Author(s)Courtney Flaherty
Fact checked by: Riley Kandel
Encorafenib (Braftovi) plus cetuximab (Erbitux) and FOLFIRI (fluorouracil, leucovorin, and irinotecan) significantly improved progression-free survival (PFS) vs standard FOLFIRI with or without bevacizumab (Avastin) in patients with previously untreated metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation, according to topline data from cohort 3 of the pivotal phase 3 BREAKWATER trial (NCT04607421).1
The regimen also meaningfully prolonged overall survival (OS) compared with the control, a key descriptive secondary end point.
“These results build on the positive objective response rate [ORR] data we recently shared, providing further evidence of the meaningful benefit this [encorafenib]-based targeted approach may offer patients with BRAF V600E–mutant mCRC,” Jeff Legos, chief oncology officer of Pfizer, stated in a news release. “The combination of significant responses and now improvement in PFS underscores the potential of [encorafenib] as a potentially practice-changing treatment option for patients and families facing this challenging diagnosis.”
What prior data have been reported from BREAKWATER?
BREAKWATER previously met its primary end point of improved ORR with encorafenib and cetuximab plus FOLFIRI over the control regimen.2Data from the primary analysis of cohort 3, which were reported at the 2026 Gastrointestinal Cancers Symposium, showed that evaluable patients treated with encorafenib and cetuximab plus FOLFIRI (n = 73) achieved a confirmed ORR by BICR of 64.4% (95% CI, 52.9%-74.4%) vs 39.2% (95% CI, 28.9%-50.6%) in the control arm (n = 74; odds ratio, 2.756 (95% CI, 1.420-5.348; 1-sided P = .0011). Among responders in the experimental arm, the complete response, partial response, and stable disease rates were 4.1%, 60.3%, and 20.5%, respectively. Non-CR/non–progressive disease (PD) and PD was experienced by 1 patient each, and 9 patients were not evaluable for response.
Regarding safety, no new safety signals were reported, and toxicities were consistent with that of the individual study drugs. Treatment-emergent AEs (TEAEs) occurred in all patients who were safety evaluable and received encorafenib and cetuximab plus FOLFIRI (n = 71) vs 98.5% of those who were safety evaluable and treated with control regimen (n = 68). Of these TEAEs, 63.4% and 70.6% of patients experienced them at grade 3/4 in severity, respectively. The incidence of fatal TEAEs was 3 with the experimental regimen and 1 with the control regimen. Serious TEAEs occurred in 39.4% vs 36.8% of patients in these respective arms. Treatment-related AEs (TRAEs) were experienced by 97.2% of those in the experimental arm vs 95.6% of those in the control arm. Of these, 53.5% and 54.4% of patients experienced them at grade 3/4 in severity, respectively. Grade 5 TRAEs occurred in 1.4% and 1.5% of patients in these respective arms, and the incidence of serious TRAEs was 23.9% vs 19.1%.
Of note, earlier data from BREAKWATER supported the December 2024 FDA approval of encorafenib and cetuximab plus mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for patients with mCRC harboring a BRAF V600E mutation.3
What was the design of BREAKWATER?
BREAKWATER was an open-label, multicenter, phase 3 study enrolling patients at least 16 years of age harboring BRAF V600E–mutant mCRC by local or central laboratory testing.2 Patients were also required to have measurable disease by RECIST 1.1 criteria, no prior exposure to systemic therapy for metastatic disease, an ECOG performance status that was no higher than 1, acceptable bone marrow, hepatic, and renal function. Those with prior exposure to BRAF or EGFR inhibition, symptomatic brain metastases, microsatellite instability–high or mismatch repair–deficient tumors, or RAS-mutated disease were not permitted to enroll.
Eligible patients in cohort 3 were randomly assigned 1:1 to receive encorafenib and cetuximab plus FOLFIRI or the control regimen of FOLFIRI with or without bevacizumab. Of note, patients were stratified by ECOG performance status.
The study’s primary end point was ORR by BICR; key secondary end points were PFS by BICR, OS, duration of response, time to response, and safety.
References
- Pfizer’s BRAFTOVI regimen improves progression-free survival in metastatic colorectal Cancer. Pfizer. February 17, 2026. Accessed February 17, 2026. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-braftovi-regimen-improves-progression-free-survival
- Kopetz S, Wasan HS, Yoshino T, et al. BREAKWATER: Primary analysis of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). J Clin Oncol. 2026;44(suppl 2):13. doi:10.1200/JCO.2026.44.2_suppl.13
- FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed February 17, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf