P14.26 Diminished Efficacy of PD-(L)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma is Impacted by KRAS Mutation Status

Abstract Introduction STK11 and KEAP1 mutations (STK11MUT and KEAP1MUT) are among the most commonly mutated genes in lung adenocarcinoma (LUAD). While STK11MUT has been associated with resistance to PD-(L)1 inhibition in KRAS mutant (KRASMUT) LUAD, its impact on immunotherapy efficacy in KRAS wild-type (KRASWT) LUAD is currently unknown. Whether KEAP1MUT differentially impacts outcomes to PD-(L)1 inhibition in KRASMUT and KRASWT 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 (DFCI/MGH cohort), and Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center (MSKCC/MDACC cohort). Clinical outcomes to PD-(L)1 inhibition were analyzed according to KRAS, STK11, and KEAP1 mutation status in two independent cohorts. TCGA transcriptomic data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 co-mutation status. Results In the combined cohort (DFCI/MGH + MSKCC/MDACC) of 1261 patients (median age 61 years [range:22-92], 708 women [56.1%], 1065 smokers [84.4%]), KRAS mutations were detected in 536 (42.5%) cases, deleterious STK11 and KEAP1 mutations were found in 20.6% (260/1261), and 19.2% (231/1202) of evaluable cases, respectively. In each independent cohort, as well as in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free (STK11 HR: 2.04, P Conclusion STK11 and KEAP1 mutations confer worse outcomes to immunotherapy among patients with KRASMUT but not among KRASWT lung adenocarcinoma. Tumors harboring concurrent KRAS/STK11 and KRAS/KEAP1 mutations display distinct immune profiles in terms of gene expression and immune cell infiltration.