Pfizer's Braftovi (encorafenib) in combination with cetuximab and mFOLFOX6 has demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation. These findings from the Phase 3 BREAKWATER trial support the potential of this targeted treatment regimen to become a new standard of care for this patient population.
The BREAKWATER trial (NCT04607421) is a randomized, active-controlled, open-label, multicenter trial evaluating Braftovi in combination with cetuximab and mFOLFOX6 in patients with previously untreated BRAF V600E-mutant mCRC. The trial's dual primary endpoints were overall response rate (ORR) and PFS, with OS as a key secondary endpoint. The study met its ORR endpoint, demonstrating a clinically meaningful and statistically significant improvement in confirmed ORR compared to patients receiving chemotherapy with or without bevacizumab (60.9% vs 40.0%, p=0.0008).
Improved Survival Outcomes
The latest results from the BREAKWATER trial showcase a statistically significant and clinically meaningful improvement in PFS with the Braftovi combination compared to chemotherapy. Furthermore, the Braftovi regimen demonstrated a statistically significant and clinically meaningful improvement in OS, a key secondary endpoint in the trial. These results suggest a potential practice-changing impact for patients with BRAF V600E-mutant mCRC, who have historically faced limited treatment options and poor outcomes.
Accelerated FDA Approval
In December 2024, the FDA granted accelerated approval to Braftovi in combination with cetuximab and mFOLFOX6 for treatment-naïve patients with BRAF V600E-mutant mCRC. This approval was based on the clinically meaningful and statistically significant improvement in confirmed ORR observed in the BREAKWATER trial. The accelerated approval was among the first in the industry to be conducted under the FDA’s Project FrontRunner, which seeks to support the development and approval of new cancer drugs for advanced or metastatic disease.
Safety and Tolerability
The safety profile of Braftovi in combination with cetuximab and mFOLFOX6 in the BREAKWATER trial was consistent with the known safety profile of each respective agent. No new safety signals were identified. Serious treatment-emergent adverse events occurred in 37.7% of patients receiving Braftovi in combination with cetuximab and mFOLFOX6 compared to 34.6% of patients receiving chemotherapy with or without bevacizumab.
Implications for Clinical Practice
The results from the BREAKWATER trial have the potential to transform the treatment landscape for patients with BRAF V600E-mutant mCRC. 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 these patients. Pfizer plans to share these data with global health authorities to bring this treatment to more patients around the world, as soon as possible.
According to 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, "These data from the BREAKWATER study show the potential for this targeted treatment regimen to become the new standard of care for people with BRAF V600E-mutant metastatic colorectal cancer, for whom long-term disease control is critical."
