Immune and Genomic Heterogeneity of MET-Altered Non–Small Cell Lung Cancer

PURPOSE Patients with non–small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations ( MET ex14) or MET amplifications ( MET amp) have demonstrated varied responses to immunotherapy. This study aimed to better understand the genomic and immune characteristics of MET- altered NSCLC. MATERIALS AND METHODS The study included 3,841 patients with NSCLC sequenced using the Strata Select assay on the Strata Oncology Platform. Genomic alterations, tumor mutational burden (TMB), PD-L1 expression, and immune gene expression were compared between high MET amp (copy number gain CNG ≥10), low MET amp (CNG 6-9), MET ex14, other MET mutations, and MET wild-type ( MET wt) patients. Immune-related gene expression was also analyzed in adenocarcinomas (n = 2,708) with targetable oncogenic drivers. RESULTS The most common genomic alterations were TP53 mutations and MDM2 amplification in MET ex14 and TP53 and CDKN2A in MET amp tumors. TMB was lowest in patients with MET ex14 and highest in patients with other MET mutations. PD-L1 expression was high in MET ex14, high in MET amp, and low in MET amp. Tumors with both MET amp and EGFR mutations had higher PD-L1 expression compared with tumors with only EGFR mutations. MET ex14 and low MET amp had higher receptor tyrosine kinase AXL gene expression relative to MET wt. Comparisons across oncogene-driven lung adenocarcinomas revealed that MET ex14 had an enriched immune landscape, whereas MET amp harbored an immunosuppressive environment. CONCLUSION MET ex14 and MET amp differed in genomic coalterations, TMB, and immune gene expression. These variations provide insight for the inconsistent response to immunotherapy in NSCLC with MET alterations, warranting further investigation.