Pfizer announced positive results from Cohort 3, a separate randomised cohort of the pivotal BREAKWATER trial, evaluating BRAFTOVI (encorafenib) in combination with cetuximab (marketed as 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 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. The trial supports the potential for another chemotherapy backbone option that may be paired with encorafenib plus cetuximab in this patient population,” said Scott Kopetz, MD, PhD, FACP, Professor and Deputy Chair—Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center and co-principal investigator of the BREAKWATER trial.

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 percent had a response lasting six months or longer, compared to 34.5 percent with FOLFIRI with or without bevacizumab.

The Overall Survival (OS) data were analysed 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.

“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. 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,” said Jeff Legos, Chief Oncology Officer, Pfizer.

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, diarrhoea, vomiting, alopecia, anaemia, 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 percent experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI.

BRAFTOVI in combination with cetuximab and FOLFIRI is an investigational regimen and is not currently approved for use. BRAFTOVI in combination with cetuximab and mFOLFOX6 received accelerated approval by the US Food and Drug Administration (FDA) in December 2024 for patients with BRAF V600E -mutant mCRC based on a clinically meaningful and statistically significant improvement in confirmed ORR in treatment-naïve patients, one of the study’s primary endpoints. Continued approval for this indication is contingent upon verification of clinical benefit.