Dr Gandara on the KRAS G12C Survival Signal With Cemiplimab in EMPOWER-Lung 1

Independent of clinical implications, KRAS G12C is a poster child for a gene that would be associated with immunotherapy benefit. It's highly associated with tobacco carcinogenesis, it's highly neoantigenic, and it tends to associate with other gene mutations that would further boost the benefit from immunotherapy, and one of those is TP53.

At the IASLC 2026 World Conference on Lung Cancer (WCLC) in Seoul, David R. Gandara, MD, professor emeritus, Division of Hematology and Oncology, and co-director, Center for Experimental Therapeutics, UC Davis Comprehensive Cancer Center, presented a genomic analysis of EMPOWER-Lung 1 (NCT03088540), which randomized patients with advanced non–small cell lung cancer (NSCLC), PD-L1 expression of ≥50%, and no EGFR, ALK, or ROS1 aberrations to cemiplimab (Libtayo) or platinum-based chemotherapy.

Baseline tumor tissue or plasma was profiled with FoundationOne Tracker or FoundationOne Liquid CDx in 69% of the PD-L1–high population (389/565), split roughly evenly between tissue and blood, and the analysis focused on 218 biomarker-evaluable patients with nonsquamous disease. Gandara noted the trial's five-year data showed more than double the overall survival (OS) with cemiplimab vs chemotherapy; the genomic analysis, he said, asks why, and whether a subgroup did extraordinarily well.

Among 89 patients with KRAS-mutant tumors, cemiplimab improved median OS vs chemotherapy (53.8 vs 17.1 months; HR, 0.46; 95% CI, 0.26 - 0.83) and median progression-free survival (PFS; 18.9 vs 4.2 months; HR, 0.31; 95% CI, 0.18 - 0.54), with objective response rates (ORRs) of 67% versus 15%.

KRAS G12C accounted for 44% (39/89) of KRAS mutations, and in that subset the benefit was larger: median OS was not reached versus 8 months (HR, 0.18; 95% CI, 0.07 - 0.49), median PFS was 24.9 versus 3.7 months (HR, 0.19; 95% CI, 0.07 - 0.50), and the ORR was 74% versus 13%. PD-L1 levels were similarly distributed across KRAS wild-type and mutant tumors, and response to cemiplimab was unaffected by TP53 co-mutation status.

Gandara said the biologic rationale precedes the data: KRAS G12C tracks with tobacco carcinogenesis, is the most neoantigenic KRAS variant, and tends to co-occur with alterations such as TP53 that further favor immunotherapy.

The larger importance, he said, is that the analysis sets a baseline for 2 directions of ongoing and planned research. First, trials pairing cemiplimab or other checkpoint inhibitors with novel immunotherapeutic approaches must account for KRAS G12C to determine whether combinations further improve outcomes in that subgroup or lift patients who fare worse.

Second, newer RAS(ON) inhibitors, including daraxonrasib (Daraxo), which received US Food and Drug Administration (FDA) approval in pancreatic cancer in August 2026 and has shown activity in RAS-mutant NSCLC, are being combined with immunotherapy, and some are G12C-selective while others hit G12C as part of a broader target.

Given that G12C represented 44% of KRAS mutations in the study, Gandara said investigators will have to decide up front whether to stratify for it or enroll all comers and risk diluting the benefit of a new combination.