{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T08:01:27Z","timestamp":1777536087991,"version":"3.51.4"},"reference-count":44,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T00:00:00Z","timestamp":1592524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Introduction: Non-small cell lung cancer (NSCLC) is the second most common cancer globally. The mesenchymal-epithelial transition (MET) proto-oncogene can be targeted in NSCLC patients. Methods: We performed a literature search on PubMed in December 2019 for studies on MET inhibitors and NSCLC. Phase II and III clinical trials published in English between 2014 and 2019 were selected. Results: Data on MET inhibitors (tivantinib, cabozantinib, and crizotinib) and anti-MET antibodies (emibetuzumab and onartuzumab) are reported in the text. Conclusion: Emibetuzumab could be used for NSCLC cases with high MET expression. Further, studies on onartuzumab failed to prove its efficacy, while the results of tivantinib trials were clinically but not statistically significant. Additionally, cabozantinib was effective, but adverse reactions were common, and crizotinib was generally well-tolerated.<\/jats:p>","DOI":"10.3390\/jcm9061918","type":"journal-article","created":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T10:43:58Z","timestamp":1592563438000},"page":"1918","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The Role of MET Inhibitor Therapies in the Treatment of Advanced Non-Small Cell Lung Cancer"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9640-4573","authenticated-orcid":false,"given":"Ramon Andrade","family":"De Mello","sequence":"first","affiliation":[{"name":"Algarve Biomedical Centre, Department of Biomedical Sciences and Medicine University of Algarve (DCBM UALG), 8005-139 Faro, Portugal"},{"name":"Division of Medical Oncology, Escola Paulista de Medicina, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 04037-004, Brazil"},{"name":"Precision Oncology and Health Economics Group (ONCOPRECH), Post-Graduation Program in Medicine, Nine of July University (UNINOVE), S\u00e3o Paulo 01525-000, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2798-9571","authenticated-orcid":false,"given":"Nath\u00e1lia Mois\u00e9s","family":"Neves","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Escola Paulista de Medicina, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 04037-004, Brazil"}]},{"given":"Giovanna Ara\u00fajo","family":"Amaral","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Escola Paulista de Medicina, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 04037-004, Brazil"}]},{"given":"Estela Gudin","family":"Lippo","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Santo Amaro University, S\u00e3o Paulo 01525-000, Brazil"}]},{"given":"Pedro","family":"Castelo-Branco","sequence":"additional","affiliation":[{"name":"Algarve Biomedical Centre, Department of Biomedical Sciences and Medicine University of Algarve (DCBM UALG), 8005-139 Faro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2119-4479","authenticated-orcid":false,"given":"Daniel Humberto","family":"Pozza","sequence":"additional","affiliation":[{"name":"Department of Biomedicine &amp; I3S, Faculty of Medicine, University of Porto (FMUP), 4200-317 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9260-2505","authenticated-orcid":false,"given":"Carla Chizuru","family":"Tajima","sequence":"additional","affiliation":[{"name":"Hospital S\u00e3o Jos\u00e9 &amp; Hospital S\u00e3o Joaquim, A Benefic\u00eancia Portuguesa de S\u00e3o Paulo, S\u00e3o Paulo 01323-001, Brazil"}]},{"given":"Georgios","family":"Antoniou","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Mount Vernon Cancer Center, London HA6 2RN, UK"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21551","article-title":"Cancer statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","unstructured":"(2019, December 07). CI5-Home. Available online: https:\/\/ci5.iarc.fr\/Default.aspx."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"De Mello, R.A., Mountzios, G., and Tavares, \u00c1.A. (2019). International Manual of Oncology Practice: IMOP-Principles of Oncology, Springer.","DOI":"10.1007\/978-3-030-16245-0"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3389\/fonc.2017.00193","article-title":"Lung Cancer: Understanding Its Molecular Pathology and the 2015 WHO Classification","volume":"7","author":"Inamura","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1158\/1535-7163.MCT-16-0472","article-title":"MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale","volume":"16","author":"Salgia","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1007\/s11523-016-0425-x","article-title":"Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: A Phase II Trial","volume":"11","author":"Arrieta","year":"2016","journal-title":"Target Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6059","DOI":"10.1158\/1078-0432.CCR-14-0543","article-title":"LY2875358, a neutralizing and internalizing anti-MET bivalent antibody, inhibits","volume":"20","author":"Liu","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jtho.2019.10.003","article-title":"A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation-Positive NSCLC Patients","volume":"15","author":"Scagliotti","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E2987","DOI":"10.1073\/pnas.1302725110","article-title":"Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent","volume":"110","author":"Merchant","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1208\/s12248-016-0029-5","article-title":"Exposure-Response and Tumor Growth Inhibition Analyses of the Monovalent Anti-c-MET Antibody Onartuzumab (MetMAb) in the Second- and Third-Line Non-Small Cell Lung