USFDA nod to Pfizer Braftovi Combination Regimen for BRAF V600E-Mutant Metastatic Colorectal Cancer

“Historically, treatment options have been limited and outcomes poor for patients diagnosed with metastatic colorectal cancer with BRAF mutations,” said Scott Kopetz, M.D., Ph.D., 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. “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 ongoing BREAKWATER trial is evaluating BRAFTOVI plus cetuximab with or without chemotherapy (mFOLFOX6) in previously untreated mCRC patients who harbor a BRAF V600E mutation. It is the only Phase 3 trial for a BRAF-targeted therapy regimen in first-line BRAF V600E -mutant mCRC. The trial met one of the dual primary endpoints of confirmed overall response rate (ORR), with a statistically significant improvement over standard of care: ORR 61% (95% confidence interval [CI]: 52, 70) for BRAFTOVI in combination with cetuximab and mFOLFOX6 compared with ORR 40% (95% CI: 31, 49) for chemotherapy, with or without bevacizumab (p=0.0008). The median duration of response (DoR) was 13.9 months (95% CI: 8.5, not estimable) for the BRAFTOVI combination regimen versus 11.1 months (95% CI: 6.7, 12.7) for chemotherapy, with or without bevacizumab. The Phase 3 BREAKWATER trial is ongoing, and results from the full dataset will be presented at upcoming medical meetings.

“For more than a decade, Pfizer has been a pioneer in delivering targeted therapies for molecular-driven cancers. With the 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, M.D., Ph.D., Chief Oncology Officer, Executive Vice President, Pfizer. “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 safety profile of BRAFTOVI in combination with cetuximab and mFOLFOX6 in the BREAKWATER trial was consistent with the known safety profile of each respective agent. No new safety signals were identified. 

“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, Chief Executive Officer of the Colorectal Cancer Alliance. “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.”

This application was granted priority review, used the Real-Time Oncology Review (RTOR) pilot program, and was conducted under Project Orbis, with application reviews ongoing for Project Orbis partners, including Canada and Brazil. The BREAKWATER data are also being discussed with other regulatory authorities around the world to support potential future additional license applications for the BRAFTOVI combination regimen in this indication. This accelerated approval follows the previous FDA approval for BRAFTOVI in combination with cetuximab for adults with mCRC with a BRAF V600E mutation after prior therapy.