FDA Grants Traditional Approval to Encorafenib-Cetuximab Plus Chemotherapy for BRAF V600E-Mutant Metastatic Colorectal Cancer

On February 24, 2026, the US Food and Drug Administration (FDA) granted traditional approval to encorafenib in combination with cetuximab and fluorouracil-based chemotherapy for the frontline treatment of patients with metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation, as detected by an FDA-authorized test. The agent had previously received accelerated approval in 2024 in combination with cetuximab and mFOLFOX6 for this patient population. 

BRAF V600E–mutant mCRC is associated with aggressive tumor biology and historically poor outcomes. The results of the BREAKWATER trial demonstrate substantial improvements in progression-free survival, overall survival, and response rates with encorafenib in combination with cetuximab and fluorouracil-based chemotherapy, establishing this regimen as a newly FDA-approved first-line option for this molecularly defined subgroup.

The approval is supported by data from the phase 3 BREAKWATER trial (NCT04607421), a randomized, active-controlled, open-label, multicenter study evaluating first-line treatment strategies in patients with previously untreated, BRAF V600E–mutant mCRC. Mutation status was confirmed using the Qiagen therascreen BRAF V600E RGQ PCR kit.

In the phase 3 portion of the trial, 236 patients were randomized to receive encorafenib plus cetuximab and mFOLFOX6, and 243 patients were assigned to investigator’s choice of standard chemotherapy (mFOLFOX6, FOLFOXIRI, or CAPOX) with or without bevacizumab. Treatment was continued until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death.

The addition of encorafenib to cetuximab and mFOLFOX6 resulted in a statistically significant and clinically meaningful improvement in progression-free survival (PFS), one of the trial’s primary end points. Median PFS was 12.8 months (95% confidence interval [CI], 11.2 to 15.9) in the encorafenib-containing arm compared with 7.1 months (95% CI, 6.8 to 8.5) in the control arm (hazard ratio [HR], 0.53; 95% CI, 0.41 to 0.68; P < .0001).

Overall survival (OS), a key secondary end point, was also significantly improved. Median OS reached 30.3 months (95% CI, 21.7 to not estimable) in the investigational arm versus 15.1 months (95% CI, 13.7 to 17.7) in the control arm (HR, 0.49; 95% CI, 0.38 to 0.63; P < .0001). The confirmed objective response rate (ORR), as assessed by blinded independent central review in the first 110 patients per arm, was 61% (95% CI, 52% to 70%) with encorafenib-based therapy compared with 40% (95% CI, 31% to 49%) in the control group ( P = .0008).

A subsequent amendment to the trial introduced an additional cohort evaluating encorafenib plus cetuximab with FOLFIRI. In this cohort, 73 patients received the investigational combination and 74 received FOLFIRI with or without bevacizumab. The primary end point was ORR by blinded independent central review. The ORR was 64% (95% CI, 53% to 74%) in the encorafenib arm compared with 39% (95% CI, 29% to 51%) in the control arm ( P = .0011), further supporting the activity of the BRAF-targeted strategy across fluorouracil-based backbones.

The prescribing information for encorafenib includes warnings and precautions for new primary malignancies (cutaneous and noncutaneous), tumor promotion in BRAF wild-type tumors, cardiomyopathy, hepatotoxicity, hemorrhage, uveitis, QT prolongation, and embryo-fetal toxicity.

Source:

US Food and Drug Administration. FDA grants traditional approval to encorafenib for metastatic colorectal cancer with a BRAF V600E mutation. Accessed February 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-encorafenib-metastatic-colorectal-cancer-braf-v600e-mutation