KRAS G12C as a Predictor of Immunotherapy Benefit in EMPOWER-Lung 1

David R. Gandara, MD, of UC Davis Comprehensive Cancer Center, discussed a genomic analysis of the phase 3 EMPOWER-Lung 1 trial (NCT03088540) presented at the IASLC 2026 World Conference on Lung Cancer (WCLC). The analysis looked at the role of KRAS G12C in response to immunotherapy in patients with non–small cell lung cancer (NSCLC). Gandara said the team preplanned the analysis of all mutations, with a specific focus on KRAS G12C.

He noted that most earlier analyses lumped KRAS mutations together, even though the group is large and biologically diverse. That approach masked the effect of G12C, which he described as having a large impact on immunotherapy activity. He gave 3 reasons the mutation fits this role. It is strongly linked to tobacco carcinogenesis, and smoking is itself a reasonably good biomarker for immunotherapy response. It is the most neoantigenic mutation, meaning it stimulates the immune system. It also has features favorable to the mechanism of checkpoint inhibitors.

On sequencing, Gandara said only 2 biomarkers, PD-L1 score and tumor mutational burden (TMB), are FDA approved to guide immunotherapy use in patients without a driver oncogene. Both have limits. In NSCLC, PD-L1 is measured only on tumor cells rather than with the combined positive score used in most other cancers. TMB is predictive mainly with monotherapy, and its value is diluted when combined with chemotherapy. KRAS G12C, he said, is associated with positive outcomes independent of both PD-L1 level and TMB.

Gandara described the findings as exploratory and hypothesis generating, but said they matter for trial design. G12C-specific inhibitors combined with immunotherapy face a higher hurdle if the comparator is immunotherapy plus chemotherapy. Pan-RAS inhibitors and novel immunotherapy combinations will need to stratify for or otherwise account for G12C.

The analysis included 712 patients, of whom 18% had the mutation, making it the largest study of G12C to date. Gandara said his group plans another study to validate the findings in a design that isolates the effect of the mutation.