FDA Grants Accelerated Approval to Pfizer’s Braftovi Combination for Metastatic Colorectal Cancer

Image Credit: Adobe Stock Images/Ahmet Aglamaz

The FDA has granted accelerated approval to Pfizer’s Braftovi (encorafenib) in combination with cetuximab and mFOLFOX6 for the treatment of patients with metastatic colorectal cancer (mCRC) harboring the BRAF V600E mutation. According to the company, the accelerated approval is based on data from the ongoing Phase III BREAKWATER trial, which demonstrated a superior confirmed objective response rate (ORR) for the encorafenib+cetuximab+mFOLFOX6 arm compared to the control arm.¹

“Historically, treatment options have been limited and outcomes poor for patients diagnosed with metastatic colorectal cancer with BRAF mutations,” said Scott Kopetz, MD, PhD, FACP, professor, deputy chair, gastrointestinal medical oncology, The University of Texas MD Anderson Cancer Center, co-principal investigator of the BREAKWATER trial, in a press release. “As the first and only combination regimen featuring a BRAF-targeted therapy for this patient population, usable even in first-line treatment, the encorafenib regimen has demonstrated high response rates that are rapid and durable. This represents an encouraging sign of continued disease control and a source of renewed hope for patients.”

BREAKWATER is a randomized, active-controlled, open-label, multicenter trial of Braftovi with cetuximab, alone or in combination with chemotherapy, in participants with previously untreated BRAF V600E-mutant mCRC. As part of the study, patients were randomized to receive Braftovi 300 mg orally once-daily in combination with cetuximab, Braftovi 300 mg orally once-daily in combination with cetuximab and mFOLFOX6, or mFOLFOX6, FOLFOXIRI, or CAPOX each with or without bevacizumab. The dual primary endpoints are ORR and progression-free survival (PFS), as assessed by blinded independent central review (BICR), while secondary endpoints include duration of response (DOR) as assessed by BICR, time to response by BICR, overall survival, and safety.

Results found that the combination treatment demonstrated a confirmed ORR of 61% for the encorafenib+cetuximab+mFOLFOX6 arm compared to 40% in the control arm. Median DOR was 13.9 months versus 11.1 months, respectively. Patients in the study were required to have the BRAF V600E mutation confirmed by an FDA-approved test.

Common adverse events (AEs) of the trial included peripheral neuropathy, nausea, and fatigue, while notable Grade 3 or 4 lab abnormalities were increased lipase and decreased neutrophil count. In patients that received Braftovi in combination with cetuximab and mFOLFOX6, 12% experienced an AE that resulted in permanent discontinuation.²

“For more than a decade, Pfizer has been a pioneer in delivering targeted therapies for molecular-driven cancers. With today’s accelerated approval of the BRAFTOVI regimen, patients with metastatic colorectal cancer with a BRAF V600E mutation now have a first-line treatment option, which contains a targeted therapy specifically for a mutation that is driving their cancer,” said Chris Boshoff, MD, PhD, chief oncology officer, EVP, Pfizer, in the press release. “This milestone adds to our legacy of developing innovative medicines in BRAF tumors, some of the hardest-to-treat cancers. We look forward to continuing to expand our portfolio, including the exploration of a next-generation brain-penetrant BRAF inhibitor.”

The approval, conducted under the FDA's Project Orbis and Project FrontRunner initiatives, aims to advance promising therapies into earlier treatment settings. Continued evaluation of progression-free survival and overall survival in the ongoing BREAKWATER trial will provide post-marketing confirmatory data.²

“Finding out that your cancer has spread can be a frightening time for those with colorectal cancer and their loved ones. The prognosis for those receiving a metastatic colorectal cancer diagnosis has improved slightly in recent years, but the same cannot be said for those with a BRAF mutation who unfortunately face an especially aggressive disease and worse outcomes,” said Michael Sapienza, CEO, Colorectal Cancer Alliance, in the press release. “Today’s approval of the first combination regimen including a BRAF-targeted therapy for BRAF V600E-mutant metastatic colorectal cancer, which can be used for previously untreated patients, offers new promise for the community and marks an important step forward in our collective mission to end this disease.”

References

1. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed December 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf

2. U.S. FDA Approves Pfizer’s BRAFTOVI® Combination Regimen as First-Line Treatment of BRAF V600E-Mutant Metastatic Colorectal Cancer. Business Wire. December 20, 2024. Accessed December 24, 2024. 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