FDA Approves Encorafenib Combination in BRAF V600E+ mCRC

The FDA has approved encorafenib (Braftovi) combined with cetuximab and fluorouracil-based chemotherapy for the treatment of patients with metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation as determined via an FDA-approved test.

The combination’s standard approval was preceded by an accelerated approved of encorafenib in combination with cetuximab and modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (mFOLFOX6) for the same patient population in December 2024.

The approval is supported by data from the randomized, active-controlled, multicenter, phase 3 BREAKWATER trial (NCT04607421), which evaluated patients with treatment-naive mCRC with BRAF V600E mutations that were identified with the Qiagen Therascreen BRAF V600E RGQ PCR Kit.

Data from the BREAKWATER trial were shared at the 2026 ASCO Gastrointestinal Cancers Symposium.

What was the BREAKWATER trial design?

Phase 3 of the BREAKWATER trial randomly assigned patients 1:1:1 to receive either 1 of 2 experimental regimens or a control regimen. Experimental regimens consisted of oral encorafenib once daily with cetuximab IV infusion every 2 weeks (Arm A) and oral encorafenib once daily with cetuximab IV infusion every 2 weeks and mFOLFOX6 every 2 weeks (Arm B).

The control arm (Arm C) received mFOLFOX6 or folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFOXIRI) or capecitabine (Xeloda) and oxaliplatin (CAPOX), with or without bevacizumab (Avastin). In the control arm, fluorouracil-based chemotherapies were administered every 2 weeks, and CAPOX was administered every 3 weeks.

Following initial randomization, the trial was amended to limit further randomization 1:1 to Arms B and C, initiating Cohort 3 of the trial with only 1 experimental arm and 1 control arm. The experimental arm (Arm D) received oral encorafenib once daily with cetuximab IV infusion every 2 weeks and FOLFIRI every 2 weeks, and the control arm (Arm E) received folinic acid, fluorouracil, and irinotecan (FOLFIRI) every 2 weeks with or without bevacizumab.

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

What were the efficacy findings of the BREAKWATER trial?

Progression-free survival (PFS) in all patients and objective response rate (ORR) in the first 110 patients randomized in each arm were major efficacy outcomes measured by blinded independent central review (BICR). Median PFS was 12.8 months (95% CI, 11.2-15.9) in Arm B and was 7.1 months (95% CI, 6.8-8.5) in Arm C (HR, 0.53; 95% CI, 0.41-0.68; P < .0001). ORR was 61% (95% CI, 52%-70%) and 40% (95% CI, 31%-49%; P = 0.0008) in Arms B and C, respectively.

Median overall survival (OS) was evaluated in all patients in Arms B and C (n = 236) as an additional efficacy outcome measure. Median OS was 30.3 months (95% CI, 21.7-NE) 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). Treatment in Arm B reduced the risk of death or progression by 47% and reduced the risk of death by 51% compared with Arm C’s regimen.

In Cohort 3 of BREAKWATER, ORR per BICR was the major efficacy outcome measured, yielding an ORR of 64% (95% CI, 53%-74%) in Arm D vs 39% (95% CI, 29%-51%; P = .0011) in Arm E.

What are the safety considerations and dosing of the encorafenib regimen?

Encorafenib’s prescribing information warns of the risk of new primary cutaneous or noncutaneous malignancies, tumor promotion in BRAF–wild-type tumors, cardiomyopathy, hepatotoxicity, hemorrhage, uneitis, QT prolongation, and embryo-fetal toxicity.

The approved dosage is 300 mg of encorafenib via 4 75-mg capsules taken daily in combination with either cetuximab and mFOLFOX6 or cetuximab and FOLFIRI until disease progression or unacceptable toxicity.

According to data presented at ASCO, the most common TRAEs experienced by at least 15% of patients in the EC plus FOLFIRI arm included nausea (grade 1/2, 56%; grade ≥ 3, 3%), diarrhea (41%; 10%), vomiting (38%; 3%), alopecia (31%; 1%), anemia (25%; 7%), decreased neutrophil count (15%; 15%), decreased appetite (25%; 4%), fatigue (30%; 0%), neutropenia (14%; 11%), skin hyperpigmentation (23%; 0%), dry skin (21%; 0%), asthenia (15%; 3%), weight decrease (18%; 0%), arthralgia (17%; 0%), Palmar-plantar erythrodysesthesia syndrome (17%; 0%), rash (17%; 0%), decreased white blood cell count (10%; 7%), and constipation (15%; 0%).

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
2. Kopetz S, Wasan HS, Yoshino T, et al. BREAKWATER: primary analysis of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). J Clin Oncol. 2026;44(suppl 2):13. doi:10.1200/JCO.2026.44.2_suppl.13