Clinicogenomic Predictors of First-line Immune Checkpoint Inhibitor Outcomes in Non-Small Cell Lung Cancer: A Nationwide CCAT 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 (CCAT) database and identified 1629 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 = .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 = .032). In a 4-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 < .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.