On February 24, 2026, the Food and Drug Administration granted traditional approval to encorafenib (Braftovi, Array BioPharma Inc., a subsidiary of Pfizer Inc.) in combination with cetuximab and fluorouracil-based chemotherapy for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-authorized test. Encorafenib received accelerated approval in combination with cetuximab and mFOLFOX6 for metastatic colorectal cancer with BRAF V600E mutation in 2024.

Efficacy was evaluated in the BREAKWATER trial (NCT04607421), a randomised, active-controlled, open-label, multicenter trial in patients with treatment-naïve, BRAF V600E mutation–positive, metastatic CRC, as detected using the Qiagen “therascreen BRAF V600E RGQ PCR Kit.” The Phase 3 portion of BREAKWATER initially randomised 1:1:1 to one of the following three arms:

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

The trial was subsequently amended to limit randomisation (1:1) to Arm B and Arm C, and a new cohort was initiated, Cohort 3, with the following two treatment arms, randomised 1:1:

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

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

Phase 3 Portion of BREAKWATER

The major efficacy outcome measures were progression-free survival (PFS) in all randomised patients and objective response rate (ORR) in the first 110 patients randomised in each arm per blinded, independent, central review (BICR). Overall survival in all patients was an additional formally tested outcome measure. A total of 236 patients were randomised to the investigational Arm B and 243 to the control, Arm C.

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 (hazard ratio [HR] 0.53 [95% CI: 0.41, 0.68]; p-value <0.0001). Median OS was 30.3 months (95% CI: 21.7, NE) and 15.1 months (95% CI: 13.7, 17.7) (HR 0.49 [95% CI: 0.38, 0.63), respectively; p-value <0.0001). ORR was 61% (95% CI: 52%, 70%) and 40% (95% CI: 31%, 49%) (p-value = 0.0008) in the respective arms.

Cohort 3 Portion of BREAKWATER

The major efficacy outcome measure was ORR per BICR; 73 patients were randomised to investigational Arm D and 74 to the control, Arm E. The ORR was 64% (95% CI: 53, 74) in Arm D, compared to 39% (95% CI: 29, 51) in Arm E (p-value = 0.0011).

Source: FDA