FDA Grants Traditional Approval to Encorafenib in BRAF-Mutated CRC

Traditional approval has been granted by the FDA for encorafenib (Braftovi) plus cetuximab (Erbitux) and luorouracil-based chemotherapy for patients with BRAF V600E-mutated colorectal cancer (CRC), as detected by an FDA-approved test.¹

The approval was based on results from the phase 3 BREAKWATER trial (NCT04607421), which assessed patients who were treatment-naive with BRAF V600E mutation-positive metastatic disease detected by the therascreen BRAF V600E RGQ PCR Kit (Qiagen).

Patients were randomly assigned 1:1:1 to either arm A (encorafenib orally once daily with cetuximab intravenous [IV] infusion every 2 weeks); arm B (encorafenib orally once daily with cetuximab IV infusion every 2 weeks and oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6] every 2 weeks); or arm C (mFOLFOX6 or 5-FU, leucovorin, oxaliplatin, and irinotecan [FOLFOXIRI], both every 2 weeks, or capcitabine plus oxaliplatin [CAPOX] given every 3 weeks, each with or without bevacizumab [Avastin]).

Of note, the trial was ammended to limit randomization and was condensed to a 1:1 ratio with arms B and C. The ammended dosing included: encorafenib orally once daily with cetuximab IV infusion every 2 weeks and FOLFIRI every 2 weeks (Arm D), or FOLFIRI every 2 weeks, with or without bevacizumab (Arm E).

Topline results from the trial showed a median progression-free survival (PFS) of 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). The median overall survival was 30.3 months (95% CI, 21.7-not evaluable [NE]) and 15.1 months (95% CI, 13.7-17.7), between each arm respectively, (HR, 0.49; 95% CI, 0.38-0.63; P <.0001). Additionally, the overall response rate (ORR) was 61% (95% CI, 52%-70%) and 40% (95% CI, 31%-49%), respectively (P = .0008).

Cohort 3 of the study showed the ORR of of 64% in arm D (95% CI, 53%-74%) vs 39% (95% CI, 29%-51%) in arm E (P = .0011).

The recommended dose of encorafenib is 300 mg or four 75 mg capsules given orally once daily plus cetuximab and mFOLFOX6 or combined with cetuximab and FOLFIRI.

In 2024, encorafenib plus cetuximab were given accelerated approval by the FDA for the same indication.²

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://tinyurl.com/4xr84a6y
2. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA. December 20, 2024. Accessed February 24, 2026. https://tinyurl.com/ys64br95