Refining patient selection of MET-activated non-small cell lung cancer through biomarker precision

Abstract

Dysregulated MET signaling plays an important role in lung oncogenesis, tumor growth and invasiveness. It may occur through various mechanisms, such as MET overexpression or gene amplification or mutation, all of which can be detected by specific methods. The utility of MET overexpression as a biomarker remains unclear due to discrepancies in its occurrence and non-standardized cut-off thresholds. MET exon 14 skipping mutation (METex14) was established as a strong predictor of response to selective MET tyrosine kinase inhibitors (TKIs), and clinical trial results in patients with non-small cell lung cancer (NSCLC) harboring METex14 led to the approval of capmatinib and tepotinib by regulatory agencies worldwide. MET amplification is an emerging biomarker, with clinical data indicating an association between MET gene copy number and response to MET-TKIs. Additionally, MET amplification represents an important mechanism of resistance to TKIs in oncogene-driven NSCLC. The identification of molecular alterations for which targeted therapies are available is important, and high-throughput next-generation sequencing techniques can provide information on multiple genes at the same time, helping to provide valuable predictive information for oncogene-driven cancers. This review summarizes the current methods used for the detection of METex14, MET amplification and MET overexpression, and discusses the evidence for the use of MET-TKIs in patients with NSCLC with MET dysregulation. We discuss the practical challenges that impact the use of METex14 in the clinic and the evidence gaps that need to be addressed to validate additional genomic markers for MET-dependent cancers.

Keywords: Biomarkers; MET; Molecular diagnostic; NSCLC; Targeted therapy.

Figure 1.. Mechanisms of dysregulated MET signaling.

A MET exon 14 skipping mutations lead to loss of the CBL juxtamembrane domain and subsequent impaired MET degradation and signaling. B MET amplification results in increased MET overexpression and oncogenic signaling. CBL, Casitas B-lineage lymphoma; HGF, hepatocyte growth factor; IPT, immunoglobulin-plexin transcription; MET, mesenchymal-epithelial transition; P, phosphorylation; PSI, plexin-semaphorin-integrin; U, ubiquitination.

Figure 2.. Summary of key developments in MET biology, biomarkers, clinical trials, and regulatory approvals of MET inhibitors in NSCLC.

MET targeting efforts spanning over 30 years of research and clinical developments have now reached the first regulatory approvals of MET-targeting drugs for patients with NSCLC and MET exon 14 skipping mutations. EGFR, epidermal growth factor receptor; FDA, Food and Drug Administration; MET, mesenchymal-epithelial transition; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.