STK11 and KEAP1 Mutations as Prognostic Biomarkers in an Observational Real-World Lung Adenocarcinoma Cohort
Authors: Papillon-Cavanagh Simon , Doshi Parul , Dobrin Radu , Szustakowski Joseph , Walsh Alice M. 
Published: January 2020

AbstractImportanceUnderstanding 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.ObjectiveTo evaluate the predictive vs prognostic effect of STK11 or KEAP1 mutations across different treatment classes in nonsquamous non–small cell lung cancer.DesignA 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.SettingMulticenter, including academic and community practices.ParticipantsPatients 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 MeasuresReal-world, progression-free survival and overall survival calculated from time of initiation of first-line treatment.ResultsWe 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 blockade cohorts. There was no observable interaction between STK11 mutations and anti–programmed death-1/anti–programmed death ligand 1 treatment on real-world, progression-free survival (HR, 1.05; 95% CI, 0.76-1.44; P = .785) or overall survival (HR, 1.13; 95% CI, 0.76-1.67; P = .540). Similarly, there was no observable interaction between KEAP1 on real-world, progression-free survival (HR, 0.93; 95% CI, 0.67-1.28; P = .653) or overall survival (HR, 0.98; 95% CI, 0.66-1.45; P = .913). Results were consistent in KRAS-mutated patients.Conclusion and RelevanceOur results show that STK11-KEAP1 mutations are prognostic, not predictive, biomarkers for anti–programmed death-1/anti–programmed death ligand 1 therapy.Key PointsQuestionAre loss-of-function somatic mutations in STK11 and KEAP1 predictive of response to immune checkpoint blockade or simply prognostic?FindingsIn this observational real-world cohort totaling 2276 patients, including 574 treated with immune checkpoint blockade, we find that mutations in STK11 and KEAP1 are associated with poor prognosis across multiple first-line treatment classes.MeaningMutations in STK11 and KEAP1 are prognostic biomarkers of poor response to both immune checkpoint blockade and chemotherapy.