Dr Pant on the FDA Approval of First-Line Encorafenib Plus Cetuximab/Chemo in BRAF V600E–Mutant mCRC

"The data [from BREAKWATER] are very strongly [in favor of] using targeted therapy upfront, and that's what [the regimen’s FDA approval confirms]. What we found out in CRC and other solid tumors is that if we hit the target early and hard, we can really improve OS [outcomes] for these patients."

Shubham Pant, MD, MBBS, a professor in the Department of Gastrointestinal (GI) Medical Oncology and director of clinical research at The University of Texas MD Anderson Cancer Center, discussed lessons learned from the phase 3 BREAKWATER study (NCT04607421), which served as the basis for the FDA’s decision to grant traditional approval to encorafenib (Braftovi) plus 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-approved test.

Of note, the February 2026 approval builds upon the FDA’s prior decision to grant accelerated approval to encorafenib plus cetuximab and modified FOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) for BRAF V600E–mutant mCRC in December 2024.

Data from BREAKWATER demonstrated substantial improvements in efficacy with the triplet of encorafenib, cetuximab, and modified FOLFOX6 across multiple end points compared with standard chemotherapy with/without bevacizumab (Avastin). Patients who in the triplet in arm B (n = 23) achieved an overall response rate (ORR) of 61% (95% CI, 52%-70%), whereas those in the control arm (arm C) had an ORR of 40% (95% CI, 31%-49%; P = .0008). Survival data were equally compelling; the median progression-free survival (PFS) was 12.8 months vs 7.1 months in these respective groups (HR, 0.53; 95% CI, 0.41-0.68; P < .0001) Notably, the median overall survival (OS) was also doubled, reaching 30.3 months with the encorafenib combination vs 15.1 months in the control arm (HR, 0.49; 95% CI, 0.38-0.63; P < .0001). Furthermore, in cohort 3, patients who received the encorafenib combination in arm D (n = 73) achieved an ORR per blinded independent central review of 64% (95% CI, 53%-74%) vs 39% (95% CI, 29%-51%) with the control regimen in arm E (n = 74; P = .0011).

Pant emphasized that these results strongly advocate for moving targeted therapy into the first-line setting. He noted that the strategy of "hitting the target early and hard" is vital because a significant percentage of patients with mCRC experience clinical decline after their initial treatment, preventing them from accessing potentially life-prolonging therapies in the second-line setting. By providing the most effective targeted agents upfront to patients who are fit enough to receive them, broader access to these benefits and significantly improvement to long-term survival outcomes can be achieved, Pant concluded.