Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC

Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) effi cacy in advanced KRASG12C- mutant NSCLC are poorly defi ned. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identifi ed and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured & SIM;50% of those with early disease progres-sion (progression-free survival & LE; 3 months) with KRASG12Ci. Pathway-level integration of less preva-lent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifi cations, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci effi cacy. Our fi ndings propose a framework for patient stratifi cation and clinical outcome prediction in KRASG12C-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 stratifi cation and treatment personalization based on the comutational status of individual tumors.