92PDComprehensive pan-cancer analysis of KRAS genomic alterations (GA) including potentially targetable subsets

AbstractBackgroundKRAS GA are common oncogenic drivers. Effective systemic treatment of KRAS altered cancers has been largely elusive; however covalent inhibitors of G12C (AMG510, MRTX849) and SHP2 inhibitors (TNO155, RMC-4630) have recently entered the clinic in multiple tumor types.MethodsHybrid capture-based comprehensive genomic profiling (CGP) was performed on tumor samples from 213,312 unique patients with solid or hematological malignancies. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA. PD-L1 expression was determined by IHC (22C3 or SP142 antibodies) for 17% of cases.ResultsKRAS GA were detected in 22% (n  = 46,182) of cases: 88% mutations (m;>99% substitutions andA), and G12V (primarily G>T) and G12C (exclusively G>T) from transversions. G12C was most frequent in LUAD (14%, 3,613/25,968) and PSC (11%, 40/353) but uncommon in pancreatic (1.7%, 161/9,723) and GI (2.7%, 941/35,019) where G12D/V were most common. Tobacco signature (TS; 20% vs 4.5% vs 3.5%), elevated TMB (median 7.0 vs 3.5 vs 3.5 mut/Mb) and PD-L1 positivity (56% vs 29% vs 31%) were all significantly associated with G12C vs non-G12C KRASm and non-KRASm cancers (all p  
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research

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