STK11 and KEAP1 Mutations as Prognostic Biomarkers in an Observational Real-World Lung Adenocarcinoma Cohort

Importance: Understanding the mechanisms of primary resistance to immune checkpoint blockade therapy is of paramount importance for treatment selection. Somatic mutations in STK11 and KEAP1, frequently co-mutated in nonsquamous non-small cell lung cancer, have been associated with poor response to immune checkpoint blockade. However, previous reports lack non-immune checkpoint blockade controls needed to properly ascertain the predictive nature of those biomarkers. Objective: To evaluate the predictive vs prognostic effect of STK11 or KEAP1 mutations across different treatment classes in nonsquamous non-small cell lung cancer. Design: A retrospective, real-world data cohort from the Flatiron Health network linked with genetic testing from Foundation Medicine, from January 1, 2011, through December 31, 2018. Setting: Multicenter, including academic and community practices. Participants: Patients diagnosed with stage IIIB, IIIC, IVA, or IVB nonsquamous non-small cell lung cancer who initiated first-line treatment within 90 days after diagnosis. Main Outcomes and Measures: Real-world, progression-free survival and overall survival calculated from time of initiation of first-line treatment. Results: We analyzed clinical and mutational data for 2276 patients with advanced, nonsquamous non-small cell lung cancer (mean age at advanced diagnosis, 66.3 years [SD 10.3], 54.4% female, 80.1% with a history of smoking), including patients treated with anti-programmed death-1/anti-programmed death ligand 1 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 immune checkpoint.