Oncology Drug Approval News Flash: Encorafenib plus cetuximab and fluorouracil-based chemotherapy receives traditional FDA approval for BRAF V600E–mutated metastatic colorectal cancer

FDA approval summary

On February 24, 2026, the U.S. Food and Drug Administration (FDA) 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 (mCRC) harboring a BRAF V600E mutation, as detected by an FDA-authorized test.

Encorafenib had previously received accelerated approval in 2024 in combination with cetuximab and mFOLFOX6 for BRAF V600E–mutated mCRC. The current decision converts and expands this to a full traditional approval in the first-line setting based on the phase 3 BREAKWATER trial.

BREAKWATER trial (NCT04607421)

Efficacy was evaluated in BREAKWATER (NCT04607421), a randomized, active-controlled, open-label, multicenter trial in patients with previously untreated, BRAF V600E–mutated metastatic colorectal cancer.

• Key eligibility: treatment-naïve mCRC with BRAF V600E mutation confirmed using the Qiagen therascreen BRAF V600E RGQ PCR Kit

Phase 3 portion: Arm B vs Arm C

The phase 3 portion initially included three arms, but was subsequently amended to focus randomization on the following two arms:

• Arm B (investigational): encorafenib orally once daily + cetuximab IV every 2 weeks + mFOLFOX6 every 2 weeks
• Arm C (control): mFOLFOX6 or FOLFOXIRI (both every 2 weeks) or CAPOX (every 3 weeks), each with or without bevacizumab
• Randomization: 236 patients to Arm B and 243 to Arm C

The major efficacy outcome measures were:

• Progression-free survival (PFS) in all randomized patients, and
• Objective response rate (ORR) per blinded independent central review (BICR) in the first 110 patients randomized to each arm

Overall survival (OS) in all randomized patients was an additional formally tested outcome measure.

Cohort 3: FOLFIRI backbone (Arm D vs Arm E)

• Arm D (investigational): encorafenib + cetuximab + FOLFIRI every 2 weeks
• Arm E (control): FOLFIRI every 2 weeks, with or without bevacizumab
• Major efficacy outcome: ORR per BICR

Key efficacy results

Phase 3 portion (Arm B vs Arm C)

• PFS (all randomized patients):
  • Arm B: median 12.8 months (95% CI: 11.2, 15.9)
  • Arm C: median 7.1 months (95% CI: 6.8, 8.5)
  • Hazard ratio (HR): 0.53 (95% CI: 0.41, 0.68); p < 0.0001
• OS (all randomized patients):
  • Arm B: median 30.3 months (95% CI: 21.7, NE)
  • Arm C: median 15.1 months (95% CI: 13.7, 17.7)
  • HR: 0.49 (95% CI: 0.38, 0.63); p < 0.0001
• ORR (first 110 patients per arm, BICR):
  • Arm B: 61% (95% CI: 52%, 70%)
  • Arm C: 40% (95% CI: 31%, 49%)
  • p = 0.0008

Cohort 3 (Arm D vs Arm E)

• ORR::contentReference[oaicite:14]{index=14}
  • Arm D: 64% (95% CI: 53, 74)
  • Arm E: 39% (95% CI: 29, 51)
  • p = 0.0011

Across both the phase 3 portion and Cohort 3, encorafenib-based triplets demonstrated clinically meaningful and statistically significant improvements in PFS, OS (phase 3), and ORR compared with fluoropyrimidine-based chemotherapy regimens alone.

Safety profile and key warnings

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
• Embryo-fetal toxicity

In clinical practice, these risks are additive to the expected toxicities of EGFR antibodies and 5-FU–based chemotherapy (e.g., dermatologic toxicities, diarrhea, myelosuppression), underscoring the need for careful monitoring and proactive management.

Recommended dosing

Recommended encorafenib dose:

• 300 mg orally once daily (four 75 mg capsules)
• In combination with:
  • cetuximab + mFOLFOX6, or
  • cetuximab + FOLFIRI
• Continue until disease progression or unacceptable toxicity

Refer to the respective prescribing information for detailed dosing of cetuximab, mFOLFOX6, and FOLFIRI components.

Regulatory context: Project FrontRunner, Project Orbis, and RTOR

• This application is highlighted as an example of the Oncology Center of Excellence’s Project FrontRunner, which aims to provide earlier access to effective therapies in earlier disease settings.
• The review was conducted under Project Orbis, a framework for concurrent submission and review of oncology drugs among international partners. For this approval, FDA collaborated with Health Canada; reviews at other agencies are ongoing.
• The application used the Real-Time Oncology Review (RTOR) program, allowing data submission and review prior to formal filing.
• An Assessment Aid, a voluntary structured submission from the applicant, was utilized to facilitate FDA’s assessment.

Editorial perspective (Morningglorysciences)

BRAF V600E–mutated metastatic colorectal cancer has long been recognized as a distinct, poor-prognosis subgroup, characterized by aggressive biology and suboptimal outcomes with conventional FOLFOX/FOLFIRI-based chemotherapy. While targeted combinations such as BRAF + EGFR inhibition have become standard in later lines, the optimal first-line approach has remained an open question.

BREAKWATER clearly demonstrates that bringing a triplet of encorafenib + cetuximab + 5-FU–based chemotherapy into the first-line setting can substantially shift the trajectory for these patients, with median OS exceeding 30 months versus approximately 15 months for standard chemotherapy. From a historical perspective in this biomarker-defined subgroup, this represents a major step forward.

For everyday practice, however, several strategic considerations remain:

• Choice of backbone: selecting between mFOLFOX6 and FOLFIRI based on patient age, comorbidities, performance status, and metastatic burden
• Toxicity management: balancing BRAF/EGFR/chemotherapy-related adverse events while maintaining dose intensity long enough to capture the survival benefit
• Sequencing beyond first line: planning subsequent options in a landscape where potent targeted therapy is already deployed upfront

Going forward, more granular analyses—including sidedness, RAS status, metastatic pattern (e.g., liver-limited disease), and molecular co-alterations—are likely to refine which patients derive the largest incremental benefit from encorafenib-based triplets. Nevertheless, this approval firmly establishes targeted therapy plus chemotherapy as a new standard-of-care paradigm for first-line treatment of BRAF V600E–mutated metastatic colorectal cancer.

*This article is based on the AACR “FDA Approval Alert” and FDA source documents, summarized and edited by Morningglorysciences.*

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