KRAS mutational status and efficacy in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC

Abstract

Background:KRAS mutations are observed in25% of lung adenocarcinomas, withsome studies suggesting it is a prognostic factor in NSCLC. We assessed the prevalenceof KRAS mutations and their association with efficacy in an exploratory analysis of theKEYNOTE-189 study of pembrolizumab plus pemetrexed and platinum chemotherapyvs placebo plus chemotherapy as first-line therapy for metastatic non-squamousNSCLC (NCT02578680).Methods:Whole-exome sequencing (WES) was used to assess KRAS status and tumormutational burden (TMB) in participants (pts) who had available tumor and matched-normal tissue. Descriptive analyses of the association of KRAS and KRAS G12C statuswith efficacy were included as part of this exploratory analysis, as was correlationbetween KRAS mutational status and shifts in TMB and PD-L1 expressiondistributions.Results:289 (47%) of 616 pts had evaluable WES data from both tumor and normalDNA. 89 (31%) of 289 pts had KRAS mutation, including 37 (13%) G12C carriers. Ptswith vs without KRAS mutations tended to have higher PD-L1 TPS (median [IQR]30% [1-71] vs 5% [0-60]) and higher TMB (median [IQR] 204 [137-276] vs 141 [85-252] mut/exome). Outcomes of pembrolizumab plus chemotherapy and of placeboplus chemotherapy in pts with and without KRAS mutation and in KRAS G12C carriersare summarized in the table. 95% CIs were wide given the modest frequency of KRASmutation, particularly KRAS G12C, and the 2:1 randomization that resulted in smallpopulations for placebo plus chemotherapy.Conclusion:Based on this descriptive exploratory analysis, pembrolizumab plus peme-trexed and a platinum should be a standard first-line treatment for pts with metastaticnon-squamous NSCLC regardless of KRAS mutation status