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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

The Treatment of a New Entity in Advanced Non-Small Cell Lung Cancer: MET exon 14 Skipping Mutation

In Press, (this is not the final "Version of Record"). Available online 22 September, 2023
Author(s): Danilo Rocco, Luigi Della Gravara, Giovanni Palazzolo and Cesare Gridelli*
Published on: 22 September, 2023

DOI: 10.2174/0929867331666230803094432

Price: $95

Abstract

Background: MET (MET Proto-Oncogene, Receptor Tyrosine Kinase) exon 14 skipping mutation represents one of the most common MET alterations, accounting for approximately 1-3% of all mutations in advanced lung adenocarcinomas. While until 2020 no specific treatment was available for this subset of patients, as of today, three MET Tyrosine Kinase Inhibitors (TKIs) are currently approved in this setting, namely capmatinib, tepotinib and savolitinib.

Objective: This article aims to provide an extensive overview of the current therapeutic standard of care for exon 14 skipped advanced Non-Small Cell Lung Cancer (NSCLC) patients, alongside with mentions of the main future challenges and opportunities.

Conclusion: FDA-approved MET-TKIs currently represent the best option for treating exon 14 skipped advanced NSCLC patients, thanks to their excellent efficacy profile, alongside their manageable safety and tolerability. However, we currently lack specific agents to treat patients progressing on capmatinib or tepotinib, due to a limited understanding of the mechanisms underlying both on- and off-target resistance. In this respect, on-target mutations presently constitute the most explored ones from a mechanistic point of view, and type II MET-TKIs are currently under investigation as the most promising agents capable of overcoming the acquired resistance.

Keywords: NSCLC, MET, exon 14 skipping, resistance mechanisms, capmatinib, tepotinib, type I MET-TKI, type II MET-TKI.


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