Comutations and KRAS^G12C Inhibitor Efficacy in Advanced NSCLC

Molecular modifiers of KRAS^G12C inhibitor (KRAS^G12Ci) efficacy in advanced KRAS^G12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non–small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRAS^G12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRAS^G12Ci. Pathway-level integration of less preva-lent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS^G12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRAS^G12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRAS^G12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors.