Dr. Kopetz on Safety Lead-in Data from the BREAKWATER Trial in BRAF V600E–Mutant 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 safety lead-in data from the phase 3 BREAKWATER trial (NCT04607421) in patients with BRAF V600E­–mutant metastatic colorectal cancer (mCRC).

The ongoing BREAKWATER study is evaluating the use of encorafenib (Braftovi) with cetuximab (Erbitux) with or without mFOLFOX6 or FOLFIRI vs chemotherapy alone in patients with BRAF V600E–mutant mCRC. The safety lead-in portion of the trial examined the toxicity data for the encorafenib/cetuximab plus chemotherapy combinations in the first- and second-line settings.

Safety data presented at the 2023 Gastrointestinal Cancers Symposium showed that encorafenib and cetuximab can be combined safely with both mFOLFOX6 and FOLFIRI, with both regimens demonstrating an acceptable safety profile, Kopetz says. Rates of serious treatment-related adverse effects were 25.9% in the encorafenib/cetuximab plus mFOLFOX6 arm and 13.3% in the encorafenib/cetuximab plus FOLFIRI arm. These findings reflected favorably on what has been seen with the targeted therapy combination alone or the chemotherapy regimens alone, Kopetz emphasizes.

Early efficacy data showed that in the first-line setting, 19 patients treated with encorafenib plus cetuximab and mFOLFOX6 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%). In the second-line setting, 8 patients treated with encorafenib plus cetuximab and mFOLFOX6 achieved an ORR of 37.5% (95% CI, 13.7%- 69.4%), and 18 patients given encorafenib plus cetuximab and FOLFIRI had an ORR of 44.4% (95% CI, 24.6%-66.3%).

In the first-line setting, encorafenib plus cetuximab and mFOLFOX6 and encorafenib plus cetuximab and FOLFIRI elicited a median progression-free survival (PFS) of 11.1 months (95% CI, 8.6–not estimable [NE]) and NE (95% CI, 13.8-NE), respectively. In the second-line setting, the median PFS was 10.8 months (95% CI, 4.3-NE) and 12.6 months (95% CI, 5.9-NE), with the 2 regimens, respectively.

While the patient population evaluated was small, the ORRs observed in the first-line setting compared favorably with historic data for patients with BRAF V600E–mutant mCRC, who generally have lower response rates with cytotoxic chemotherapy, according to Kopetz.

Despite the small number of patients included in the safety lead-in portion of the trial, the data give enthusiasm that encorafenib plus cetuximab plus chemotherapy may provide benefit for patients, and the findings support the continued enrollment of the phase 3 portion of the BREAKWATER trial, Kopetz concludes.