Genomic comparison of MET exon 14 skipping and MET amplified non-small cell lung cancer.

Abstract

8553 Background: In non-small cell lung cancer (NSCLC), the MET tyrosine kinase receptor can be dysregulated by mutations and/or gene amplification. The most common MET mutation is in exon 14 (METex14), leading to impaired receptor degradation and increased MET-mediated signaling causing sustained tumor proliferation. MET amplification also leads to continued MET signaling and oncogenesis and can be a mechanism of resistance to targeted therapy. We sought to compare the genomic landscape of METex14 and high-level MET amplified tumors, both of which can be targeted with tyrosine kinase inhibitors. Methods: We analyzed 18,047 NSCLC tumors (any stage/subtype) sequenced with Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Tumors were queried for METex14 mutations, high MET amplification (METamp), defined as copy number gain (CNG) ≥10, and other MET mutations (METother). Immuno-oncology (IO) biomarkers were compared across MET-altered and MET wild-type (METwt) groups. The prevalence of somatic gene alterations was compared similarly with the false-discovery rate (FDR) adjustment. Results: A total of 276 (1.53%) METex14, 138 (0.76%) METamp, 27 (0.15%) METother, and 17,606 (97.56%) METwt tumors were identified. Across groups, patients with METex14 were older, more likely to be female, and nonsmokers. METex14 exhibited the lowest tumor mutational burden (TMB) and lowest neoantigen tumor burden (NTB). PD-L1 positivity rates were higher in METex14 tumors compared to METamp and METwt tumors. MET log10 gene expression was highest in METamp. METamp exhibited the lowest proportion of CD4 T cells and the highest proportion of NK cells. Compared to METex14, METamp exhibited increased prevalence of TP53 (83% vs 37%), TFEC (46% vs 1.1%), CFTR (37% vs 1.4%), EGFR (31% vs. 7.6%), WNT2 (11% vs 0.4%), KEAP1 (14% vs 0.7%), and STK11 (8% vs 1.4%), and decreased prevalence of MDM2 (4.3% vs. 14%), and FRS2 (2.9% vs. 12%). Conclusions: In this large population-based analysis of MET-altered NSCLC, METex14 tumors exhibited differences in IO biomarkers and the somatic landscape compared to non-METex14 NSCLC tumors. Variations in immune profiles may affect immunotherapy selection in MET-altered NSCLC and require further exploration. [Table: see text]