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 (METex14) or MET amplifications (METamp) 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 METamp (copy number gain [CNG] ≥10), low METamp (CNG 6-9), METex14, other MET mutations, and MET wild-type (METwt) 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 METex14 and TP53 and CDKN2A in METamp tumors. TMB was lowest in patients with METex14 and highest in patients with other MET mutations. PD-L1 expression was high in METex14, high in METamp, and low in METamp. Tumors with both METamp and EGFR mutations had higher PD-L1 expression compared with tumors with only EGFR mutations. METex14 and low METamp had higher receptor tyrosine kinase AXL gene expression relative to METwt. Comparisons across oncogene-driven lung adenocarcinomas revealed that METex14 had an enriched immune landscape, whereas METamp harbored an immunosuppressive environment.

Conclusion: METex14 and METamp 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.