Braftovi combination regimen demonstrates improved response in patients with BRAF V600E-mutant metastatic colorectal cancer – Pfizer

Pfizer Inc. announced positive results from the Phase III BREAKWATER trial evaluating Braftovi (encorafenib) in combination with cetuximab  (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  in an oral presentation (Abstract 16) at the ongoing 2025 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI) and were simultaneously published in Nature Medicine.

BREAKWATER is a randomized, active-controlled, open-label, multicenter trial of Braftovi  with cetuximab, alone or in combination with mFOLFOX6 in participants with previously untreated BRAF V600E-mutant mCRC. Patients were randomized to receive Braftovi  300 mg orally once daily in combination with cetuximab (discontinued after randomization of 158 patients), Braftovi 300 mg orally once daily in combination with cetuximab and mFOLFOX6 (n=236) or mFOLFOX6, FOLFOXIRI, or CAPOX each with or without bevacizumab (control-arm) (n=243). The dual primary endpoints are ORR, which was met at the time of analysis, and PFS as assessed by BICR. OS is a key secondary endpoint.

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 onBraftovi 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 BraftoviI 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.

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.

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 Prof. Scott Kopetz,  Deputy Chairman 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.”

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 Dr. Roger Dansey, 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.”

See citation-  Kopetz S., Yoshino T., Van Cutsem E. et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med  2025. https://doi.org/10.1038/s41591-024-03443-3