At a Glance
- Pfizer reports positive PFS BREAKWATER Cohort 3 BRAFTOVI + cetuximab + FOLFIRI significantly improves outcomes vs. FOLFIRI ± bevacizumab in first-line BRAF V600E-mutant mCRC.
- Builds on prior ORR success presented at 2026 ASCO GI, with OS trends favourable and safety consistent with known profiles.
- FDA accelerated approval granted Dec 2024 for BRAFTOVI + cetuximab + mFOLFOX6; continued approval pending confirmatory data.
- Full Cohort 3 results to support FDA submission for BRAFTOVI + cetuximab + FOLFIRI approval in this indication.
Written By: Sana Khan BPharm
Reviewed By: Pharmacally Editorial Team
Pfizer announced positive progression-free survival (PFS) results from Cohort 3 of the Phase 3 BREAKWATER trial, evaluating BRAFTOVI (encorafenib) with cetuximab and FOLFIRI in previously untreated metastatic colorectal cancer (mCRC) patients harboring BRAF V600E mutations.
The regimen met its key secondary PFS endpoint with statistically significant and clinically meaningful improvement over standard FOLFIRI with or without bevacizumab, as assessed by blinded independent central review (BICR). Overall survival (OS) also trended positively as a descriptive secondary endpoint.
Pfizer’s Chief Oncology Officer Jeff Legos highlighted that the PFS results build on prior positive ORR data, reinforcing BRAFTOVI’s meaningful benefits for BRAF V600E-mutant mCRC patients. He emphasized the combination of strong responses and survival gains as evidence of its potential to transform treatment for this challenging disease.
BREAKWATER Trial
BREAKWATER (NCT04607421) Cohort 3 randomized 73 patients to BRAFTOVI (300 mg orally daily) plus cetuximab and FOLFIRI versus 74 to control FOLFIRI ± bevacizumab. The primary endpoint was objective response rate (ORR) by BICR, previously reported as positive at the 2026 ASCO GI Symposium with 64% ORR in the experimental arm versus 39% in control. PFS served as a key secondary endpoint, building on prior ORR data to demonstrate tumor control benefits in this high-risk population.
The trial results were published in New England Journal of Medicine.
Clinical Implications
BRAF V600E mutations occur in 8-12% of mCRC cases and double mortality risk compared to wild-type tumors, with limited prior first-line targeted options until recent approvals. These results reinforce BRAFTOVI combinations as potential standards,
following FDA accelerated approval in December 2024 for BRAFTOVI + cetuximab + mFOLFOX6 based on ORR in treatment-naïve patients (continued approval pending confirmatory data).
Detailed PFS and OS data will support FDA submission for BRAFTOVI + cetuximab + FOLFIRI.
Safety Profile
At PFS analysis, the safety of BRAFTOVI with cetuximab and FOLFIRI aligned with known profiles of individual agents, showing no new signals. Common adverse reactions (≥25%) from related BREAKWATER data with mFOLFOX6 include peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia; Grade 3/4 lab abnormalities (≥10%) feature increased lipase, decreased neutrophils/haemoglobin/WBCs, and increased glucose.
For full details on adverse events, warnings, and precautions, refer to the [BRAFTOVI prescribing information].
BRAFTOVI
BRAFTOVI is a BRAF V600E-targeted kinase inhibitor disrupting aberrant MAPK signaling in BRAF-mutant cancers like mCRC. Pfizer holds rights in key regions; the regimen remains investigational with FOLFIRI pending approval. Colorectal cancer affects 1.8 million globally yearly, with mCRC posing high unmet need.
Reference
Pfizer’s BRAFTOVI Regimen Improves Progression-Free Survival in Metastatic Colorectal Cancer, 17 Feb 2026. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-braftovi-regimen-improves-progression-free-survival
A Study of Encorafenib Plus Cetuximab with or Without Chemotherapy in People with Previously Untreated Metastatic Colorectal Cancer, ClinicalTrials.gov ID NCT04607421, https://clinicaltrials.gov/study/NCT04607421
Elena Elez et al, Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer, N Engl J Med 2025;392:2425-2437, https://www.nejm.org/doi/abs/10.1056/NEJMoa2501912