Clinicogenomic predictors of first-line immune checkpoint inhibitor outcomes in non-small cell lung cancer: a nationwide C-CAT cohort from Japan

Background: The efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) varies, requiring predictive biomarkers.Methods: We analyzed the nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database and identified 1,629 patients with stage IV NSCLC who received first-line ICI-based therapy between 2019 and 2025.The primary endpoint was time to treatment failure (TTF); the secondary endpoint was overall survival (OS).Age-stratified Cox models were adjusted for covariates.Genomic covariates included KRAS, KEAP1, and STK11, with genes from exploratory screening.We tested KRAS-KEAP1 and KRAS-STK11 interactions.Sensitivity analyses included an FFPE-only subset with tumor mutational burden (TMB) and models adjusting for the ECOG status.Results: BRAF mutation was independently associated with longer TTF (HR 0.77, 95% CI 0.59-1.00;p = 0.049), whereas KRAS, KEAP1, and STK11 alone were not.A significant KRAS-KEAP1 interaction was associated with shorter TTF (HR 1.89, 95% CI 1.06-3.36;p = 0.032).In a four-level comparison versus wild-type, KRAS-only and KEAP1-only were not significant, whereas KRAS-KEAP1 co-mutation was associated with higher risk of failure (HR 2.48, 95% CI 1.50-4.10;p < 0.001).Results were consistent across sensitivity analyses.KEAP1 and STK11 were associated with worse OS, while BRAF showed no OS advantage.Conclusions: In first-line ICI-treated stage IV NSCLC, KRAS-KEAP1 co-mutation, not KRAS or KEAP1 alone, identifies patients at high risk of early failure, whereas BRAF was associated with longer TTF.These findings highlight the importance of co-mutation profiling and warrant prospective validation with integrative models incorporating PD-L1 and TMB.