Dr Chiorean on Encorafenib Plus Cetuximab for BRAF V600E–Mutated mCRC

“Our patients need any help we can provide, as fast as possible, for better outcomes starting with [the] first-line [setting] because chemotherapy alone is simply not sufficient.”

E. Gabriela Chiorean, MD, FASCO, clinical director, GI Medical Oncology Program, professor, Clinical Research Division, and affiliate investigator, Translational Science and Therapeutics Division Fred Hutchinson Cancer Center; professor, medicine, University of Washington; director, Clinical Research GI Oncology Program, University of Washington/Fred Hutch, discusses the significance of the FDA approval of encorafenib (Braftovi) plus cetuximab (Erbitux) and chemotherapy for patients with BRAF V600E–mutated metastatic colorectal cancer (mCRC).

On December 20, 2024, the FDA granted accelerated approval to encorafenib plus cetuximab and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for the treatment of patients with mCRC harboring a BRAF V600E mutation, as detected by an FDA-approved test.

Historically, patients with BRAF V600E–mutated CRC have had limited targeted therapy options, with encorafenib plus cetuximab available only in the second-line setting following disease progression on standard chemotherapy, Chiorean begins. However, BRAFV600E–mutated CRC is characterized by aggressive tumor biology, with poor overall survival (OS) outcomes, she says. Even with intensive chemotherapy regimens, such as FOLFIRINOX (fluorouracil, oxaliplatin, irinotecan, and leucovorin) plus bevacizumab (Avastin), the median OS in this population remains shorter than 18 months, she notes.

The FDA approval of encorafenib plus cetuximab and mFOLFOX6 as a first-line regimen in this population represents a significant advancement in the treatment paradigm, Chiorean emphasizes. This development highlights the critical need for rapid genomic profiling at the time of diagnosis to identify BRAF mutations early and promptly initiate the most effective treatments, she explains. Given the poor prognosis associated with BRAF V600E mutations, optimizing first-line therapy is important for improving patient outcomes, she reports.

Patients with BRAF V600E–mutated mCRC receiving standard chemotherapy, including FOLFIRINOX, achieve a median OS only approximately 14 to 17 months, with limited responses, she adds. Furthermore, in the second-line setting, the use of encorafenib plus cetuximab has yielded a median progression-free survival (PFS) of approximately 4 months and a second-line median OS of approximately 9 months, she states. The introduction of this first-line targeted regimen is promising, as in the pivotal phase 3 BREAKWATER trial (NCT04607421), it delivered an overall response rate of 61% (95% CI, 52%-70%) compared with 40% (95% CI, 31%-49%) with chemotherapy alone, she says. As OS and PFS data continue to mature, this regimen may redefine the standard of care for this population, reinforcing the need for precision medicine approaches in the frontline setting to optimize outcomes, she concludes.