MET alterations and their impact on the future of non-small cell lung cancer (NSCLC) targeted therapies

ABSTRACT

Introduction: The MET gene and its pathway normally plays a crucial role in cell homeostasis, motility, and apoptosis. However, when the MET gene is altered, there is an imbalance toward cell proliferation and invasion commonly seen in numerous different types of cancers. The heterogeneous group of MET alterations that includes MET amplification, MET exon 14 skipping mutation, and MET fusions has been difficult to diagnose and treat. Currently, treatments are focused on tyrosine kinase inhibitors but now there is emerging data on novel MET-targeted therapies including monoclonal antibodies and antibody-drug conjugates that have emerged.

Areas covered: We introduce new emerging data on MET alterations in non-small cell lung cancer (NSCLC) that has contributed to advances in MET targeted therapeutics. We offer our perspective and examine new information on the mechanisms of the MET alterations in this review.

Expert opinion: Given the trends currently involving the targeting of MET altered malignancies, there will most likely be a continued rapid expansion of testing, novel tyrosine kinase inhibitors and potent antibody approaches. Combination treatments will be necessary to optimize management of advanced and early disease.

KEYWORDS:

• MET exon 14 mutation
• MET amplification
• NSCLC
• MET fusion
• MET overexpression
• non-small cell lung cancer
• lung cancer

Article highlights

• MET pathway dysregulation can lead to increased cell proliferation, migration, motility and angiogenesis that subsequently causes oncogenesis

• MET pathway activity can be altered in numerous ways including MET overexpression, MET amplification, MET mutations including key exon 14 skipping mutations and MET fusions

• MET amplification can either present de-novo in different cancers or importantly secondarily as an acquired resistance mechanism in patients with oncogene-positive NSCLC treated with targeted tyrosine kinase inhibitor therapy, such as EGFR TKI therapy

• The unique MET exon 14 skipping mutation leads to decreased ubiquitination and thereby increased proliferation and is an important actionable mutation in NSCLC that needs to be part of standard testing with available therapies, such as the FDA-approved MET TKI capmatinib

While MET TKIs are the current mainstay treatment options for MET altered patients however many novel options, such as anti-MET antibodies, ADCs and novel combination strategies are emerging offering hope for more durable benefits.

This box summarizes key points contained in the article.

Declaration of Interests

B Halmos has received research support (to institution) from Merck, BMS, Boehringer-Ingelheim, Novartis, Pfizer, AbbVie, Mirati, Eli-Lilly, Astra-Zeneca, Boehringer-Ingelheim, Amgen, BeiGene, Blueprint, Elevation, Advaxis and consulting fees from Merck, BMS, Amgen, Boehringer-Ingelheim, TPT, Apollomics, Astra-Zeneca, Novartis, Pfizer. Eli-Lilly, Genentech.

The other authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties and other conflicts of interest.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.