Characterization of KRAS mutations (mt) in non-small cell lung cancer (NSCLC).

Abstract

9544 Background: KRAS is the most commonly mutated oncogene in NSCLC and the development of direct KRAS inhibitors has renewed interest in this molecular subtype. However, there are several different KRAS mts, representing unique biology and different prognostic and therapeutic impact. A more comprehensive understanding of the genomic landscape relative to each KRAS mt subset will help guide therapeutic development. Methods: Molecular profiles of 17,113 NSCLC specimens were obtained using next-generation sequencing of 592 genes (Caris Life Sciences) and classified based on presence and types of KRAS mt. Incidence of KRAS mts was noted across the cohort and by histology. Co-occurring genomic alterations, tumor mutational burden (TMB) and PD-L1 IHC (22C3, TPS score) were analyzed by KRAS mt type. Results: Across the entire cohort, 4706 (27%) of samples harbored a KRAS mt (Table). The most common was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mt was 37.2% among adenocarcinoma and only 4.4% in squamous. High TMB, defined by > 10 mts/Mb, varied across the different KRAS mt types, most common in G13X (68.3%) and least common in G12D (43.2%). PD-L1 expression also varied. G12C was the most likely to be PD-L1 positive, with 65.5% TPS > 1%, and the most likely to be PD-L1 high, with 41.3% TPS > 50%. STK11 was mutated in 8.6% of KRAS wild type NSCLC but more frequently noted in every KRAS subtype, with the highest rate in G13X (36.2%) and the lowest in G12D(14.2%). TP53 mts were more frequent in KRAS wild type NSCLC (73.6%), with the highest rate among KRAS mutants at 55.4% (G12other) and the lowest at 36.8% (Q61X). NF1 was noted to be mutated in 21.4% of KRAS G13X cases, while all other KRAS mts had a lower frequency of NF1 mts than KRAS wild type (11.5%). Conclusions: KRAS mts are relatively common in lung adenocarcinoma and KRAS G12C is the most common variant. The different KRAS mts have different co-occurring mutations and a different genomic landscape. KRAS G12C was associated with the highest rate of PD-L1 expression. The clinical relevance of these differences in the context of therapeutic intervention warrants investigation. [Table: see text]