Dr Le on Innovations and Future Directions for KRAS Inhibition in NSCLC

"[In the near future], we probably will see KRAS G12C inhibitors combined with either other bispecific antibodies or antibody-drug conjugates to amplify their benefit."

Xiuning Le, MD, PhD, an associate professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Internal Medicine at The University of Texas MD Anderson Cancer Center, discussed novel treatment approaches for targeting KRAS G12C in patients with non–small cell lung cancer (NSCLC). She also highlighted other emerging avenues for KRAS inhibition in this disease.

Le noted that the use of KRAS G12C inhibitors has become widespread in clinical practice, at least within the United States. However, research efforts continue to focus on improving the current state of treatment for patients with KRAS-mutated disease. Le highlighted that optimizing currently available therapies is crucial; achieving higher potency and better brain penetrance in existing KRAS G12C inhibitors is expected to improve clinical outcomes. Furthermore, Le confirmed that a “wave of new KRAS inhibitors” may be coming to the clinic.

Another significant way to improve patient outcomes is by identifying appropriate patient populations for combination therapy, particularly in the frontline setting, according to Le. She pointed to encouraging results emerging from studies evaluating combination regimens. As an example, the combination of adagrasib (Krazati) and the immune checkpoint inhibitor pembrolizumab (Keytruda) has elicited promising results in KRAS-mutated NSCLC, she reported.

This combination strategy leverages both the KRAS component of the disease and the tumor component involved in immune checkpoint regulation, Le noted. She explained that this dual-targeting approach aims to provide patients with longer and better progression-free survival.

Looking ahead, Le suggested that future therapies will likely involve combining KRAS G12C inhibitors with other drug classes, such as bispecific antibodies or antibody-drug conjugates, which would be used to amplify the overall therapeutic benefit of KRAS inhibitors. Le expressed confidence that the field will see a new wave of KRAS G12C–focused clinical trials.