Tumor mutational burden (TMB) profile of K-RAS/TP-53 co-mutation in metastatic non-small cell lung cancer (m-NSCLC).

Abstract

2626 Background: Early data suggests that co-occurring genetic events define biological heterogeneity in K-RAS mutant NSCLC, with K-RAS/ TP-53 (KP) co-mutated subset having potential therapeutic vulnerabilities to immune checkpoint blockade (ICB). To explore the immunological basis for these findings, we evaluated the immune biomarker profile (TMB/PD-L1) in KP mutant m-NSCLC using a large next-generation sequencing (NGS) dataset. Methods: Caris life sciences NGS dataset consisting of 1317 m-NSCLC tissue samples from 2016-18 was queried. PD-L1pos was defined as ≥ 1% staining using 22c3 Dako assay. TMB was measured by counting all somatic non-synonymous missense mutations using targeted NGS (592 genes). TMB-high (H) was defined as ≥ 10 mutations/Megabase (mut/Mb). P-values were calculated using Chi-square and Mann-Whitney test. Results: K-RAS mutations were identified in 28.7% (378/1317). Within this K-RAS mutant group, KP subset constituted 49.4% (187/378), remaining were K-RAS mutated/ TP-53 wild type (K-Pwt). 72.2 % (135/187) of KP had PD-L1pos with 51.9% (97/187) having PD-L1 ≥ 50%. KP had higher median TMB vs. K-Pwt (14.5 vs. 9.0 mut/Mb, p<0.001) and higher % of TMB-H vs. K-Pwt (79.9 vs. 45.1%, p<0.001; Table). Even in the PD-L1neg group, KP had higher % of TMB-H vs. K-Pwt (86.5 vs. 41.5%, p<0.001). K-RAS or TP-53 exon-subtypes had no difference in median TMB or % of TMB-H. Across metastatic sites, brain tissue had the highest % of KP subset (38.3%, 68/187) followed by bone (28.9%, 54/187). Within KP subset, brain tissue had higher median TMB vs. bone (16 vs. 11 mut/Mb, p<0.01) as well as greater % of TMB-H vs. bone (86.5 vs. 68.5%, p=0.01). Conclusions: This is the largest dataset to date highlighting the unique immune profile of KP mutant m-NSCLC. Our results show that KP subset has a significantly higher TMB than K-Pwt, especially in the PD-L1neg subgroup. Metastatic site-specific variations in TMB were also observed for the KP subset. These findings could have therapeutic implications in guiding patient selection for ICB and merit prospective investigation.[Table: see text]