Pfizer's BRAFTOVI Regimen Shows Significant PFS Improvement in Colorectal Cancer Trial

Pfizer announced groundbreaking results from Cohort 3 of its pivotal BREAKWATER trial on February 17, showing that its BRAFTOVI (encorafenib) regimen significantly extends progression-free survival in patients with previously untreated metastatic colorectal cancer. The regimen combines BRAFTOVI with cetuximab and FOLFIRI chemotherapy.

Results from a blinded independent central review (BICR) showed a statistically significant and clinically meaningful improvement in PFS compared with standard treatments. Overall survival (OS) also trended favorably.

"These results build on the positive objective response rate data we recently shared, providing further evidence of the meaningful benefit this BRAFTOVI-based targeted approach may offer patients with BRAF V600E–mutant metastatic colorectal cancer," said the Chief Oncology Officer at Pfizer. "The combination of significant responses and now improvement in progression‑free survival underscores the potential of BRAFTOVI as a potentially practice-changing treatment option for patients and families facing this challenging diagnosis."

BREAKWATER is a Phase 3, randomized, open-label trial testing BRAFTOVI in combination with cetuximab, either alone or with chemotherapy, in patients with untreated BRAF V600E-mutant metastatic colorectal cancer. Cohort 3 included 73 patients receiving BRAFTOVI with cetuximab and FOLFIRI and 74 in a control arm receiving FOLFIRI, with or without bevacizumab. The cohort's primary endpoint was objective response rate (ORR), with PFS and OS as secondary endpoints.

The primary endpoint of this cohort was objective response rate by BICR. Positive ORR results were achieved and recently presented at the 2026 American Society of Clinical Oncology Gastrointestinal (ASCO GI) Cancers Symposium. At the time of the PFS analysis, the safety profile of BRAFTOVI in combination with cetuximab and FOLFIRI was consistent with the known profile of each regimen component and no new safety signals were identified.

Pfizer is hoping to seek US regulatory approval for the combination of BRAFTOVI and cetuximab plus chemotherapy as a first-line treatment for BRAF V600E-mutant metastatic colorectal cancer. Detailed results from this cohort will be submitted for presentation at an upcoming medical meeting and shared with the FDA.

BRAFTOVI in combination with cetuximab and mFOLFOX6 received accelerated approval by the FDA in December 2024 for patients with BRAF V600E-mutant metastatic colorectal cancer 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.

The broader BREAKWATER trial is a Phase 3, 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 metastatic colorectal cancer. 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).

Colorectal cancer is the third most common type of cancer in the world, with approximately 1.8 million new diagnoses in 2022. It is the second leading cause of cancer-related deaths. Overall, the lifetime risk of developing colorectal cancer is about 1 in 24 for men and 1 in 26 for women. BRAF mutations are estimated to occur in 8 to 12 percent of metastatic colorectal cancer cases.

BRAFTOVI is an oral small molecule kinase inhibitor that targets BRAF V600E. Inappropriate activation of proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK) has been shown to occur in certain cancers, including colorectal cancer.