Genetic Heterogeneity of MET-aberrant Non-Small Cell Lung Cancer and its Impact on the Outcome of Immunotherapy

ABSTRACT Purpose Robust data on the outcome of MET-aberrant non-small cell lung cancer (NSCLC) with non-targeted therapies is limited, especially in consideration of the heterogeneity of MET-amplified tumors. Patients and Methods 337 tumor specimens of MET-altered UICC stage IIIB/IV NSCLC patients were analyzed using next-generation sequencing (NGS), fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC). The evaluation focused on the type of MET-aberration, co-occurring mutations, PD-L1 expression, and overall survival (OS). Results METamp tumors (n=278) showed a high frequency of co-occurring mutations (>80% for all amplification levels), while 57.6% of the 59 patients with METex14 tumors showed no additional mutations. In METamp tumors, with increasing gene copy number (GCN), the frequency of inactivating TP53 mutations increased (GCN Conclusions METex14, METamp GCN≥10, and METamp GCN