Current and future treatment options for MET exon 14 skipping alterations in non-small cell lung cancer

Abstract

It has been over three decades since the hepatocyte growth factor (HGF) ligand and its receptor MET proto-oncogene (MET) pathway was established as promoting cancer growth and metastasis. MET exon 14 skipping ( METex14) alterations occur in 3–4% of all non-small cell lung cancer (NSCLC) patients, typically in elderly patients (older than 70 years), and result in constitutive activation of the MET receptor by altering a region required for receptor degradation. Multi-kinase inhibitor of MET, such as crizotinib, and more recently selective MET inhibitors, such as capmatinib and tepotinib, have demonstrated clinical efficacy and safety in METex14 NSCLC patients in clinical trials. These results have led to the approval of MET inhibitors by regulatory agencies across the globe. The success also fueled the excitement of further development of therapeutic strategies to target METex14 in lung cancers. This article provides an overview of the clinical development program targeting METex14 in NSCLC, including small molecular tyrosine kinase inhibitors and anti-MET antibodies. Furthermore, combination therapy immune checkpoint inhibitors or other targeted therapies are also under development in various patient populations, with acquired resistance immune or targeted therapy. Clinical trials in different development stages are ongoing and more drugs targeted to c-MET will be available for NSCLC patients with METex14 skipping mutations in the future.

Prognosis and Concurrent Genomic Alterations in Patients With Advanced NSCLC Harboring MET Amplification or MET Exon 14 Skipping Mutation Treated With MET Inhibitor: A Retrospective Study

“…This is supported by a previous study showing that high-level amplification is more selective for treatment response as compared to low-level amplification ( 25 , 26 ). Furthermore, several studies focusing on METex14 skipping mutations as target alterations in NSCLC have also been published ( 27 – 29 ). Paik et al.…”

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

“…Thus, mutations in MET on exon 14 will soon be systematically examined at diagnosis of advanced-stage NS-NSCLC. There is a need to identify the oncogenic role of each type of MET alteration and to standardize the diagnostic approach [161]. MET exon 14 alterations have been shown to act as oncogenes and to be potentially actionable regardless of gene amplification.…”

In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer

“…EGFR, ALK, MET, NTRK) or allele-specific inhibitors (eg. BRAF V600E , KRAS G12C ) [16][17][18][19][20][21][22][23][24] . However, prolonged treatment with these targeted therapies often results in the development of acquired drug resistance that limits the duration of their clinical benefit.…”