Data from Characterization of KRAS Mutation Subtypes in Non–small Cell Lung Cancer

Abstract

<div>Abstract<p><i>KRAS</i> is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different <i>KRAS</i> mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, <i>KRAS</i>-mutated non–small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development.</p><p>Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of <i>KRAS</i> mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by <i>KRAS</i> mutation type.</p><p>Across the cohort, 4,706 (27.5%) samples harbored a <i>KRAS</i> mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of <i>KRAS</i> mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across <i>KRAS</i> mutation subtypes. <i>KRAS</i> G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). <i>STK11</i> was mutated in 8.6% of <i>KRAS</i> wild-type NSCLC but more frequent in <i>KRAS</i>-mutant NSCLC, with the highest rate in G13 (36.2%). <i>TP53</i> mutations were more frequent in <i>KRAS</i> wild-type NSCLC (73.6%).</p><p><i>KRAS</i> mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.</p></div>