Abstract 230P
Background
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.
Methods
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).
Results
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 <1%, 35% for 1-49% and 18% 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.
Conclusions
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.
Legal entity responsible for the study
Lung Cancer Consortium Singapore.
Funding
Lung Cancer Large Collaborative Grant (LCG) from National Medical Research Council Singapore, AstraZeneca.
Disclosure
P.L.S. Saw: Financial Interests, Institutional, Invited Speaker: AstraZeneca, MSD; Financial Interests, Institutional, Advisory Board: Pfizer, Bayer, AstraZeneca; Financial Interests, Institutional, Research Grant: Guardant Health, AstraZeneca; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, Novartis, BeiGene, Dracen. G. Lai: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Amgen, Pfizer, BMS, Roche; Other, Personal, Other, sponsorship for meeting: DKSH. A. Tan: Financial Interests, Personal, Advisory Board: Amgen, Pfizer, Bayer; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Guardant Health, Merck, AstraZeneca. W.L. Tan: Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Other, Focus Group meeting for expert advice: Merck; Financial Interests, Institutional, Other, Reimbursement for conference meetings: MSD, AstraZeneca, Ipsen, Boehringer Ingelheim, Bristol Myers Squibb, DKSH; Financial Interests, Institutional, Funding, Educational Grant: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, Clinical trial: Novartis, Amgen. D.S.W. Tan: Financial Interests, Personal, Advisory Board: Amgen, Novartis, Boehringer Ingelheim, C4 Therapeutics, AstraZeneca, GSK, Takeda, Eisai, Guardant, Merck, Pfizer, Roche; Financial Interests, Institutional, Research Grant: AstraZeneca, Amgen, Pfizer, ACM Biolabs; Financial Interests, Personal, Invited Speaker: Novartis. All other authors have declared no conflicts of interest.