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Phase 3 Trial Shows Promising Results for Encorafenib Combination Regimen for Patients with Metastatic Colorectal Cancer
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Key Takeaways
- Encorafenib with cetuximab and mFOLFOX6 significantly improved response rates in BRAF V600E-mutant mCRC compared to standard chemotherapy.
- The combination therapy received FDA accelerated approval, becoming the first targeted regimen for untreated BRAF V600E-mutant mCRC.
Encorafenib in combination with cetuximab and mFOLFOX6 met its dual primary end point of overall response rate of 61%.
In the phase 3 BREAKWATER trial (NCT04607421), encorafenib (Braftovi; Array BioPharma Inc.) in combination with cetuximab (Erbitux; Eli Lilly and Company) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) demonstrated clinically meaningful and statistically significant results in treating individuals with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation. Encorafenib in combination with cetuximab and mFOLFOX6 was granted FDA accelerated approval for individuals with mCRC with BRAF V600E mutation in December 2024.1,2
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“Despite the high unmet need in this patient population, prior to the recent encorafenib combination regimen approval, there were no approved biomarker-driven therapies indicated for people with previously untreated BRAF V600E-mutant mCRC,” Scott Kopetz, MD, PhD, 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, said in a news release. “These data from the BREAKWATER study show the potential for this targeted treatment regimen to become the new standard of care for people with BRAF V600E-mutant mCRC, for whom long-term disease control is critical.”1
According to research published in Clinical Colorectal Cancer, BRAF V600E mutant mCRC indicates a distinct molecular phenotype that is often resistant to standard therapies, resulting in poor survival rates.3
As a small molecule kinase inhibitor, encorafenib targets BRAF V600E and has demonstrated its ability in treating CRC and other certain types of cancer.1
The active-controlled, open-label, multicenter phase 3 trial randomly assigned patients with BRAF V600E-mutant mCRC to receive an oral once daily 300 mg dose of encorafenib in combination with cetuximab every 2 weeks and mFOLFOX6 every 2 weeks; or mFOLFOX6, FOLFOXIRI (both every 2 weeks) or CAPOX (every 3 weeks) each with or without bevacizumab, the control arm.1
The encorafenib combination regimen met its dual primary end point of overall response rate (ORR) of 61%, assessed by blinded independent central review compared to 40% in patients receiving chemotherapy with or without bevacizumab.1
Additionally, the estimated median duration of response was longer with encorafenib plus cetuximab and mFOLFOX6 (13.9 months) than with chemotherapy (11.1 months). The study authors noted that more patients in the encorafenib group experienced a response lasting at least 12 months (22.4% vs 11.4%), while the median time to response was similar between the 2 groups (7.1 weeks vs 7.3 weeks).1
While overall survival (OS) data remains ongoing, there’s a promising trend favoring encorafenib in combination with cetuximab and mFOLFOX6 over chemotherapy. However, further results demonstrating the OS and progression-free survival is expected to be released this year.1
The study authors noted that while no new safety signals were identified in the phase 3 trial, serious treatment adverse events occurred in 37.7% of individuals that received encorafenib in combination with cetuximab and mFOLFOX6, compared to 34.6% in patients that received chemotherapy with or without bevacizumab.1
“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,” Roger Dansey, MD, chief oncology officer, Pfizer, said in a news 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 OS. We look forward to additional read-outs from the BREAKWATER trial this year.”1
