230P Clinicopathologic and molecular features of STK11-mutated NSCLC

STK11 mutations (STK11+) predict for poor response to anti-PD1 therapy in non-small cell lung cancer (NSCLC). Subset analysis from 2 randomised trials suggest benefit from CTLA4 combinations, although this remains poorly understood. We sought to characterise the molecular landscape of STK11+ NSCLC. STK11+ NSCLC in our database were identified. Patient demographics, treatment and survival data were collated. Whole exome sequencing (WES) and RNA-seq were performed and compared against The Cancer Genome Atlas (TCGA). Among 2686 consecutive NSCLC patients undergoing routine next generation sequencing using a 29-gene hotspot panel (2019-2023), the prevalence of STK11+ was 1.7% (n=46). Of 37 patients with available clinical data, median age at diagnosis was 65 years, 84% were males and 22% were never-smokers. Distribution by PD-L1 TPS was 47% for 50%. Among 9 patients who received first-line platinum doublet chemotherapy plus anti-PD1 therapy, 6 (67%) had progressive disease as best response. Median time to treatment failure (TTF) was 2 months (m) (range 0 – 3) and median overall survival (OS) was 9 m (2 – 23). No patient received CTLA4-directed treatment. Of 3 patients who received first-line EGFR TKI monotherapy, median TTF was 14m (12 – 16) and median OS was 39m (29 – 54). WES and RNA-seq were performed for 17 patients and compared against 88 STK11+ and 131 STK11-wildtype from TCGA. Among STK11+, KRAS co-mutations were more common in TCGA (29% vs 53%, p=0.11) and EGFR was more common in our cohort (18% vs 1%, p=0.02). Mutational signatures, TMB, GEP score and transcriptomic subtypes were similar between both cohorts. CIBERSORT analysis revealed resting CD4+ memory T cells (21%), M2 macrophages (15%) and M0 macrophages (13%) as the predominant immune cell infiltrate among STK11+. Among KRAS-mutated tumours, STK11+ tumours had a significantly lower GEP score (median -2.1 vs -1.5, p=0.01) and higher representation of PP subtype (77% vs 25%, p<0.001) as compared to STK11-wildtype. STK11 are rare mutations that can co-occur with oncogenic drivers such as KRAS and EGFR. Limited responses to chemo-immunotherapy were observed in our small cohort of patients. Deep molecular characterisation can reveal relevant therapeutic insights.