Pfizer Inc. (NYSE: PFE) announced positive results from the Phase 3 BREAKWATER trial evaluating BRAFTOVI^® (encorafenib) in combination with cetuximab (marketed as ERBITUX^® ) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) in patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation. At the time of this analysis, the BRAFTOVI combination regimen demonstrated a clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) assessed by blinded independent central review (BICR) compared to patients receiving chemotherapy with or without bevacizumab (60.9% vs 40.0%, odds ratio =2.443, p=0.0008). These results will be presented today in an oral presentation (Abstract 16) at the 2025 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI) and were simultaneously published in Nature Medicine.

“Despite the high unmet need in this patient population, prior to the recent encorafenib combination regimen approval, there were no approved biomarker-driven therapies indicated for people with previously untreated 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. “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.”

The estimated median duration of response as assessed by BICR was 13.9 months (95% Confidence Interval [CI]: 8.5-not estimable [NE]) with BRAFTOVI plus cetuximab and mFOLFOX6 and 11.1 months (95% CI: 6.7-12.7) with chemotherapy with or without bevacizumab. Of patients on BRAFTOVI plus cetuximab and mFOLFOX6, 22.4% (n=15) had a response lasting 12 months or longer, compared to 11.4% (n=5) with chemotherapy with or without bevacizumab. The median time to response as assessed by BICR was 7.1 weeks (range 5.7-53.7) with BRAFTOVI plus cetuximab and mFOLFOX6 and 7.3 weeks (range 5.4-48.0) with chemotherapy with or without bevacizumab.

Overall survival (OS) data were immature at the time of this analysis but demonstrated a promising trend in favor of BRAFTOVI plus cetuximab and mFOLFOX6 compared to patients receiving chemotherapy with or without bevacizumab. Median OS with BRAFTOVI plus cetuximab with chemotherapy was not estimable (95% CI: 19.8-NE) and 14.6 months (95% CI: 13.4-NE) with chemotherapy with or without bevacizumab (Hazard Ratio [HR]: 0.47, 95% CI: 0.318-0.691). The BREAKWATER trial is ongoing for OS and progression-free survival (PFS), with PFS results expected in 2025.

“These results of this first analysis were the basis for the first approval of a targeted therapy regimen for use in the first-line setting for patients with metastatic colorectal cancer with a BRAF V600E mutation,” said Roger Dansey, M.D., Chief Oncology Officer, Pfizer. “We are highly encouraged by these response results, which are indicative of the clinically meaningful benefit of BRAFTOVI in reducing tumor size or having no detectable cancer, along with the promising interim analysis of overall survival. We look forward to additional read-outs from the BREAKWATER trial this year.”

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.

BRAFTOVI in combination with cetuximab and mFOLFOX6 was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of patients with BRAFV600E -mutant mCRC in December 2024. The 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. The BREAKWATER data are also being discussed with other regulatory authorities around the world to support potential future additional license applications for the BRAFTOVI combination regimen in this indication.

Pfizer is continuing its commitment to help non-scientists understand the latest findings with the development of abstract plain language summaries (APLS) for company-sponsored research being presented, which are written in non-technical language. Those interested in learning more can visit www.Pfizer.com/apls to access the summaries.