Dr Kopetz on the Safety of Encorafenib Plus Cetuximab in BRAF V600E+ CRC

"The safety data were commensurate with what was expected from the individual agents. Encorafenib and cetuximab [led to an] increase in some low-grade arthralgia and low-grade rashes, and a slightly higher rate of anemia."

Scott Kopetz, MD, PhD, FACP, deputy chair and professor in the Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine; leader of the Department of Cancer Center Support Grant, GI Program; TRACTION medical director of the Division of Therapeutics Discovery Division; and associate vice president for Translational Integration at The University of Texas MD Anderson Cancer Center, discussed safety findings from the phase 3 BREAKWATER trial (NCT04607421), which evaluated the combination of encorafenib (Braftovi) plus cetuximab (Erbitux) with or without chemotherapy in the frontline treatment of patients with BRAF V600E–mutant metastatic colorectal cancer (mCRC).

Data from BREAKWATER supported the December 2024 FDA accelerated approval of encorafenib in combination with cetuximab and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test.

Kopetz reported that study results showed the safety profile of encorafenib plus cetuximab with or without chemotherapy was consistent with known toxicities of the individual agents. Encorafenib-related effects included low-grade arthralgias and dermatologic toxicities, including rash, which are well-documented in the context of BRAF inhibition, he said, explaining that the addition of cetuximab did not appear to significantly exacerbate these toxicities.

Kopetz noted that a slightly higher incidence of anemia was observed in the combination arm, although this was not deemed clinically significant. Importantly, no new safety signals emerged, and the overall safety profile of the combination was manageable. Rates of treatment-emergent adverse effects were similar between the treatment arms, and there were no statistically significant differences in the frequency of treatment interruptions or discontinuations due to toxicity related to chemotherapy.

Kopetz emphasized that these findings suggest that the addition of targeted agents to frontline chemotherapy in BRAF V600E–mutated CRC does not substantially increase toxicity burden. This is particularly relevant as treatment intensification strategies are considered for this high-risk subgroup, where progression-free and overall survival remain limited with standard chemotherapy alone.