Background: Data on the prevalence of emerging mutations /co-mutations (e.g., STK11, KRAS, and KEAP1) and associated clinical outcomes in metastatic non-small cell lung cancer (mNSCLC) patients are lacking therefore the objective of this study is to address these gaps in the current data. Methods: This study used the Flatiron clinico-genomic database and included newly diagnosed patients (≥18 years old) with stage IV NSCLC and known histology/PD-L1 status. Patients enrolled in clinical trials, with positive/missing EGFR or ALK, other malignancies, mixed histology, or without structured data within 90 days of diagnosis were excluded. The prevalence of STK11, KEAP1, KRAS mutations and co-mutations for each combination were evaluated in the overall study cohort and stratified by histology and PD-L1 status ( > or ≤1%). The overall survival (OS) from the date of diagnosis with stage IV was analyzed using Kaplan-Meier methods. Results: Of the 17,020 patients with NSCLC, 964 met the selection criteria and were included in the study. The prevalence of STK11, KEAP1, and KRAS is 18%, 15%, and 35%, respectively. With the exception of KRAS, the prevalence of all selected mutations and the co-mutations is higher in patients with PD-L1 negative and non-squamous NSCLC. The prevalence of KRAS is higher in patients with PD-L1 positive and non-squamous NSCLC (Table). The median OS was 10.1 months (95% CI, 8.6, 11.2) for the overall population, and 6.6 (5.7-8.3), 7.1 (5.8-8.8) and 9.9 (7.6-11.9) months in patients with STK11, KEAP1, and KRAS mutations, respectively. The median OS in patients with co-mutations ranges from 6.1 to 6.7 months. Conclusions: STK11, KEAP1, and KRAS mutations and co-mutations are common in mNSCLC patients. Current treatments, particularly in STK11, KEAP1, and co-mutation patients, are associated with poor OS. To address these harder to treat subgroups new treatment options or clinical trials should be considered.

OS= overall survival in months; ^†Prevalence is calculated among patients tested for each biomarker; *not statistically significant.