FDA Approves Encorafenib Combination for BRAF V600E–Mutated Metastatic Colorectal Cancer

Encorafenib (Braftovi; Pfizer Inc) in combination with cetuximab (Erbitux; Eli Lilly and Company) and fluorouracil-based chemotherapy received FDA approval for adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation. The decision was supported by data from the BREAKWATER trial (NCT04607421).^1,2

Encorafenib for Metastatic CRC

CRC is the fourth most common cancer in the United States. It is estimated to have affected 152,810 individuals in 2024, with 53,010 expected to die from the disease. According to study findings published in JAMA, CRC is now the leading cause of cancer-related deaths in people under age 50 years, surpassing lung cancer.^3,4

Treatment options for patients with mCRC have greatly improved over the past few decades. The most recent approval of encorafenib marks another step in advancing therapeutic options and optimizing outcomes.³

Encorafenib is an oral small molecule kinase inhibitor that targets BRAF V600E and is used for various cancer types. It received initial approval in 2024 in combination with cetuximab and mFOLFOX6 (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) for the treatment of patients with mCRC with a BRAF V600E mutation. That decision was also supported by data from BREAKWATER.³

Encorafenib and Cetuximab Improved Survival, Response

BREAKWATER is a phase 3, active-controlled, open-label, multicenter trial evaluating the safety and efficacy of encorafenib and cetuximab in patients with treatment-naive BRAF V600E mutation–positive mCRC, as detected by the Qiagen therascreen BRAF V600E RGQ PCR Kit.¹

Initially, investigators randomly assigned patients in a 1:1:1 ratio before amending the protocol to a 1:1 randomization between the encorafenib plus cetuximab plus mFOLFOX6 arm and the control arm (phase 3)¹:

1. Encorafenib orally once daily with cetuximab intravenous (IV) infusion every 2 weeks and mFOLFOX6 every 2 weeks (arm B), or
2. mFOLFOX6 or 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (every 2 weeks), or oxaliplatin and capecitabine (every 3 weeks) with or without bevacizumab (arm C)

Additionally, the researchers added a third cohort (cohort 3), which consisted of either encorafenib orally once daily with cetuximab IV infusion every 2 weeks with either leucovorin calcium, fluorouracil, and irinotecan hydrochloride (FOLFIRI) every 2 weeks (arm D), or FOLFIRI every 2 weeks with or without bevacizumab (arm E).¹

The primary end point was confirmed objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was also prespecified as a key secondary end point.¹

Phase 3 enrollment included 479 patients, with 236 assigned to the investigational arm (arm B) and 243 to the control arm (arm C). Patients in arm B demonstrated significantly improved clinical outcomes. The median PFS was 12.8 months (95% CI, 11.2-15.9), compared with 7.1 months (95% CI, 6.8-8.5) in arm C, representing a 47% reduction in the risk of disease progression or death (HR, 0.53; 95% CI, 0.41-0.68; P < .0001).¹

OS was also significantly prolonged, with a median of 30.3 months (95% CI, 21.7-not evaluable) in arm B vs 15.1 months (95% CI, 13.7-7.7) in arm C (HR, 0.49; 95% CI, 0.38-0.63; P < .0001). The ORR further favored the investigational regimen, with 61% (95% CI, 52%-70%) vs 40% (95% CI, 31%-49%) in the control arm (P = .0008).¹

In cohort 3, 73 patients were randomly assigned to arm D and 74 to arm E. The investigational regimen achieved a significantly higher ORR of 64% (95% CI, 53%-74%), compared with 39% (95% CI, 29%-51%) in the control group (P = .0011).¹

Safety and Dosage for Encorafenib

The product labeling outlines important safety considerations, including the risk of secondary primary malignancies (both cutaneous and noncutaneous), paradoxical tumor growth in BRAF wild-type malignancies, cardiomyopathy, liver toxicity, bleeding events, uveitis, QT interval prolongation, and embryo-fetal harm.¹

Encorafenib is administered at 300 mg orally once daily (four 75-mg capsules), in combination with cetuximab and either mFOLFOX6 or FOLFIRI. Therapy should be continued until disease progression or the development of unacceptable toxicity.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. A study of encorafenib plus cetuximab with or without chemotherapy in people with previously untreated metastatic colorectal cancer. ClinicalTrials.gov. Updated August 14, 2025. Accessed February 24, 2026. https://clinicaltrials.gov/study/NCT04607421

3. Gerlach A. Encorafenib with cetuximab and mFOLFOX6 receives accelerated approval for patients with metastatic colorectal cancer. Pharmacy Times. December 20, 2024. Accessed February 24, 2026. https://www.pharmacytimes.com/view/encorafenib-with-cetuximab-and-mfolfox6-receives-accelerated-approval-for-patients-with-metastatic-colorectal-cancer

4. Siegel RL, Wagle NS, Jemal A. Leading cancer deaths in people younger than 50 years. JAMA. 2026;335(7):632-634. doi:10.1001/jama.2025.25467