Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status

Introduction: STK11 and KEAP1 mutations (STK11 mutant [STK11(MUT)] and KEAP1(MUT)) are among the most often mutated genes in lung adenocarcinoma (LUAD). Although STK11(MUT) has been associated with resistance to programmed death-(ligand)1 (PD-[L]1) inhibition in KRAS(MUT) LUAD, its impact on immunotherapy efficacy in KRAS wildtype (KRAS(WT)) LUAD is currently unknown. Whether KEAP1(MUT) differentially affects outcomes to PD-(L)1 inhibition in KRAS(MUT) and KRAS(WT) LUAD is also unknown. Methods: Clinicopathologic and genomic data were collected from September 2013 to September 2020 from patients with advanced LUAD at the Dana-Farber Cancer Institute/Massachusetts General Hospital cohort and the Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center cohort. Clinical outcomes to PD-(L)1 inhibition were analyzed according to KRAS, STK11, and KEAP1 mutation status in two independent cohorts. The Cancer Genome Atlas transcriptomic data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 comutation status. Results: In the combined cohort (Dana-Farber Cancer Institute/Massachusetts General Hospital thorn Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center) of 1261 patients (median age = 61 y [range: 22-92], 708 women [56.1%], 1065 smokers [84.4%]), KRAS mutations were detected in 536 cases (42.5%), and deleterious STK11 and KEAP1 mutations were found in 20.6% (260 of 1261) and 19.2% (231 of 1202) of assessable cases, respectively. In each independent cohort and in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free (STK11 hazard ratio [HR] = 2.04, p < 0.0001; KEAP1 HR = 2.05, p < 0.0001) and overall (STK11 HR = 2.09, p < 0.0001; KEAP1 HR = 2.24, p < 0.0001) survival to immunotherapy uniquely among KRAS(MUT) but not KRAS(WT) LUADs. Gene expression ontology and immune cell enrichment analyses revealed that the presence of STK11 or KEAP1 mutations results in distinct immunophenotypes in KRAS(MUT), but not in KRAS(WT), lung cancers. Conclusions: STK11 and KEAP1 mutations confer worse outcomes to immunotherapy among patients with KRAS(MUT) but not among KRAS(WT) LUAD. Tumors harboring concurrent KRAS/STK11 and KRAS/KEAP1 mutations display distinct immune profiles in terms of gene expression and immune cell infiltration. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Automated summary

STK11 and KEAP1 mutations have a negative impact on the efficacy of immunotherapy in lung adenocarcinoma, but this effect is only observed in KRAS-positive tumors. Tumors with concurrent KRAS/STK11 and KRAS/KEAP1 mutations exhibit distinct immune characteristics.