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  • Review Article
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Evolving roles of MET as a therapeutic target in NSCLC and beyond

Nature Reviews Clinical Oncology volume 22, pages 640–666 (2025)Cite this article

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Abstract

Alterations in the proto-oncogene MET are associated with tumour development, invasion and metastasis across various solid cancers. Therapeutically actionable MET alterations include MET exon 14 skipping (METex14) mutations, MET amplification and/or MET overexpression and MET fusions, which vary in incidence by tumour type. In contrast to rare de novo MET alterations, acquired MET amplification and/or MET overexpression is a relatively common phenomenon that is associated with distinct clinical implications and responses to treatment. METex14 is a distinct oncogenic driver mutation in non-small-cell lung cancer (NSCLC). To date, the MET tyrosine-kinase inhibitors (TKIs) capmatinib, tepotinib and savolitinib have been approved for the treatment of advanced-stage METex14-mutant NSCLC. However, the treatment paradigms for MET-altered solid tumours are rapidly evolving to include diverse MET-targeted agents. Emerging data support the role of MET TKIs, anti-MET antibodies and MET-directed antibody–drug conjugates (ADCs) as monotherapy or in combination with other therapies for NSCLC or other tumour types with MET amplification and/or overexpression. Indeed, in May 2025, the MET-directed ADC telisotuzumab vedotin was approved by the FDA for patients with previously treated advanced-stage nonsquamous NSCLC overexpressing MET (≥50% of tumour cells with 3+ staining on immunohistochemistry). Understanding the unique MET-related adverse events will be crucial when incorporating these agents into daily clinical practice. In this Review, we highlight the rationale for targeting MET alterations across various solid tumour types and provide a summary of the clinical efficacy and toxicity profiles of the approved and emerging MET-targeted TKIs, monoclonal or bispecific antibodies and ADCs.

Key points

  • Therapeutically targetable MET alterations found in various cancers include MET exon 14 skipping (METex14) mutations, MET amplifications, MET overexpression and MET fusions. METex14 mutation is an oncogenic driver mutation of a distinct molecular subset of non-small-cell lung cancers (NSCLCs).

  • Several different MET tyrosine-kinase inhibitors (TKIs), including ensartinib, crizotinib, capmatinib, tepotinib, savolitinib, gumarontinib and bozitinib, have been tested in patients with advanced-stage METex14 NSCLC; capmatinib, tepotinib and savolitinib have been approved for this indication.

  • Despite the antitumour activity of MET TKIs in METex14-mutant NSCLC, various intrinsic or acquired mechanisms of resistance limit their effectiveness, and METex14 mutations account for only a small proportion of MET-altered cancers.

  • MET-directed antibody–drug conjugates such as telisotuzumab vedotin and telisotuzumab adizutecan have demonstrated promising clinical activity in treatment-refractory MET-overexpressing or MET-amplified cancers, particularly EGFR-wild-type nonsquamous NSCLC.

  • MET amplification is a common mechanism of acquired resistance to EGFR TKIs in EGFR-mutant NSCLC, and strategies to overcome this resistance include combination treatment with osimertinib plus tepotinib or savolitinib.

  • Ongoing research efforts include clinical trials focusing on the feasibility of perioperative MET TKIs for the treatment of early stage, resectable MET-altered NSCLC.

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Fig. 1: MET signalling pathways and MET-targeted therapeutic strategies.
Fig. 2: The history of MET in cancer research and therapy.
Fig. 3: MET alterations and MET-targeted therapeutic strategies across cancer types.
Fig. 4: Mechanisms of resistance to MET inhibitors.

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Author notes

  1. These authors contributed equally: Jii Bum Lee, Joo Sung Shim.

Authors and Affiliations

  1. Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea

    Jii Bum Lee & Byoung Chul Cho

  2. Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea

    Joo Sung Shim

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Competing interests

B.C.C. declares royalties from Champions Oncology, Crown Bioscience, Imagen and PearlRiver; research funding from AstraZeneca, Champions Oncology, CJ Bioscience, Cyrus Therapeutics, Dong-A ST, GIInnovation, ImmuneOncia, Janssen, JINTSbio, MSD, Therapex, Vertical Bio and Yuhan; consultancy roles with Amgen, AnHeart Therapeutics, ArriVent, AstraZeneca, BeiGene, Boehringer-Ingelheim, Bristol Myers Squibb, CJ Bioscience, Cyrus Therapeutics, Daiichi Sankyo, Eli Lilly, Gliead, GSK, Harpoon Therapeutics, Janssen, MSD, Novartis, Ono Pharmaceuticals, Pfizer, Regeneron, Roche, Sanofi, Seagen, Takeda and Yuhan; advisory board roles for Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, J INTS BIO, KANAPH Therapeutics and Therapex; Speaker’s honoraria from ASCO, AstraZeneca, the Chinese Thoracic Oncology Society, ESMO, Guardant Health, IASLC, the Korean Cancer Association, Korean Cancer Study Group, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, MSD, Novartis, Pfizer, Roche and Zailab; stocks/shares in Bridgebio Therapeutics, Cyrus Therapeutics, Gencurix, Interpark Bio Convergence, J INTS BIO, KANAPH Therapeutics and TheraCanVac; is a Founder of DAAN Biotherapeutics; and a member of the board of directors of J INTS BIO. The other authors declare no competing interests.

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Lee, J.B., Shim, J.S. & Cho, B.C. Evolving roles of MET as a therapeutic target in NSCLC and beyond. Nat Rev Clin Oncol 22, 640–666 (2025). https://doi.org/10.1038/s41571-025-01051-9

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