Dr Herzberg on Future Research Directions in KRAS-Mutant NSCLC

"Major questions are going to be: What combinations are tolerable? What can be used? What combinations are very good, synergistic, or better than just using the drugs individually? Those are somewhat separate questions that tend to get lumped together, but we have a number of trials ongoing that are trying to answer those questions. "

Benjamin Herzberg, MD, an assistant professor of medicine at Columbia University Herbert Irving Comprehensive Cancer Center, as well as an assistant professor of medicine at Columbia University Medical Center, discussed efforts to clarify the use and development of KRAS inhibitors for the treatment of patients with non–small cell lung cancer (NSCLC).

Key challenges in the evolution of KRAS-targeted therapies include identifying effective combination strategies and overcoming resistance mechanisms, particularly in KRAS G12C–mutant and non-G12C–mutant tumors, Herzberg began. Although KRAS G12C inhibitors, such as adagrasib (Krazati) and sotorasib (Lumakras), have demonstrated clinical activity in patients with NSCLC, their use as monotherapy has shown limited response durability, prompting the need to explore synergistic combinations with these agents, he noted.

Combination EGFR inhibitor combination partners currently under investigation include chemotherapy agents, immune checkpoint inhibitors, and targeted agents, Herzberg stated. Of these, the most promising data to have emerged from combinations with EGFR inhibitors include those with the agents cetuximab (Erbitux) and panitumumab (Vectibix), Herzberg detailed. Notably, preclinical reports of KRAS G12C inhibitors combined with immunotherapy have not demonstrated clear synergy between these classes of agents, with response rates appearing additive rather than enhanced beyond those generated by each agent as monotherapy, according to Herzberg.

Several trials are ongoing to determine which combinations are feasible and tolerable, as well as which combinations provide superior clinical benefit, Herzberg continued. Studies evaluating adagrasib in combination with checkpoint inhibitors in PD-L1–high tumors and sotorasib with chemotherapy in PD-L1–low tumors are anticipated to provide greater clarity on optimal sequencing and combination strategies in molecularly defined patient subsets, he concluded.