FDA Grants Accelerated Approval to Encorafenib Plus Cetuximab and Chemo for BRAF V600E+ Metastatic Colorectal Cancer

FDA

The FDA has granted accelerated approval to encorafenib (Braftovi) in combination with cetuximab (Erbitux) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for patients with metastatic colorectal cancer with a BRAF V600E mutation, as detected by an FDA-approved test.¹

The regulatory decision was supported by data from the phase 3 BREAKWATER trial (NCT04607421), which showed that patients treated with encorafenib plus cetuximab and mFOLFOX6 achieved an overall response rate (ORR) of 61% (95% CI, 52%-70%) compared with 40% (95% CI, 31%-49%) for patients treated with chemotherapy with or without bevacizumab (Avastin; P = .0008).^1,2 The median duration of response (DOR) was 13.9 months (95% CI, 8.5-not estimable) vs 11.1 months (95% CI, 6.7-12.7), respectively.

“Historically, treatment options have been limited and outcomes poor for patients diagnosed with mCRC with BRAF mutations,” 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, stated in a news release.² “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.”

The randomized, active-controlled, open-label, multicenter BREAKWATER trial enrolled patients at least 18 years of age for the safety run-in portion of the study, and it included those at least 16 years of age for the phase 3 portion.³ Patients needed to have histologically or cytologically confirmed stage IV CRC harboring a BRAF V600E mutation. During the safety run-in, up to 1 prior line of therapy was permitted; in the phase 3 portion, no prior systemic therapy in the metastatic setting was allowed. Other key inclusion criteria consisted of measurable disease for phase 3; measurable or evaluable disease for the safety run-in; and ECOG performance status of 0 to 1; and adequate organ function.

In the phase 3 portion of the study, patients were randomly assigned 1:1:1 to receive oral encorafenib at 300 mg once per day plus cetuximab (n = 158); encorafenib at 300 mg once per day plus cetuximab and mFOLFOX6 (n=236), or mFOLFOX6, FOLFOXIRI, or CAPOX each with or without bevacizumab (n = 243).² Notably, enrollment in the encorafenib plus arm was discontinued after reaching 158 patients.

The primary end points in phase 3 were progression-free survival and ORR. Secondary end points included overall survival, DOR, time to response, and safety.³

Regarding safety, the most common adverse effects reported in at least 25% of patients treated with encorafenib plus cetuximab and mFOLFOX6 included peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia.¹ The most common grade 3 or 4 laboratory abnormalities that occurred in at least 20% of patients were increased lipase levels and decreased neutrophil counts.

The recommended dose of encorafenib is 300 mg once per day in combination with cetuximab and mFOLFOX6 until disease progression or unacceptable toxicity.

“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 encorafenib regimen, patients with mCRC 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,” Chris Boshoff, MD, PhD, chief oncology officer and executive vice president of Pfizer, added in a news release.² “This milestone adds to our legacy of developing innovative medicines in BRAF[-mutated] 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.”

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 20, 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. News release. Pfizer. December 20, 2024. Accessed December 20, 2024. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-braftovir-combination-regimen-first
3. 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 December 20, 2024. https://clinicaltrials.gov/study/NCT04607421