (mCRC) patients with a BRAF V600E mutation. The trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), as assessed by blinded independent central review (BICR), compared to patients receiving chemotherapy with or without bevacizumab.
Furthermore, the Braftovi combination regimen showed a significant improvement in overall survival (OS), a key secondary endpoint, reinforcing its potential as a groundbreaking treatment.
Pfizer’s Commitment to Advancing Treatment
Dr. Roger Dansey, Chief Oncology Officer at Pfizer, emphasized the importance of these results. “We are extremely pleased with the clinically meaningful progression-free survival and overall survival results from the BREAKWATER study. These findings have the potential to change clinical practice for this patient population, which has historically had limited treatment options and poor outcomes,” he stated.
Braftovi is emerging as a new standard of care, being the first targeted therapy approved for first-line use in patients with BRAF V600E-mutant mCRC. Pfizer plans to discuss these data with global health authorities to expand patient access as quickly as possible.
Regulatory Approval and Accelerated FDA Pathway
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. This approval was based on a statistically significant improvement in the confirmed objective response rate (ORR), another dual primary endpoint.
The ORR results were presented at the 2025 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI) and published in Nature Medicine in January 2025. At that time, the safety profile of Braftovi in combination with cetuximab and mFOLFOX6 remained consistent with known profiles of each agent, with no new safety concerns identified.
Future Plans for Full Approval
Pfizer is working closely with the FDA and other global regulatory authorities to support full approval of the Braftovi combination regimen. The BREAKWATER data will be key in potentially expanding its indication worldwide. The approval process is also aligned with the FDA’s Project FrontRunner, which supports the development and approval of innovative cancer treatments for advanced or metastatic disease.
Study Overview: BREAKWATER Trial Design
The phase 3 BREAKWATER trial is a randomized, active-controlled, open-label, multicenter study evaluating Braftovi with cetuximab, alone or in combination with mFOLFOX6, in previously untreated patients with BRAF V600E-mutant metastatic CRC. Participants were randomized into three treatment arms:
Braftovi (300 mg orally once daily) with cetuximab (discontinued after 158 patients were randomized)
Braftovi (300 mg orally once daily) with cetuximab and mFOLFOX6 (n=236)
Control group receiving mFOLFOX6, Folfoxiri, or Capox, with or without bevacizumab (n=243)
The study’s dual primary endpoints were objective response rate (ORR) and progression-free survival (PFS), both assessed by BICR. Overall survival (OS) was a key secondary endpoint.
Colorectal Cancer: A Growing Global Health Concern
Colorectal cancer (CRC) remains the third most common cancer worldwide, with approximately 1.8 million new cases diagnosed in 2022. It is the second leading cause of cancer-related deaths. The lifetime risk of developing CRC is about 1 in 24 for men and 1 in 26 for women. In the United States, an estimated 154,270 new CRC cases are expected in 2025, with approximately 53,000 deaths annually.
For 20% of patients, CRC is already metastatic at diagnosis, making treatment more challenging. Additionally, up to 50% of patients with localized disease eventually develop metastases.
BRAF Mutations and Their Impact on CRC Prognosis
BRAF mutations occur in approximately 8-12% of metastatic CRC cases and indicate a poor prognosis. The BRAF V600E mutation, the most common BRAF mutation, more than doubles the mortality risk compared to patients without the mutation. Before December 2024, no biomarker-driven therapies were approved for previously untreated BRAF V600E-mutant mCRC, highlighting the urgent need for targeted treatment options.
How Braftovi Works
Braftovi (encorafenib) is an oral small-molecule kinase inhibitor that targets BRAF V600E. The MAPK signaling pathway (RAS-RAF-MEK-ERK) plays a crucial role in certain cancers, including CRC. By inhibiting BRAF V600E, Braftovi disrupts the inappropriate activation of this pathway, helping to control tumor growth.
Global Commercialization and Availability
Pfizer holds exclusive rights to commercialize Braftovi in the U.S., Canada, Latin America, the Middle East, and Africa. Other companies manage distribution in various regions:
Ono Pharmaceutical Co., Ltd. – Japan and South Korea
Medison – Israel
Pierre Fabre Laboratories – Europe and Asia (excluding Japan and South Korea)
Indications and Usage
Braftovi, in combination with cetuximab and mFOLFOX6, is approved for treating metastatic colorectal cancer (mCRC) patients with a BRAF V600E mutation, as confirmed by an FDA-approved test. This approval is based on response rate and durability of response, with continued approval contingent upon further confirmatory trials.
Additionally, Braftovi, in combination with cetuximab, is indicated for adult patients with BRAF V600E-mutant mCRC after prior therapy. However, it is not approved for patients with wild-type BRAF CRC.
Looking Ahead
As reported by pharmabiz.com, with these promising results from the BREAKWATER study, Pfizer aims to solidify Braftovi’s role as a leading targeted therapy for metastatic colorectal cancer. By working with global regulators, Pfizer hopes to make this innovative treatment available to more patients worldwide, offering a new standard of care for those with BRAF V600E-mutant mCRC.