Pfizer’s BRAFTOVI Cuts Progression Risk by 56% in BRAF V600E mCRC

Pfizer reported Phase 3 BREAKWATER Cohort 3 (NCT04607421) results showing that BRAFTOVI (encorafenib) combined with cetuximab and FOLFIRI significantly improved progression-free survival (PFS) and overall survival (OS) versus standard chemotherapy in previously untreated patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC).

The findings were presented in a late-breaking session at the 2026 ASCO Annual Meeting and simultaneously published in Annals of Oncology.

The randomized cohort previously met its primary endpoint of objective response rate. Newly reported data further demonstrated meaningful improvements in disease control and survival.

Scientific Context

BRAFTOVI is an oral BRAF inhibitor that targets the BRAF V600E mutation, a key driver of tumor growth through activation of the MAPK signaling pathway. BRAF mutations occur in approximately 8% to 12% of metastatic colorectal cancer cases and are associated with aggressive disease and poor prognosis.

BREAKWATER was launched to evaluate whether combining targeted therapy with standard chemotherapy could improve outcomes in the first-line setting for this high-risk patient population.

Efficacy Results

Cohort 3 randomized 147 patients to receive either BRAFTOVI, cetuximab, and FOLFIRI (n=73) or FOLFIRI with or without bevacizumab (n=74).

The targeted regimen nearly doubled median progression-free survival, extending PFS to 15.2 months compared with 8.3 months in the control arm. Treatment reduced the risk of disease progression or death by 56% (HR 0.44; 95% CI, 0.27–0.70; p=0.0002).

Updated overall survival results also favored the BRAFTOVI-based regimen. With approximately 20 months of median follow-up, treatment reduced the risk of death by 44% (HR 0.56; 95% CI, 0.34–0.94). Median OS was not reached in the experimental arm, compared with 20.3 months in the control group.

At 18 months, 72% of patients receiving the BRAFTOVI regimen were estimated to be alive versus 54.5% in the comparator arm.

Safety Profile

The safety profile remained consistent with the known profiles of the individual agents, and no new safety signals were identified.

Grade 3 or higher adverse events occurred in 70.4% of patients receiving the BRAFTOVI regimen compared with 80.9% in the control arm. Common adverse events included nausea, diarrhea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, constipation, arthralgia, and abdominal pain. Treatment discontinuation occurred in 15.5% and 10.3% of patients, respectively.

Clinical Significance and Regulatory Pathway

Scott Kopetz, MD, PhD, co-principal investigator of BREAKWATER at The University of Texas MD Anderson Cancer Center, said the findings reinforce encorafenib-based therapy as a first-line standard of care for patients with BRAF V600E-mutant mCRC.

Pfizer’s Chief Oncology Officer Jeff Legos said the results strengthen evidence supporting the BRAFTOVI combination across multiple chemotherapy backbones.

The findings build on the broader BREAKWATER program, which supported the FDA’s full approval of BRAFTOVI in February 2026 for patients with BRAF V600E-mutant mCRC. The expanded indication allows use with cetuximab and fluorouracil-based chemotherapy, including both mFOLFOX6 and FOLFIRI regimens.

Together with earlier BREAKWATER data, Cohort 3 further supports biomarker-driven therapy as a preferred first-line treatment approach for patients with BRAF V600E-mutant metastatic colorectal cancer.

Reference

Pfizer’s BRAFTOVI Regimen Nearly Doubles Median Progression-Free Survival in Metastatic Colorectal Cancer | Pfizer