Several next-generation KRAS G12C inhibitor plus checkpoint inhibitor combinations are already in clinical development. A retrospective analysis of the phase 3 EMPOWER-Lung 1 trial (NCT03088540), presented at the IASLC 2026 World Conference on Lung Cancer (WCLC), showed that patients with KRAS G12C-mutated, nonsquamous advanced non–small cell lung cancer (NSCLC) and PD-L1 expression of 50% or higher had an objective response rate of 74% with first-line cemiplimab (Libtayo) monotherapy.1
David R. Gandara, MD, director of thoracic oncology and co-director of the Center for Experimental Therapeutics in Cancer at UC Davis Comprehensive Cancer Center, who presented these findings at the meeting, spoke with CancerNetwork® about whether these data should influence how future combination trials are designed. He detailed how factors such as selecting patients based on specific PD-L1 expression statuses may help isolate the effects of novel regimens vs standard-of-care therapy in future trials.
Transcript:
CancerNetwork: Several next-generation KRAS G12C inhibitor plus checkpoint inhibitor combinations are already in development. Do these data give you pause about how those combination trials should be designed, particularly around whether they need a chemotherapy-free, immune checkpoint inhibitor monotherapy comparator arm?
Gandara: That would depend; the design will depend on other factors. For example, the study we just reported is specific to patients whose cancers have a PD-L1 score of at least 50%. We know that group of patients tends to respond better to checkpoint immunotherapy. For example, one design could be one of the new KRAS G12C–specific drugs vs cemiplimab, or another checkpoint inhibitor, as monotherapy, in patients with a PD-L1 level greater than 50%. That would be the type of design to isolate these effects vs current standard-of-care therapy in that group of patients. Alternatively, if the trial design included lower levels of PD-L1 expression, like 1% to 49%, then the comparator would probably be platinum chemotherapy plus immunotherapy.
If you were designing a trial for those drugs, you might ask whether you should give your drug together with platinum chemotherapy against immunotherapy plus platinum chemotherapy to isolate the effects of your drug but have a better chance of showing superiority. This sort of design has played out in other targeted therapies for non–small cell lung cancer, where your drug sometimes needs the help of another drug in order to show superiority.
Reference
Gandara DR, Anagnostou V, Forde P, et al. KRAS G12C predicts superior outcomes with 1st line cemiplimab for non-squamous aNSCLC with PD-L1 ≥50%: data from EMPOWER-Lung 1. Presented at: 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract MO05.07.
