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

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.

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Copyright © 2022. Published by Elsevier Ltd.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gillianne GY Lai reports receiving honoraria from Amgen and grants from Merck, Astra Zeneca, Pfizer, Bristol Myers Squibb and Roche outside the submitted work. Robin Guo reports receiving honoraria from Pfizer outside the submitted work. Alexander Drilon reports receiving advisory board honoraria from Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Oncology, ArcherDX, Monopteros, Novartis, EMD Serono, Medendi, Repare RX, Nuvalent, Merus, Chugai Pharmaceutical, Remedica Ltd , mBrace, AXIS, EPG Health, Harborside Nexus, Liberum, RV More, Ology, Amgen, TouchIME, Janssen, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc, AiCME, i3 Health, MonteRosa; equity from Treeline Bio; grants from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar; Royalties from Wolters Kluwer; CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Clinical Care Options, EPG Health, JNCC/Harborside, Liberum, Remedica Ltd; and other financial/non-financial interests in Merck, Puma, Merus, Boehringer Ingelheim outside the submitted work. Dr. Drilon and Dr. Guo were supported in part by the National Cancer Institute of the National Institutes of Health P30 CA008748. Daniel S.W. Tan reports receiving honoraria from Takeda Pharmaceuticals, Novartis, Roche, Pfizer, Merck and Boehringer Ingelheim; consulting fees from Novartis, Bayer, Boehringer Ingelheim, Astra-Zeneca, Eli-Lilly, MSD, GlaxoSmithKline, LOXO as well as grants from Amgen, Novartis, GlaxoSmithKline, AstraZeneca and Pfizer outside the submitted work.