Updated BREAKWATER Trial Data Show Significant Survival Improvement with Braftovi Combination in Metastatic Colorectal Cancer

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Updated topline data from the Phase III BREAKWATER trial (NCT0460742) show the combination of Braftovi (encorafenib) plus Erbitux (cetuximab) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) produced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) compared to chemotherapy with or without bevacizumab in patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation.^1,2 These data follow recently released results showing the Braftovi combination produced a favorable objective response rate (ORR) compared to chemotherapy with or without bevacizumab.³

“We are extremely pleased with the clinically meaningful progression-free survival and overall survival results from the BREAKWATER study, which have the potential to be practice-changing for this patient population that has historically had limited treatment options and poor outcomes,” said Roger Dansey, MD, chief oncology officer, Pfizer. “The Braftovi regimen is emerging as a new standard of care as the first targeted therapy approved for use as early as first-line for patients with mCRC with a BRAF V600E mutation. We look forward to discussing these data with global health authorities to bring this treatment to more patients around the world, as soon as possible.”¹

Braftovi, an oral small molecule kinase inhibitor targeting BRAF V600E, 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 marked the first and only targeted therapy combination approved as early as the first-line of treatment for this indication.⁴

Trial Design

The randomized, active-controlled, open-label, multicenter BREAKWATER trial is evaluating Braftovi with Erbitux, either alone or combined with mFOLFOX6, in previously untreated patients with BRAF V600E-mutant mCRC. Patients were randomly assigned to 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 was administered mFOLFOX6, FOLFOXIRI, or CAPOX, with or without bevacizumab (n=243). The trial’s dual primary endpoints are ORR and PFS as assessed by blinded independent central review, with OS being a key secondary endpoint.

Data released last month showed 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 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.

In terms of safety, the profile of the Braftovi combination was consistent with the previously established profile for each medication and no new safety signals were identified.

“These results of this first analysis were the basis for the first approval of a targeted therapy regimen for use in the first-line setting for patients with metastatic colorectal cancer with a BRAF V600E mutation,” Dansey said in the release. “We are highly encouraged by these response results, which are indicative of the clinically meaningful benefit of Braftovi in reducing tumor size or having no detectable cancer, along with the promising interim analysis of overall survival. We look forward to additional read-outs from the BREAKWATER trial this year.”³

Pfizer stated that it will share these latest findings with the FDA in support of a full approval for the Braftovi combination in patients with mCRC with a BRAF V600E mutation.

References

1. 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 February 3, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-braftovir-combination-regimen-significantly

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 February 3, 2025. https://clinicaltrials.gov/study/NCT04607421

3. Pfizer’s BRAFTOVI® Combination Regimen Demonstrates Improved Response in Patients with BRAF V600E-Mutant Metastatic Colorectal Cancer. News release. Pfizer. January 25, 2025. Accessed February 3, 2025. https://www.businesswire.com/news/home/20250124736884/en/Pfizer%E2%80%99s-BRAFTOVI%C2%AE-Combination-Regimen-Demonstrates-Improved-Response-in-Patients-with-BRAF-V600E-Mutant-Metastatic-Colorectal-Cancer

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 February 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