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FDA Grants Full Approval to Encorafenib Plus Cetuximab/Chemotherapy for BRAF V600E+ mCRC

Author(s)Courtney Flaherty

Fact checked by: Kyle Doherty

  • Traditional approval covers encorafenib plus cetuximab with fluorouracil-based chemotherapy for adult BRAF V600E–mutant mCRC, requiring mutation detection via an FDA-approved companion diagnostic test.
  • BREAKWATER arm B achieved ORR 61% versus 40% with chemotherapy ± bevacizumab (P = .0008), supporting superior antitumor activity with the targeted doublet plus mFOLFOX6.
  • Median PFS improved to 12.8 months versus 7.1 months (HR, 0.53; P < 0.0001), indicating substantial disease-control benefit over standard chemotherapy-based approaches.
  • Median OS was 30.3 months versus 15.1 months (HR, 0.49; P < 0.0001), demonstrating a marked survival advantage consistent with confirmatory evidence for full approval.
  • The decision formalizes and replaces the December 2024 accelerated approval of the encorafenib/cetuximab/mFOLFOX6 regimen by substantiating clinical benefit in a phase 3 setting.

The FDA has granted traditional approval to encorafenib (Braftovi) in combination with cetuximab (Erbitux) and fluorouracil-based chemotherapy for the treatment of adult patients with metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation, as detected by an FDA-approved test.1

The regulatory decision was supported by data from the phase 3 BREAKWATER trial (NCT04607421), in which patients in arm B (n = 236) who received encorafenib plus cetuximab and mFOLFOX6 achieved an overall response rate (ORR) of 61% (95% CI, 52%-70%) compared with 40% (95% CI, 31%-49%) for patients in arm C (n = 243) treated with chemotherapy with or without bevacizumab (Avastin; P = .0008). The median progression-free survival (PFS) was 12.8 months (95% CI, 11.2-15.9) in arm B vs 7.1 months (95% CI, 6.8-8.5) in arm C (HR, 0.53; 95% CI, 0.41-0.68; P < .0001). The median overall survival (OS) in these arms was 30.3 months (95% CI, 21.7-not evaluable) vs 15.1 months (95% CI, 13.7-17.7), respectively (HR, 0.49; 95% CI, 0.38-0.63; P < .0001).

In cohort 3, patients who received the encorafenib combination in arm D (n = 73) achieved an ORR per blinded independent central review (BICR) of 64% (95% CI, 53%-74%) vs 39% (95% CI, 29%-51%) with the control regimen in arm E (n = 74; P = .0011).

Of note, this approval builds upon the FDA’s prior decision to grant accelerated approval to encorafenib plus cetuximab and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for BRAF V600E–mutant mCRC in December 2024.2

What was the design of BREAKWATER?

This randomized, active-controlled, open-label, multicenter trial enrolled treatment-naive patients with mCRC harboring a BRAF V600E mutation.1 In the phase 3 portion of BREAKWATER, patients were randomly assigned 1:1:1 to one of 3 arms:

  • encorafenib orally once daily with intravenous (IV) cetuximab infusion every 2 weeks (Arm A)
  • encorafenib orally once daily with cetuximab IV infusion every 2 weeks and mFOLFOX6 every 2 weeks (Arm B)
  • mFOLFOX6 or FOLFOXIRI every 2 weeks or CAPOX every 3 weeks, each with or without bevacizumab (Arm C)

Upon amendment to the trial to limit randomization to Arms B and C, a new cohort was initiated. In Cohort 3, patients were randomly assigned 1:1 to the following 2 regimens:

  • encorafenib orally once daily with IV cetuximab IV infusion every 2 weeks and FOLFIRI every 2 weeks (Arm D)
  • FOLFIRI every 2 weeks, with or without bevacizumab (Arm E)

Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death.

The primary efficacy outcomes in the phase 3 portion were PFS in the overall population and ORR in the first 110 patients randomly assigned to each arm per BICR. OS in all patients was an additional end point. The major efficacy outcome measure in cohort 3 was ORR per BICR.

What Should Be Known About the Combination’s Safety Profile?

Regarding safety, the most frequently reported adverse effects in at least 25% of patients treated with encorafenib plus cetuximab and mFOLFOX6 were peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia.2 The most common grade 3 or 4 laboratory abnormalities that occurred in at least 20% of patients were increased lipase levels and decreased neutrophil counts.

The recommended dose of encorafenib is 300 mg administered orally as four 75-mg capsules once daily alongside cetuximab and mFOLFOX6 or FOLFIRI.1

References

  1. FDA grants traditional approval to encorafenib for metastatic colorectal cancer with a BRAF V600E mutation. 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?utm_medium=email&utm_source=govdelivery
  2. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed February 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf