A primary analysis of the Phase III BREAKWATER trial (NCT0460742) show that a Braftovi (encorafenib)-based regimen delivered the first statistically significant and clinically meaningful overall survival (OS) benefit ever reported in the first-line setting for patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC).^1,2

BREAKWATER Trial Delivers First Survival Benefit in First-Line BRAF V600E Mutant Metastatic Colorectal Cancer

Results from the trial, presented at the 2025 ASCO Annual Meeting and published in The New England Journal of Medicine (NEJM), show the combination of Braftovi plus Erbitux (cetuximab) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) may offer a potential new standard-of-care for the hard-to-treat mCRC subset, which is associated with a poor prognosis and limited responsiveness to traditional therapies.³

“Patients with metastatic colorectal cancer whose tumors harbor a BRAF V600E mutation generally face a daunting prognosis, as this aggressive tumor often does not respond well to standard-of-care chemotherapy,” BREAKWATER co-principal investigator Elena Élez, MD, PhD, senior investigator at Vall d’Hebron Institute of Oncology in Barcelona, Spain, said in a press release. “The BREAKWATER results are the first promising survival outcomes ever reported for BRAF-mutant metastatic colorectal cancer in the first-line setting, representing a practice-changing breakthrough for patients.”¹

Overall and Progression-Free Survival Significantly Extended With Braftovi Combination

Braftovi, an oral small molecule kinase inhibitor, was granted accelerated approval by the FDA in December 2024 in combination with Erbitux and mFOLFOX6 for patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test. The regulatory action, based on results from the BREAKWATER trial, marked the first and only targeted therapy combination approved as early as the first line of treatment for this patient population.⁴

“Encorafenib is a highly selective, ATP-competitive, small-molecule BRAF inhibitor with antiproliferative and apoptotic activity in tumor cells expressing BRAF V600E mutations and has longer pharmacodynamic activity than other approved BRAF inhibitors,” the study authors wrote in NEJM. “In colorectal cancer, BRAF inhibition alone can cause the BRAF pathway to be reactivated by epidermal growth factor receptor (EGFR) owing to feedback loops within the signaling network (also known as rapid pathway feedback reactivation), which attenuates the activity of BRAF inhibitors. The value of targeting BRAF simultaneously with EGFR inhibition to overcome reactivation has been shown previously.”³

BREAKWATER Trial Design and Enrollment

• The randomized, active-controlled, open-label, multicenter BREAKWATER trial analyzed Braftovi with Erbitux, either alone or combined with mFOLFOX6, in previously untreated patients with BRAF V600E-mutant mCRC.
• Patients were randomly assigned to receive either Braftovi 300 mg administered orally once daily with Erbitux (discontinued after 158 patients were randomly assigned), Braftovi 300 mg administered orally once daily with Erbitux and mFOLFOX6 (n=236), or a control cohort who received mFOLFOX6, FOLFOXIRI, or CAPOX, with or without bevacizumab (n=243).
• The trial’s dual primary endpoints are objective response rate (ORR) and progression-free survival (PFS) as assessed by blinded independent central review (BICR), with OS being a key secondary endpoint.

Objective Response Rate and Duration of Response Reinforce Clinical Value

• These latest data show the Braftovi combination regimen lowered the risk of death by 51% compared to standard-of-care chemotherapy with or without bevacizumab (Hazard Ratio [HR] 0.49; 95% Confidence Interval [CI], 0.38, 0.63, p<0.0001).
• Patients administered the Braftovi combination had a median OS of 30.3 months (95% CI, 21.7, Not Estimated) compared to 15.1 months among patients administered chemotherapy with or without bevacizumab (95% CI, 13.7, 17.7).
• For the PFS endpoint, the Braftovi combination lowered the risk of disease progression or death by 47% versus standard-of-care chemotherapy with or without bevacizumab (HR 0.53; 95% CI, 0.41, 0.68, p<0.0001) as assessed by BICR.
• Patients administered the Braftovi combination had a median PFS of 12.8 months (95% CI, 11.2, 15.9) compared to 7.1 months (95% CI, 6.8, 8.5) in the chemotherapy cohort.

“The early separation of the Kaplan–Meier curves for progression-free survival indicated an early clinical benefit in the [Braftovi plus Erbitux and mFOLFOX6] group as compared with the standard-care group,” the study authors wrote in NEJM. “The median overall survival was more than twice as long in the [Braftovi plus Erbitux and mFOLFOX6] group as in the standard-care group, with early separation of the Kaplan–Meier curves. The survival advantage that had been observed at the previous interim analysis was sustained, which supports the significant survival benefit in the [Braftovi plus Erbitux and mFOLFOX6] group.”³

Data released earlier this year show patients administered Braftovi 300 mg with Erbitux and mFOLFOX6 had an ORR of 61% compared to 40% in the chemotherapy with or without bevacizumab cohort. Estimated median duration of response (DoR) in the Braftovi with Erbitux and mFOLFOX6 cohort was 13.9 months compared to 11.1 months in the chemotherapy cohort, with or without bevacizumab.⁵

Regulatory Context and Potential for Full FDA Approval in 2025

Updated data for ORR as per BICR confirmed the prior advantage for the Braftovi combination compared to chemotherapy with or without bevacizumab (65.7%; 95% CI, 59.4, 71.4 and 37.4%; 95% CI, 31.6, 43.7, respectively), while estimated median DoR and median time to response stayed consistent with the previously released results.¹

“The risk of death for patients with BRAF V600E-mutant metastatic colorectal cancer is more than double compared to those with no known mutation,” Michael Sapienza, CEO, Colorectal Cancer Alliance, said in the release. “These survival outcomes from the BREAKWATER study bring renewed hope to patients and their loved ones, providing the possibility of more time together. We are thrilled to see important cancer research propel us closer to our goal of ending this disease.”¹

References

1. Pfizer’s BRAFTOVI® Combination Regimen Cuts the Risk of Death in Half for Patients with BRAF V600E-Mutant Metastatic Colorectal Cancer. News release. Pfizer. May 30, 2025. Accessed June 3, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-braftovir-combination-regimen-cuts-risk-death-half

2. A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer. ClinicalTrials.gov. Updated December 17, 2024. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT04607421

3. Elez E., et al. Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. N Engl J Med 2025; DOI: 10.1056/NEJMoa2501912.

4. U.S. FDA Approves Pfizer’s BRAFTOVI® Combination Regimen as First-Line Treatment of BRAF V600E-Mutant Metastatic Colorectal Cancer. News release. Pfizer. December 20, 2024. Accessed June 3, 2025. https://www.businesswire.com/news/home/20241210321033/en/U.S.-FDA-Approves-Pfizer%E2%80%99s-BRAFTOVI%C2%AE-Combination-Regimen-as-First-Line-Treatment-of-BRAF-V600E-Mutant-Metastatic-Colorectal-Cancer

5. Pfizer’s BRAFTOVI® Combination Regimen Significantly Improved Progression-Free Survival and Overall Survival in Phase 3 BREAKWATER Trial. News release. Pfizer. February 3, 2025. Accessed June 3, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-braftovir-combination-regimen-significantly