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

Abstract

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