Pfizer's Braftovi Combo Shows Improved Survival in Metastatic Colorectal Cancer Trial

Pfizer Inc. announced positive topline progression-free survival results from Cohort 3, a separate randomized 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. The Braftovi regimen demonstrated a statistically significant and clinically meaningful improvement in PFS, a key secondary endpoint, as assessed by blinded independent central review (BICR) compared to treatment with Folfiri with or without bevacizumab.

Overall survival (OS), a descriptive secondary endpoint, also showed clinically meaningful prolonged improvement with the Braftovi regimen. The primary endpoint of this cohort of BREAKWATER was objective response rate (ORR) by BICR. Positive ORR results were achieved and recently presented at the 2026 American Society of Clinical Oncology Gastrointestinal (ASCO GI) Cancers Symposium.

The Braftovi combination regimen with cetuximab demonstrated a clinically meaningful and statistically significant improvement in confirmed objective response rate 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). Overall, the Phase 3 BREAKWATER trial demonstrated a clinically meaningful and statistically significant improvement in confirmed ORR compared to patients receiving chemotherapy with or without bevacizumab (60.9% vs. 40.0%).

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.

Braftovi in combination with cetuximab and Folfiri is an investigational regimen and is not currently approved. Detailed results from this cohort will be submitted for presentation at an upcoming medical meeting and shared with the US Food and Drug Administration (FDA) to support potential approval for Braftovi in combination with cetuximab and Folfiri in patients with BRAF V600E-mutant mCRC.

Braftovi in combination with cetuximab and mFOLFOX6 received accelerated approval by the 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. The approved Braftovi regimen reduced the risk of disease progression or death by 47% compared to standard-of-care chemotherapy with or without Avastin, meeting the study's dual primary endpoint. The regimen also lowered the risk of death by 51% compared to chemotherapy with or without Avastin.

BREAKWATER 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 mCRC. 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). The dual primary endpoints for these study groups are ORR and PFS as assessed by BICR. OS is a key secondary endpoint. In Cohort 3, patients were randomized to receive Braftovi 300 mg orally once daily in combination with cetuximab and Folfiri (n=73) or Folfiri, with or without bevacizumab (control-arm) (n=74). The primary endpoint of Cohort 3 is ORR as assessed by BICR. PFS is a key secondary endpoint; OS is a secondary endpoint.

Colorectal cancer (CRC) 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 CRC is about 1 in 24 for men and 1 in 26 for women. In the US alone, an estimated 154,270 people will be diagnosed with cancer of the colon or rectum in 2025, and approximately 53,000 are estimated to die from the disease each year. For 20% of those diagnosed with CRC, the disease has metastasized, or spread, making it harder to treat, and up to 50% of patients with localized disease eventually develop metastases.

BRAF mutations are estimated to occur in 8-12% of people with mCRC and represent a poor prognosis for these patients. The BRAF V600E mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAF V600E mutation is more than double that of patients with no known mutation present. Despite the high unmet need in BRAF V600E-mutant mCRC, prior to December 20, 2024 there were no approved biomarker-driven therapies specifically indicated for people with previously untreated BRAF V600E-mutant mCRC.

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