FDA Grants Traditional Approval to Encorafenib Combination for Metastatic CRC With BRAF V600E Mutation

Today, the FDA granted a traditional approval to encorafenib (Braftovi; Array BioPharma Inc) in combination with cetuximab and fluorouracil-based chemotherapy for adult patients with metastatic colorectal cancer (CRC) harboring a BRAF V600E mutation.¹

The therapy previously received accelerated approval in December 2024 for the same indication in combination with cetuximab and the modified FOLFOX-6 (mFOLFOX6) chemotherapy regimen.² Like the accelerated approval, today’s decision was based on data from the BREAKWATER trial (NCT04607421), a randomized, active-controlled, open-label, multicenter study in treatment-naive patients with metastatic CRC with a BRAF V600E mutation.¹

“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,” Aamir Malik, executive vice president and chief US commercial officer of Pfizer, said in a news release.³ “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.”

In the phase 3 portion of the trial, patients were initially randomized 1:1:1 to encorafenib orally once daily with a cetuximab intravenous (IV) infusion every 2 weeks (arm A)¹; encorafenib orally once daily with a cetuximab IV infusion every 2 weeks and mFOLFOX6 every 2 weeks (arm B); or mFOLFOX6/FOLFOXIRI every 2 weeks or CAPOX every 3 weeks, with or without bevacizumab (arm C). Arms A and B were experimental, whereas arm C was the control arm.

The trial was later amended to limit randomization to arms B and C. At the same time, cohort 3 was added, in which patients were randomized 1:1 to encorafenib orally once daily with a cetuximab IV infusion and FOLFIRI every 2 weeks (arm D) or FOLFIRI every 2 weeks, with or without bevacizumab (arm E); arm D was experimental, while arm E was the control arm. Treatment continued in all arms until disease progression, unacceptable toxicity, consent withdrawal, loss to follow-up, or death.

The primary efficacy outcomes in the phase 3 portion included progression-free survival (PFS) in all randomized patients and objective response rate (ORR) in the first 110 patients per blinded, independent, central review (BICR). Overall survival (OS) was an additional formally tested outcome measure, analyzed across all patients.

A total of 236 patients were randomized to arm B and 243 to arm C. The median PFS was 12.8 months (95% CI, 11.2-15.9) in arm B and 7.1 months (95% CI, 6.8-8.5) in arm C (HR, 0.53; 95% CI, 0.41-0.68; P < .0001). In addition, the median OS was 30.3 months (95% CI, 21.7–not estimable) in arm B and 15.1 months (95% CI, 13.7-17.7) in arm C (HR, 0.49; 95% CI, 0.38-0.63; P < .0001), with an objective response rate (ORR) of 61% and 40% (95% CI, 31%-49%; P = .0008), respectively.

Meanwhile, in cohort 3, the major efficacy outcome measure was ORR per BICR. A total of 73 patients were randomized to arm D and 74 to arm E, with an ORR of 64% (95% CI, 53%-74%) and 39% (95% CI, 29%-51%), respectively (P = .0011).

The recommended encorafenib dose is 300 mg, or four 75-mg capsules, orally once daily in combination with either cetuximab and mFOLFOX6 or cetuximab and FOLFIRI until disease progression or unacceptable toxicity. Key safety considerations include new primary malignancies, tumor promotion in BRAF-wild-type tumors, cardiomyopathy, hepatotoxicity, hemorrhage, uveitis, QT prolongation, and embryo-fetal toxicity.

References

1. FDA grants traditional approval to encorafenib for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA. February 24, 2026. Accessed February 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-encorafenib-metastatic-colorectal-cancer-braf-v600e-mutation
2. Bonavitacola J. FDA approves encorafenib with cetuximab and mFOLFOX6 for metastatic CRC. AJMC. December 20, 2024. Accessed February 24, 2026. https://www.ajmc.com/view/fda-approves-encorafenib-with-cetuximab-and-mfolfox6-for-metastatic-crc
3. US FDA grants full approval to Pfizer’s Braftovi combination regimen in first-line metastatic colorectal cancer. News release. Pfizer. February 24, 2026. Accessed February 24, 2026. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-grants-full-approval-pfizers-braftovi-combination