Pfizer Inc has announced encouraging new clinical data from Cohort 3 of the pivotal Phase 3 BREAKWATER trial, reinforcing the potential of its targeted therapy BRAFTOVI® (encorafenib) to improve outcomes for patients with previously untreated metastatic colorectal cancer (mCRC) harboring the BRAF V600E mutation. The findings demonstrate that combining BRAFTOVI with cetuximab (marketed as ERBITUX®) and the chemotherapy regimen FOLFIRI (fluorouracil, leucovorin, and irinotecan) significantly improves tumor response rates compared with current standard-of-care treatment options.
Cohort 3 of the BREAKWATER study was designed as a separate randomized cohort to evaluate whether adding BRAFTOVI and cetuximab to a FOLFIRI chemotherapy backbone could enhance efficacy in the first-line treatment setting for this particularly aggressive molecular subtype of colorectal cancer. Patients with BRAF V600E–mutant mCRC typically have a poor prognosis and limited response to conventional chemotherapy, highlighting the need for more effective, targeted treatment strategies.
At the time of analysis, the BRAFTOVI-based combination demonstrated a clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR), as assessed by blinded independent central review (BICR). Specifically, 64.4% of patients treated with BRAFTOVI plus cetuximab and FOLFIRI achieved a confirmed objective response, compared with 39.2% of patients receiving standard-of-care FOLFIRI with or without bevacizumab. This translated to an odds ratio of 2.76, with a p-value of 0.001, underscoring the robustness of the observed benefit.
These results are being presented in an oral session (Abstract 13) at the 2026 American Society of Clinical Oncology Gastrointestinal (ASCO GI®) Cancers Symposium and have also been selected for inclusion in the ASCO GI official press program, reflecting their potential significance for clinical practice.
Commenting on the findings, Dr. Scott Kopetz, M.D., Ph.D., FACP, Professor and Deputy Chair of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center and co–principal investigator of the BREAKWATER trial, emphasized the clinical relevance of the data. He noted that patients treated with the BRAFTOVI-based regimen experienced not only higher response rates but also responses that were rapid and durable. According to Dr. Kopetz, the data support the possibility of expanding the chemotherapy backbone options that can be effectively paired with encorafenib and cetuximab for patients with BRAF V600E–mutant metastatic colorectal cancer.
Durability of response was another key aspect of the analysis. The estimated median duration of response, as assessed by BICR, was not estimable in the BRAFTOVI plus cetuximab and FOLFIRI arm, with a 95% confidence interval ranging from not estimable to not estimable. In contrast, the median duration of response for patients receiving FOLFIRI with or without bevacizumab was estimated at 7.0 months, with the upper bound not estimable. Importantly, 57.4% of patients in the BRAFTOVI combination arm maintained their response for six months or longer, compared with 34.5% in the control arm, further highlighting the durability of benefit associated with the targeted regimen.
Overall survival (OS) was evaluated descriptively at this interim analysis. With a median follow-up of approximately 10 months in both treatment arms, the hazard ratio for overall survival was 0.49 (95% confidence interval: 0.24–1.03), suggesting a favorable trend toward improved survival for patients receiving the BRAFTOVI-based combination. However, Pfizer emphasized that the BREAKWATER trial is ongoing, with final analyses planned as more mature data become available. The study is expected to be completed in 2027.
Jeff Legos, Chief Oncology Officer at Pfizer, highlighted the broader implications of the results, stating that the significant improvement in response rates strengthens the potential role of BRAFTOVI in the treatment landscape for BRAF V600E–mutant metastatic colorectal cancer. He noted that these findings reflect a meaningful clinical benefit for patients facing an aggressive form of the disease and underscore Pfizer’s continued commitment to advancing precision medicine approaches that tailor therapy based on the molecular characteristics of a patient’s cancer.
From a safety perspective, the combination of BRAFTOVI, cetuximab, and FOLFIRI was generally consistent with the known safety profiles of the individual agents. No new safety signals were identified during the analysis. The most commonly reported adverse events, occurring in 15% or more of patients, included nausea, diarrhea, vomiting, alopecia, anemia, decreased neutrophil count, decreased appetite, fatigue, neutropenia, skin hyperpigmentation, dry skin, asthenia, weight loss, arthralgia, palmar-plantar erythrodysaesthesia syndrome, rash, decreased white blood cell count, and constipation. Among patients receiving the BRAFTOVI combination, 8.5% experienced adverse reactions that led to permanent discontinuation of BRAFTOVI.
It is important to note that BRAFTOVI in combination with cetuximab and FOLFIRI remains investigational and is not currently approved for use. However, BRAFTOVI combined with cetuximab and mFOLFOX6 received accelerated approval from the U.S. Food and Drug Administration (FDA) in December 2024 for the treatment of patients with BRAF V600E–mutant metastatic colorectal cancer in the first-line setting. That approval was based on a clinically meaningful and statistically significant improvement in confirmed ORR, one of the primary endpoints of the study, and continued approval is contingent upon verification of clinical benefit.
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