FDA grants full approval to Braftovi combination regimen in first-line metastatic colorectal cancer – Pfizer

Pfizer Inc. announced the  FDA has granted full approval to Braftovi (encorafenib) in combination with cetuximab (Erbitux ) and fluorouracil-based chemotherapy for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation based on results from the global Phase III BREAKWATER trial (NCT04607421).

Braftovi in combination with cetuximab and mFOLFOX6 was granted accelerated approval by the FDA in December 2024 based on objective response rate (ORR) results, one of the BREAKWATER trial’s dual primary endpoints. The conversion from accelerated approval to full approval is based on significant benefit in outcomes for both progression-free survival (PFS), the trial’s other primary endpoint, and overall survival (OS), a key secondary endpoint, from the Phase III portion of the study that evaluated Braftovi  in combination with cetuximab and mFOLFOX6, as well as the ORR results from the Cohort 3 portion of the study, which evaluated Braftovi  in combination with cetuximab and FOLFIRI.

In the BREAKWATER study, the safety profile of both combination regimens continued to be consistent with the known safety profile of each respective agent in the regimen. No new safety signals were identified. The most common side effects (≥25%) in the mFOLFOX6 regimen were peripheral neuropathy, nausea, fatigue, diarrhea, decreased appetite, rash, vomiting, hemorrhage, abdominal pain, arthralgia, pyrexia, and constipation. The most common side effects (≥25%) in the FOLFIRI regimen were nausea, diarrhea, fatigue, vomiting, alopecia, constipation, abdominal pain, decreased appetite, and rash.

Among patients receiving Braftovi in combination with cetuximab and mFOLFOX6, 14% experienced an adverse reaction that resulted in permanent discontinuation of Braftovi.  There was no substantial difference in chemotherapy discontinuation due to side effects in the Braftovi in combination with cetuximab and mFOLFOX6 arm compared with the chemotherapy, with or without bevacizumab arm. Among patients receiving Braftovi in combination with cetuximab and FOLFIRI, 9% experienced an adverse reaction that resulted in permanent discontinuation of Braftovi.

The  Braftovi. combination regimen with mFOLFOX6 is also under regulatory review in Europe, where Pierre Fabre Laboratories has exclusive commercialization rights, and was recently approved for use in several other countries.

BREAKWATER (NCT04607421) is a Phase III, randomized, active-controlled, open-label, multicenter trial of Braftovi with cetuximab, alone or in combination with mFOLFOX6 or FOLFIRI (both fluorouracil-based chemotherapies) in participants with previously untreated BRAF V600E-mutant mCRC.

Phase III Analysis:  Braftovi in combination with cetuximab and mFOLFOX6:
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.

At the time of the PFS primary analysis,  Braftovi in combination with cetuximab and mFOLFOX6 significantly reduced the risk of disease progression or death by 47% compared to chemotherapy with or without bevacizumab (hazard ratio [HR] 0.53; 95% confidence interval [CI], 0.41, 0.68; p<0.0001) as assessed by blinded independent central review (BICR). Median PFS was 12.8 months (95% CI, 11.2, 15.9) with the  Braftovi combination regimen compared to 7.1 months (95% CI, 6.8, 8.5) with chemotherapy with or without bevacizumab. In a second interim analysis of median OS,  Braftovi plus cetuximab and mFOLFOX6 significantly reduced the risk of death by 51% compared to chemotherapy, with or without bevacizumab (HR 0.49; 95% CI, 0.38, 0.63; p<0.0001). Median OS doubled from 15.1 months with chemotherapy, with or without bevacizumab (95% CI, 13.7, 17.7) to 30.3 months (95% CI, 21.7, Not Estimated) with the  Braftovi combination regimen. These data were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the New England Journal of Medicine.

Cohort 3 Analysis:  Braftovi in combination with cetuximab and FOLFIRI:
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 summarized descriptively.

Braftovi plus cetuximab and FOLFIRI demonstrated a clinically meaningful and statistically significant improvement in confirmed ORR assessed by BICR compared to patients receiving FOLFIRI with or without bevacizumab (64% vs 39%, odds ratio =2.76, p=0.0011). These data were presented at the 2026 American Society of Clinical Oncology Gastrointestinal (ASCO GI) Cancers Symposium. Detailed PFS results from Cohort 3 will be submitted for presentation at an upcoming medical meeting.

“This landmark approval, achieved through the robust clinical benefit demonstrated in the BREAKWATER trial, validates that this targeted therapy can impact outcomes for people living with an aggressive, hard-to-treat cancer,” said Aamir Malik, Executive Vice President, Chief U.S. Commercial Officer, Pfizer. “As the only targeted combination regimen shown to deliver a significant improvement in certain outcomes for patients with BRAF V600E‑mutant metastatic colorectal cancer, BRAFTOVI is uniquely positioned to redefine first‑line treatment and establish a new standard of care. This approval reinforces our leadership in bringing differentiated, potentially practice‑changing cancer therapies to patients and healthcare providers who urgently need improved options.”

“This approval gives oncologists confidence to use encorafenib plus cetuximab in combination with fluorouracil-based chemotherapy as a first-line standard of care for patients with BRAF V600E-mutant metastatic colorectal cancer,” said Dr. Scott Kopetz, Professor and Deputy Chairman of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center and co-principal investigator of the BREAKWATER trial. “The BREAKWATER study demonstrated that these targeted combination regimens provided statistically significant benefit, providing the robust evidence we need to make treatment decisions that can meaningfully impact patient outcomes.”

See most recent citation- Elez E, Yoshino T, Shen L, et al. Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. N Engl J Med. 2025, 392:2425 doi: 10.1056/NEJMoa2501912.