Braftovi (encorafenib) regimen with additional chemotherapy backbone increased response rates for certain patients with metastatic colorectal cancer – Pfizer

Pfizer Inc.  announced positive results from Cohort 3, a separate randomized cohort of the pivotal BREAKWATER trial, evaluating Braftovi (encorafenib) in combination with cetuximab (Erbitux) and FOLFIRI (fluorouracil, leucovorin, and irinotecan) in patients with previously untreated metastatic colorectal cancer (mCRC) with a BRAF V600E mutation. At the time of this analysis, the Braftovi combination regimen with FOLFIRI and cetuximab 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 standard-of-care treatment FOLFIRI with or without bevacizumab (64.4% vs 39.2%, odds ratio =2.76, p=0.001). These data will be presented in an oral presentation (Abstract 13) at the 2026 American Society of Clinical Oncology Gastrointestinal (ASCO GI) Cancers Symposium and highlighted in the ASCO GI official press program.

The estimated median duration of response as assessed by BICR was not estimable with Braftovi plus cetuximab and FOLFIRI (95% Confidence Interval [CI]: not estimable [NE]-NE) or with FOLFIRI with or without bevacizumab (95% CI: 7.0 months-NE). Of patients on Braftovi plus cetuximab and FOLFIRI, 57.4% had a response lasting 6 months or longer, compared to 34.5% with FOLFIRI with or without bevacizumab.

Overall survival (OS) data were analyzed descriptively (Hazard Ratio [HR]: 0.49, 95% CI: 0.24-1.03; median follow-up of approximately 10 months for both arms). The BREAKWATER trial is ongoing with an estimated completion in 2027.

The safety profile of Braftovi in combination with cetuximab and FOLFIRI was consistent with the known safety profile of each respective agent. No new safety signals were identified. The most common side effects (≥15%) were nausea, diarrhea, vomiting, alopecia, anemia, neutrophil count decreased, decreased appetite, fatigue, neutropenia, skin hyperpigmentation, dry skin, asthenia, weight decreased, arthralgia, palmar-plantar erythrodysaesthesia syndrome, rash, white blood cell count decreased, and constipation. Among patients receiving Braftovi in combination with cetuximab and FOLFIRI, 8.5% experienced an adverse reaction that resulted in permanent discontinuation of Braftovi.

“These results represent a great advance for patients with BRAF V600E-mutant metastatic colorectal cancer. We’ve seen this approach significantly increase the response compared to FOLFIRI with or without bevacizumab, and these responses were rapid and durable,” said Dr. Scott Kopetz, Professor and Deputy Chairman of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center and co-principal investigator of the BREAKWATER trial. “The trial supports the potential for another chemotherapy backbone option that may be paired with encorafenib plus cetuximab in this patient population.”

“These data further strengthen the potential utility of BRAFOTVI for patients with BRAF V600E-mutant metastatic colorectal cancer. The significant improvement in response rates reflects the meaningful clinical benefit of this targeted combination therapy regimen for patients,” said Jeff Legos, Chief Oncology Officer, Pfizer. “These results underscore the potential of BRAFTOVI as a standard of care for patients with this aggressive cancer and reflect our commitment to advancing precision medicine options that help tailor treatment based on patients’ needs.”

BREAKWATER is a Phase III, randomized, active-controlled, open-label, multicenter trial of Braftovi  with cetuximab, alone or in combination with chemotherapy (mFOLFOX6 or FOLFIRI) in participants with previously untreated BRAF V600E-mutant mCRC (NCT04607421). 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, with or without bevacizumab (control arm) (n=243). The dual primary endpoints for these study groups are ORR and PFS as assessed by BICR. OS is a key secondary endpoint. In Cohort 3, patients were randomized to receive Braftovi 300 mg orally once daily in combination with cetuximab and FOLFIRI (n=73) or FOLFIRI, with or without bevacizumab (control-arm) (n=74). The primary endpoint of Cohort 3 is ORR as assessed by BICR. PFS is a key secondary endpoint; OS is a secondary endpoint.