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Review
. 2021 Feb 15:13:1758835921992976.
doi: 10.1177/1758835921992976. eCollection 2021.

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

Lingzhi Hong  1 , Jianjun Zhang  1 , John V Heymach  1 , Xiuning Le  2
Affiliations
Review

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

Lingzhi Hong et al. Ther Adv Med Oncol. .

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.

Keywords: MET exon 14 skipping; antibody; hepatocyte growth factor; non-small cell lung cancer; tyrosine kinase inhibitor.

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Conflict of interest statement

Conflict of interest statement: Zhang reports research funding from Merck and Johnson and Johnson, personal fees from AstraZeneca, Bristol-Myers Squibb, GenePlus-Beijing Institute, Innovent outside the submitted work. Heymach receives advisory/consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, Kairos Venture Investments, BrightPath Therapeutics, Hengrui Therapeutics, Eli Lilly, EMD Serono, and Foundation One Medicine, Spectrum, AstraZeneca, and research Funding from NIH/NCI, American Cancer Society, and Checkmate Pharmaceuticals, and AstraZeneca, Spectrum; and Royalties and Patents from Spectrum. Le receives consultant and advisory fee from Eli Lilly, AstraZeneca, EMD Serono, and research funds from Eli Lilly, Boehringer Ingelheim, and Spectrum Pharmaceuticals. All outside of the submitted work.

Figures

Figure 1.
Figure 1.
METex14 in non-small lung cancers. (a) schematic diagram of genomic areas flanking MET exon 14 and key amino acid residuals within exon 14. (b) Skipping of MET exon 14 leads to upregulated MET signaling. Tyrosine kinase inhibitors (TKIs) and antibody-based therapies are two major therapeutic approaches to target METex14. (c) Incidence of known driver oncogenes for lung adenocarcinoma. CBL, Casitas-B-lineage lymphoma; JX, juxtamembrane; SEMA, sema homology region; TK, tyrosine kinase; TKIs, tyrosine kinase inhibitors; TM, transmembrane.
See this image and copyright information in PMC

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