FDA Approves BRAFTOVI Combination as First-Line Treatment for BRAF V600E–Mutant Colorectal Cancer

The US FDA has approved BRAFTOVI® (encorafenib) with cetuximab and mFOLFOX6 as a first-line therapy for BRAF V600E-mutant metastatic colorectal cancer. The Phase 3 BREAKWATER trial showed significantly higher response rates (61% vs 40%) and longer response duration. This approval, offers renewed hope by introducing a targeted combination that may reshape treatment outcomes.

Pfizer announced that the US Food and Drug Administration (FDA)  has granted accelerated approval to Pfizer’s BRAFTOVI® (encorafenib) in combination with cetuximab (ERBITUX®) and the chemotherapy regimen mFOLFOX6 for the treatment of metastatic colorectal cancer (mCRC) harbouring the BRAF V600E mutation. The green light comes under the FDA’s Project FrontRunner, aimed at speeding up new cancer therapies for advanced or metastatic disease.

A First-Line Targeted Regimen

This marks the first and only approved combination regimen featuring a BRAF-targeted therapy available as early as the first line of treatment. Historically, metastatic colorectal cancer patients with BRAF mutations have had limited therapy options and overall poor outcomes.

“Historically, treatment options have been limited and outcomes poor for patients diagnosed with metastatic colorectal cancer with BRAF mutations. 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,” said Dr. Scott Kopetz, Professor and Deputy Chair of Gastrointestinal Medical Oncology at UT MD Anderson Cancer Center.

Impressive Response Rates

The FDA’s decision is based on interim findings from the ongoing Phase 3 BREAKWATER trial:

• Overall Response Rate (ORR): Patients receiving BRAFTOVI with cetuximab and mFOLFOX6 showed a 61% ORR (95% CI: 52, 70), compared to 40% (95% CI: 31, 49) for those on standard chemotherapy with or without bevacizumab.
• Median Duration of Response (DoR): 13.9 months (95% CI: 8.5, not estimable) for the BRAFTOVI combination, compared to 11.1 months (95% CI: 6.7, 12.7) in the control group.

Safety and Side Effects

According to Pfizer, the safety profile in the BREAKWATER study is in line with known side effects of BRAFTOVI, cetuximab, and standard chemotherapies. The most common side effects experienced by at least 25% of patients included peripheral neuropathy, nausea, fatigue, rash, and diarrhoea. About 12% of those on the new combination permanently discontinued BRAFTOVI due to side effects, most commonly elevated lipase levels.

No unexpected safety concerns were identified, offering confidence that the therapy is well-tolerated when carefully monitored by healthcare professionals.

“With today’s accelerated approval, patients now have a first-line treatment option, which contains a targeted therapy specifically for a mutation that is driving their cancer. 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,” said Dr. Chris Boshoff, Chief Oncology Officer and EVP at Pfizer.

Global Access and Further Investigations

The approval was granted priority status by the FDA, using the Real-Time Oncology Review (RTOR) pilot programme. Alongside Project Orbis, several regulatory bodies, including those in Canada and Brazil, are reviewing the therapy. Pfizer has confirmed it will seek potential approvals in other regions.

“Today’s approval of the first combination regimen including a BRAF-targeted therapy for BRAFV600E -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,” said Michael Sapienza, CEO of the Colorectal Cancer Alliance.

BREAKWATER, the Phase 3 study supporting this accelerated approval, will continue to evaluate the combination’s impact on other key measures, such as progression-free survival and overall survival, to confirm the long-term clinical benefit.