Dr Kopetz on the Rationale of the BREAKWATER Study in BRAF V600E­mutant mCRC

Scott Kopetz, MD, PhD, FACP, professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the rationale for launching the phase 3 BREAKWATER trial (NCT04607421) in BRAF V600E­–mutant metastatic colorectal cancer (mCRC).

The ongoing phase 3 trial is evaluating encorafenib (Braftovi) in combination with cetuximab (Erbitux) with or without mFOLFOX6 or FOLFIRI vs chemotherapy alone in patients with BRAF V600E–mutant mCRC. Data from the safety lead-in portion of the trial presented at the 2023 Gastrointestinal Cancer Symposium showed that encorafenib and cetuximab can be combined safely with both mFOLFOX6 and FOLFIRI.

Moreover, early efficacy data showed that 19 patients treated with encorafenib plus cetuximab and mFOLFOX6 in the first-line setting experienced an overall response rate (ORR) of 68.4% (95% CI, 46.0%-84.6%), and 12 patients given encorafenib plus cetuximab and FOLFIRI had an ORR of 75.0% (95% CI, 46.8%-91.1%).

Patients BRAF V600E–mutant mCRC have an aggressive tumor type, and these tumors are dependent on tumor signaling through the MAPK pathway, Kopetz explains. Prior research demonstrated that a BRAF inhibitor in combination with an EGFR inhibitor could improve survival in this subset of patients, Kopetz expands.

The combination of encorafenib and cetuximab is a standard of care in the second- and third-line of treatment, Kopetz continues. Therefore, the hope is that the combination of targeted therapies and cytotoxic chemotherapy could improve the outcome of these patients, Kopetz concludes.