Dr Herzberg on Notable Ongoing Research in KRAS-Mutated NSCLC

"The key questions with KRAS-targeted agents are: [Will] the drugs be allele-specific, targeting 1 specific KRAS mutation like G12C, G12D, or G12V, or are we making drugs that can target all potential KRAS mutations or even RAS mutations? How are those different approaches going to play out in terms of toxicity, activity, and success?"

Benjamin Herzberg, MD, an assistant professor of medicine at Columbia University Irving Medical Center and an oncologist at Herbert Irving Comprehensive Cancer Center, discussed the ongoing investigation of KRAS-targeted treatment approaches for patients with non–small cell lung cancer (NSCLC).

KRAS-targeted drug development remains a major focus in NSCLC, with ongoing advances in medicinal chemistry and pharmacology driving innovative strategies to inhibit KRAS mutations, Herzberg began. A key question in this arena is whether KRAS inhibitors should be allele-specific—targeting G12C, G12D, or G12V—or whether pan-KRAS or pan-RAS inhibitors capable of targeting multiple mutations will offer greater therapeutic benefit, Herzberg shared. These approaches differ in terms of toxicity, efficacy, and clinical success, necessitating further investigation, he added.

Currently approved KRAS inhibitors selectively target the GDP-bound, inactive state of KRAS, but emerging strategies aim to inhibit the GTP-bound, active state as well, Herzberg explained. Novel agents include direct inhibitors and molecular glue inhibitors, which function by tethering KRAS to another molecule, thereby disrupting its activity, Herzberg detailed. Tri-complex inhibitors from Revolution Medicines exemplify this approach and include both allele-specific inhibitors and pan-RAS inhibitors that can broadly target any RAS mutation, he noted.

Early-phase clinical trials have reported promising responses with KRAS inhibitors in patients with RAS-mutated tumors, highlighting the potential for these next-generation inhibitors, Herzberg reported. However, given the wide range of investigational compounds in development, further research is needed to determine optimal patient selection, toxicity profiles, and combination strategies, he noted. As the field continues to evolve, KRAS inhibition in NSCLC is expected to become increasingly refined, with the potential to improve outcomes for a broader patient population, Herzberg concluded.