FDA Grants Encorafenib Combo Traditional Approval in BRAF V600E+ mCRC

The FDA has approved encorafenib (Braftovi) in combination with cetuximab (Erbitux) 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.¹ This decision converts its previous accelerated approval in this indication to a full traditional approval.

This transition from accelerated approval to traditional approval signifies a definitive confirmation of the clinical benefit of the combination in a patient population historically associated with poor prognosis and limited treatment options. The FDA originally granted accelerated approval to the oral small-molecule kinase inhibitor plus cetuximab and modified FOLFOX6 (mFOLFOX6) chemotherapy in this indication in December 2024 based on initial data from the phase 3 BREAKWATER trial (NCT04607421).²

Patients in arm B of the trial (n = 236), who received the encorafenib-based triplet, achieved a median progression-free survival (PFS) of 12.8 months (95% CI, 11.2-15.9), almost doubling the 7.1-month PFS (95% CI, 6.8-8.5) observed in arm C, the control group (n = 243). This translated to a 47% reduction in the risk of disease progression or death (HR, 0.53; 95% CI, 0.41-0.68; P <.0001).

Furthermore, the overall survival (OS) data, formally tested in the traditional approval pathway, showed a median OS of 30.3 months (95% CI, 21.7-not estimable [NE]) for the encorafenib triplet vs 15.1 months (95% CI, 13.7-17.7) in the control arm (HR, 0.49; 95% CI, 0.38-0.63; P <.0001). The objective response rate (ORR) was also significantly higher in the investigational group at 61% compared to 40% in the control group.

The approval also covers the use of encorafenib with cetuximab and FOLFIRI chemotherapy. Data from cohort 3 (n = 147) of the BREAKWATER trial, inclusive of study arms D and E, substantiate this decision, showing an ORR of 64% (95% CI, 53%-74%) for the FOLFIRI-based experimental arm vs 39% (95% CI, 29%-51%) for standard-of-care FOLFIRI with or without bevacizumab (Avastin). This difference was statistically significant (P =.0011).

The recent regulatory decision also comes soon after an announcement of positive topline PFS data from cohort 3. Here, the encorafenib-based regimen significantly reduced the risk of disease progression or death compared with standard-of-care chemotherapy with or without bevacizumab.³ The inclusion of FOLFIRI as a chemotherapy backbone provides critical clinical flexibility, particularly for patients where oxaliplatin-induced peripheral neuropathy is a concern or where irinotecan-based therapy is clinically preferred.

The movement of this targeted triplet into the first-line setting represents a paradigm shift from the previous standard of care established by the phase 3 BEACON CRC trial (NCT02928224), which utilized the encorafenib-cetuximab doublet in the progressed setting.

About the BREAKWATER Trial

The multicenter, open-label BREAKWATER trial enrolled patients with previously untreated, BRAF V600E mutation-positive mCRC to assess the efficacy and safety of encorafenib plus cetuximab with or without chemotherapy vs standard of care.⁴ Eligible patients had confirmed BRAF V600E-mutated mCRC as determined by an FDA-authorized test and had not received prior systemic therapy for metastatic disease.

Patients were randomly assigned to receive encorafenib plus cetuximab with modified mFOLFOX6 or FOLFIRI, or to a control arm consisting of investigator’s choice of standard chemotherapy regimens, including mFOLFOX6 or FOLFIRI, with or without bevacizumab.

The trial’s dual primary end points included PFS and ORR, with OS as a key secondary end point. The study was structured in multiple cohorts to evaluate different chemotherapy backbones in combination with the targeted doublet, enabling assessment of both oxaliplatin- and irinotecan-based regimens.

REFERENCES

1. FDA grants traditional approval to encorafenib for metastatic colorectal cancer with a BRAF V600E mutation. News release. US Food and Drug Administration. February 24, 2026. Accessed February 24, 2026. https://tinyurl.com/2umnzhvn

2. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. US Food and Drug Administration. December 20, 2024. Accessed February 24, 2026. https://tinyurl.com/yxnzzp6s

3. Pfizer’s Braftovi regimen improves progression-free survival in metastatic colorectal cancer. News release. Pfizer. February 17, 2026. Accessed February 24, 2026. https://tinyurl.com/bdcu84ry

4. 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