STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort

• Published in: ESMO open 2020, Vol.5 (2), p.e000706, Article e000706
• Main Authors: Papillon-Cavanagh, Simon, Doshi, Parul, Dobrin, Radu, Szustakowski, Joseph, Walsh, Alice M
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - mortality; Adenocarcinoma - pathology; AMP-Activated Protein Kinase Kinases; Biomarkers, Tumor; Cohort Studies; Female; Humans; immune checkpoint inhibitor; KEAP1; Kelch-Like ECH-Associated Protein 1 - genetics; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Mutation; non-squamous non-small cell lung cancer; Original Research; Prognosis; prognostic; Protein Serine-Threonine Kinases - genetics; STK11; Survival Analysis
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1136/esmoopen-2020-000706

IntroductionSomatic mutations in STK11 and KEAP1, frequently comutated in non-squamous non-small cell lung cancer (NSQ NSCLC), have been associated with poor response to immune checkpoint blockade (ICB). However, previous reports lack non-ICB controls needed to properly ascertain the predictive nature of those biomarkers. The objective of this study was to evaluate the predictive versus prognostic effect of STK11 or KEAP1 mutations in NSQ NSCLC.MethodsPatients diagnosed with stage IIIB, IIIC, IVA or IVB NSQ NSCLC from a real-world data cohort from the Flatiron Health Network linked with genetic testing from Foundation Medicine were retrospectively assessed. Real-world, progression-free survival (rwPFS) and overall survival (OS) were calculated from time of initiation of first-line treatment.ResultsWe analysed clinical and mutational data for 2276 patients including patients treated with anti-programmed death-1 (PD-1)/anti-programmed death ligand 1 (PD-L1) inhibitors at first line (n=574). Mutations in STK11 or KEAP1 were associated with poor outcomes across multiple therapeutic classes and were not specifically associated with poor outcomes in ICB cohorts. There was no observable interaction between STK11 mutations and anti-PD-1/anti-PD-L1 treatment on rwPFS (HR, 1.05; 95% CI 0.76 to 1.44; p=0.785) or OS (HR, 1.13; 95% CI 0.76 to 1.67; p=0.540). Similarly, there was no observable interaction between KEAP1 mutations and treatment on rwPFS (HR, 0.93; 95% CI 0.67 to 1.28; p=0.653) or OS (HR, 0.98; 95% CI 0.66 to 1.45; p=0.913).ConclusionOur results show that STK11-KEAP1 mutations are prognostic, not predictive, biomarkers for anti-PD-1/anti-PD-L1 therapy.