Dr Eng on Unmet Needs Within the mCRC Treatment Paradigm

Cathy Eng, MD, FACP, FASCO, David H. Johnson Endowed Chair in Surgical and Medical Oncology, professor, medicine, Hematology and Oncology, director, Strategic Relations, co-director, Gastrointestinal (GI) Oncology, co-leader, GI Cancer Research Program, director, Young Adult Cancers Program, Vanderbilt-Ingram Cancer Center, discusses unmet needs within the metastatic colorectal cancer (mCRC) treatment paradigm.

One significant unmet need in the management of mCRC is addressing BRAF V600E–mutant tumor types, particularly in microsatellite-stable (MSS) patients, Eng begins. Although the FDA has approved the combination of cetuximab (Erbitux) plus encorafenib (Braftovi) for the treatment of previously treated adult patients with BRAFV600E–mutated mCRC, there is still a lack of effective options once patients progress after BRAF inhibitor therapy, she says. The ongoing phase 3 BREAKWATER trial (NCT04607421), which is evaluating the combination of encorafenib and chemotherapy in the frontline BRAF V600E–mutated mCRC setting, holds promise, but final results are still pending, Eng reports. This leaves clinicians unsure of how best to treat patients who progress on BRAF-targeted therapies, according to Eng. In these cases, it is critical to consider clinical trials for all patients, regardless of mutation status or current treatment, she adds.

Another major area of interest is addressing KRAS mutations, particularly since the combination of adagrasib (Krazati) and cetuximab is now approved for KRAS G12C–mutated mCRC, Eng expands. There is also research into targeting KRAS G12V mutations with combination therapies, but patients with other KRAS mutations still lack viable treatment options, she notes. Eng adds that this unmet need has led to significant interest in the development of pan-RAS inhibitors, although these treatments are still in the early stages of research.

The refractory patient population remains another area of unmet need, especially for those without actionable mutations, Eng continues. Although therapies targeting HER2-amplified mCRC have shown some success, many patients still lack effective treatment options, she reports. Ongoing research offers hope, but for now, participation in clinical trials is essential for patients with surgically unresectable disease, Eng emphasizes. Clinical trials provide access to emerging therapies and help address the gaps in available treatments for this challenging-to-treat patient population, she concludes.