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

Area of Science:

• Oncology
• Genomics
• Immunotherapy

Background:

• Non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations (METex14) or MET amplifications (METamp) show variable responses to immunotherapy.
• Understanding the genomic and immune characteristics of MET-altered NSCLC is crucial for optimizing treatment strategies.

Purpose of the Study:

• To investigate the genomic and immune profiles of NSCLC patients with METex14 and METamp.
• To identify differences in tumor mutational burden (TMB), PD-L1 expression, and immune gene expression between MET-altered and MET wild-type NSCLC.

Main Methods:

• Analysis of genomic alterations, TMB, PD-L1 expression, and immune gene expression in 3,841 NSCLC patients using the Strata Select assay.
• Comparison of METex14, high METamp, low METamp, other MET mutations, and MET wild-type (METwt) groups.
• Analysis of immune gene expression in MET-altered adenocarcinomas with targetable oncogenic drivers.

Main Results:

• METex14 and METamp tumors exhibit distinct genomic co-alterations, including TP53 mutations and MDM2 amplification (METex14) or CDKN2A (METamp).
• Tumor mutational burden (TMB) varied, being lowest in METex14 and highest in other MET mutations. PD-L1 expression was generally high in METex14 and METamp.
• METex14 demonstrated an enriched immune landscape, while METamp showed an immunosuppressive environment, with METex14 and low METamp having higher AXL gene expression.

Conclusions:

• METex14 and METamp present unique genomic and immune characteristics, influencing immunotherapy outcomes in NSCLC.
• These molecular differences provide insights into the inconsistent responses observed with immunotherapy in MET-altered NSCLC.
• Further research is warranted to leverage these findings for improved therapeutic strategies in MET-altered NSCLC.