Alexander I. Spira, MD, PhD, FACP, on Necessary Next Steps for Research in KRAS G12C+ NSCLC

In an interview with CancerNetwork®, Alexander I. Spira, MD, PhD, FACP, director of the Thoracic and Phase I Programs as well as co-director of the Virginia Cancer Specialists Research Institution and clinical assistant professor at Johns Hopkin University, discussed future research efforts related to KRAS G12C–positive non–small cell lung cancer. He spoke about the necessity of assessing KRAS inhibitor plus immunotherapy combinations, resistance mechanisms, and drugs targeting other KRAS mutations.

His words are especially poignant following presentations at the 2022 World Conference on Lung Cancer, where several presentations surrounding KRAS G12C­–targeted therapies, alone and in combination, were presented, such as:

• a phase 1b trial (NCT04185883) assessing sotorasib (Lumakras) and the small molecule SHP2 inhibitor RMC-4630 in patients with pretreated and KRAS G12C inhibitor–naïve KRAS G12C–mutant NSCLC.
• a phase 1a trial (NCT04449874) of the KRAS G12C inhibitor GDC-6036 in patients with previously treated KRAS G12C–mutant NSCLC.
• efficacy and safety data from the phase 1/2 CodeBreak 100 (NCT03600883) and CodeBreak 101 (NCT04185883) trials showing promise of sotorasib plus either pembrolizumab (Keytruda) or atezolizumab (Tecentriq) for patients with KRAS G12C–positive NSCLC with a lead-in dosing strategy.

Transcript:

KRAS G12C [targeted drugs are] good, but not great. These drugs work, but everybody is looking at [mechanisms] to overcome resistance. There are new compounds [such as those targeting] SHP2 and SOS1 combined with immunotherapy [that may] improve on this. We all think about, as with all other targeted therapies, whether there will be a new generation of drugs that act even better. Most importantly, these are just [targeting] KRAS G12C. It’s the most common [KRAS mutation], but it still [represents a minority of patients with KRAS mutations overall]. What do we do about all the other KRAS mutations?

You can’t treat a target if you don’t test for the target. As a reminder to everybody, please test all patients. I get full next-generation sequencing panels and blood-based panels; it’s the most important thing.