Pfizer has reported strong new data from its Phase 3 BREAKWATER study showing that its targeted cancer drug BRAFTOVI, when combined with cetuximab and the FOLFIRI chemotherapy backbone, significantly improves tumor response in patients with previously untreated metastatic colorectal cancer carrying the BRAF V600E mutation.
Results from Cohort 3 of the trial showed that 64.4 percent of patients treated with the BRAFTOVI-based combination achieved an objective tumor response, compared with 39.2 percent of patients receiving standard FOLFIRI chemotherapy with or without bevacizumab. The difference was statistically significant and was confirmed by an independent central review.
More than half of patients in the BRAFTOVI group, 57.4 percent, maintained their response for at least six months, compared with 34.5 percent in the control arm. Median duration of response has not yet been reached in either group, indicating continued benefit in many patients.
Early overall survival analysis also favored the BRAFTOVI combination, with a hazard ratio of 0.49 after a median follow-up of about ten months, although the study is ongoing and survival data are still maturing. The full BREAKWATER trial is expected to conclude in 2027.
The data support the use of FOLFIRI as an additional chemotherapy backbone alongside BRAFTOVI and cetuximab, expanding treatment flexibility for patients with BRAF V600E-mutant metastatic colorectal cancer, a form of the disease associated with particularly poor outcomes.
The safety profile of the BRAFTOVI-cetuximab-FOLFIRI regimen was consistent with known side effects of the individual drugs. The most common adverse events included nausea, diarrhea, vomiting, hair loss, anemia, fatigue, neutropenia, appetite loss, skin reactions, weight loss, joint pain and rash. About 8.5 percent of patients stopped BRAFTOVI permanently due to side effects.
The BRAFTOVI-cetuximab-FOLFIRI regimen is not yet approved. However, BRAFTOVI in combination with cetuximab and mFOLFOX6 received accelerated approval from the U.S. Food and Drug Administration in December 2024 for first-line treatment of BRAF V600E-mutant metastatic colorectal cancer based on improved response rates. Continued approval is dependent on confirmation of long-term clinical benefit.
BREAKWATER is a global Phase 3 trial evaluating BRAFTOVI with cetuximab, alone or with chemotherapy, in patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer. In Cohort 3, 147 patients were randomized to receive either BRAFTOVI plus cetuximab and FOLFIRI or standard FOLFIRI with or without bevacizumab. The primary endpoint was objective response rate, with progression-free survival and overall survival as key secondary measures.
Colorectal cancer is the third most common cancer globally and the second leading cause of cancer-related deaths. BRAF mutations are found in about 8–12 percent of metastatic colorectal cancers, with the V600E mutation linked to aggressive disease and poor survival.
BRAFTOVI is an oral targeted therapy designed to inhibit the BRAF V600E mutation, which drives cancer growth through the MAPK signaling pathway.
