Abstract SY42-02: Inactivating STK11/LKB1 genomic alterations are a major driver of primary resistance to PD-1 axis blockade in non-squamous non-small cell lung cancer

Despite improvements in overall survival (OS) and clinical responses of unprecedented duration with the use of therapeutic monoclonal antibodies that target PD-1 or PD-L1, the majority of patients with non-small cell lung cancer (NSCLC) fail to respond to PD-1/PD-L1 axis inhibitors. The genomic determinants of PD-1/PD-L1 inhibitor efficacy in NSCLC are incompletely understood and likely key to the development of novel personalized immunotherapy approaches. Through integrative analysis of multiple independent datasets of patients with KRAS-mutant lung adenocarcinoma (LUAC) - the most prevalent oncogenic driver event in LUAC- we identified three major disease subsets defined on the basis of co-occurring genomic events in STK11/LKB1 (the KL subgroup), TP53 (KP) and CDKN2A/B, the latter coupled with low expression of the TTF1 transcription factor (KC) (Skoulidis F et al., Cancer Discovery, 2015). STK11/LKB1 is somatically mutated in ~17% of LUAC and encodes a serine/threonine kinase with an established role in the regulation of cellular metabolism, growth and polarity. Gene set enrichment analysis of RNASeq data from the TCGA LUAC cohort indicated striking de-enrichment of multiple gene expression signatures pertaining to anti-tumor immunity in the KL subgroup, raising the possibility that inactivation of STK11/LKB1 may promote establishment of a non-T-cell inflamed immune microenvironment in lung adenocarcinoma. Indeed, STK11/LKB1-mutant LUAC exhibited significantly lower density of infiltrating CD3+ (P=0.0019) and CD8+ (P=0.0072) T-lymphocytes by automated quantitative immunohistochemistry (IHC) in a tumor microarray encompassing early stage, surgically resected, chemotherapy-naive tumors with available whole exome sequencing (PROSPECT cohort). In an independent, unbiased analysis of a large dataset of 924 LUAC with comprehensive NGS-based genomic profiling and available tumor cell PD-L1 expression (Foundation Medicine dataset) seeking to identify candidate genomic drivers of immune evasion and immunotherapy resistance, STK11/LKB1 genomic alterations emerged as the only significantly enriched gene in PD-L1Negative;TMBIntermediate/High compared to PD-L1High Positive;TMBIntermediate/High tumors (adjusted P 0). Therefore, quantitative IHC for STK11/LKB1 can capture STK11/LKB1-deficient tumors with intact STK11/LKB1 genomic locus and may enhance the predictive utility of STK11/LKB1 genomic alterations. Importantly, the impact of STK11/LKB1 mutations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1 positive tumors. Among 66 PD-L1-positive (≥1%) non-squamous NSCLC treated with PD-1/PD-L1 inhibitors, STK11/LKB1-mutated tumors exhibited significantly lower objective response rates to PD-1/PD-L1 blockade compared with NSCLC with intact STK11/LKB1 (ORR 0% vs. 34.5%, P = 0.026) and dramatically shorter PFS (HR 4.76; 95% CI, 2.0-11.1, P = 0.00012, log-rank test) and OS (HR 14.3; 95% CI, 3.4-50.0, P Citation Format: Ferdinandos Skoulidis. Inactivating STK11/LKB1 genomic alterations are a major driver of primary resistance to PD-1 axis blockade in non-squamous non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY42-02.