Dr Bekaii-Saab on the Ongoing Development of Targeted Therapies in GI Malignancies

Tanios Bekaii-Saab, MD, FACP, professor, medicine, Mayo Clinic College of Medicine and Science; leader, Gastrointestinal Cancer Program, Mayo Clinic Comprehensive Cancer Center; medical director, Cancer Clinical Research Office; vice chair, section chief, Medical Oncology, Department of Internal Medicine, Mayo Clinic, discusses the need for widespread use of next-generation sequencing (NGS) and the ongoing development of RAS-targeted therapies in gastrointestinal (GI) cancers.

NGS testing is now considered essential and should be available to all patients due to its significant benefits, Bekaii-Saab begins. Not only does NGS help identify targeted therapies that match specific genetic alterations in patients, but it is also required for enrollment onto many clinical trials. For example, genetic markers such as HER2 and BRAF have long been established targets for drug development, but more recent interest has focused on RAS mutations, he explains. He adds thatRAS genes have been a target of research for decades, and recent advancements have made it possible to target these mutations more effectively.

One key advancement in this arena is the development of agents targeting the KRAS G12C mutation within the RAS family, he continues. For example, agents such as adagrasib (Krazati) and sotorasib (Lumakras) have demonstrated efficacy in colorectal cancer when combined with EGFR inhibitors, Bekaii-Saab states. Data from studies in pancreatic and biliary cancers also look promising, with adagrasib now included in the National Comprehensive Cancer Network Guidelines for patients harboring G12C mutations. However, G12C is one of many RAS mutations and has a low incidence in GI cancers, making it a more straightforward target, he elucidates.

As research progresses, there is increasing interest in targeting other RAS mutations such as G12D , he reports. Emerging studies are focused on developing agents that target the entire RAS pathway rather than just specific mutations. Although this approach offers a broader treatment strategy, targeted agents may remain the preferred approach for some patients due to their specificity, Bekaii-Saab expands. Although investigators are making strides, there is still much work to be done, Bekaii-Saab concludes.