Cancer","volume":"19","author":"Han","year":"2017","journal-title":"AAPS J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.cllc.2016.05.011","article-title":"Efficacy and Safety Results From a Phase II, Placebo-Controlled Study of Onartuzumab Plus First-Line Platinum-Doublet Chemotherapy for Advanced Squamous Cell Non-Small-Cell Lung Cancer","volume":"18","author":"Hirsch","year":"2017","journal-title":"Clin. Lung Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.cllc.2016.09.013","article-title":"Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Non-Squamous Non-Small-Cell Lung Cancer","volume":"18","author":"Wakelee","year":"2017","journal-title":"Clin. Lung Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1200\/JCO.2016.69.2160","article-title":"Results From the Phase III Randomized Trial of Onartuzumab Plus Erlotinib Versus Erlotinib in Previously Treated Stage IIIB or IV Non-Small-Cell Lung Cancer: METLung","volume":"35","author":"Spigel","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_14","first-page":"397","article-title":"Targeting the MET receptor tyrosine kinase in non-small cell lung cancer: Emerging role of tivantinib","volume":"6","author":"Agwa","year":"2014","journal-title":"Cancer Manag. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.molonc.2014.08.011","article-title":"Tivantinib (ARQ 197) efficacy is independent of MET inhibition in non-small-cell lung cancer cell lines","volume":"9","author":"Calles","year":"2015","journal-title":"Mol. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"69","DOI":"10.2147\/JHC.S106072","article-title":"Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: The evidence to date","volume":"3","author":"Pievsky","year":"2016","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1200\/JCO.2014.60.7317","article-title":"Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-Cell Lung Cancer","volume":"33","author":"Scagliotti","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.jtho.2017.12.009","article-title":"Tivantinib in Combination with Erlotinib versus Erlotinib Alone for EGFR-Mutant NSCLC: An Exploratory Analysis of the Phase 3 MARQUEE Study","volume":"13","author":"Scagliotti","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.lungcan.2018.01.010","article-title":"Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer","volume":"117","author":"Gerber","year":"2018","journal-title":"Lung Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1093\/annonc\/mdv288","article-title":"A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB\/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study)","volume":"26","author":"Yoshioka","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1158\/1535-7163.MCT-11-0264","article-title":"Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth","volume":"10","author":"Yakes","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1016\/S1470-2045(16)30562-9","article-title":"Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: An open-label, single-centre, phase 2, single-arm trial","volume":"17","author":"Drilon","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1016\/S1470-2045(16)30561-7","article-title":"Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): A randomised, controlled, open-label, multicentre, phase 2 trial","volume":"17","author":"Neal","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.ejca.2017.09.011","article-title":"Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours","volume":"86","author":"Gordon","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.cllc.2018.10.006","article-title":"Results of a Phase II Placebo-controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non-small-cell Lung Carcinoma","volume":"20","author":"Hellerstedt","year":"2019","journal-title":"Clin. Lung Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4427","DOI":"10.1021\/jm401427c","article-title":"Targeting receptor tyrosine kinase MET in cancer: Small molecule inhibitors and clinical progress","volume":"57","author":"Cui","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3109\/00498254.2014.941964","article-title":"Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects","volume":"45","author":"Johnson","year":"2015","journal-title":"Xenobiotica"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1200\/JCO.2017.75.5587","article-title":"Phase II Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced Non-Small-Cell Lung Cancer","volume":"36","author":"Wu","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1097\/COC.0b013e3182a46896","article-title":"Multiple Endocrine Disruption by the MET\/ALK Inhibitor Crizotinib in Patients with Non-small Cell Lung Cancer","volume":"38","author":"Sargis","year":"2015","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0140-6736(17)30565-2","article-title":"Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): An open-label, randomised phase 3 trial","volume":"390","author":"Hida","year":"2017","journal-title":"Lancet"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2214","DOI":"10.1093\/annonc\/mdy405","article-title":"Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study","volume":"29","author":"Gadgeel","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1158\/1078-0432.CCR-18-2814","article-title":"Capmatinib (INC280) Is Active Against Models of Non\u2013Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation","volume":"25","author":"Baltschukat","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9004","DOI":"10.1200\/JCO.2019.37.15_suppl.9004","article-title":"Capmatinib (INC280) in MET\u0394ex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study","volume":"37","author":"Wolf","year":"2019","journal-title":"JCO"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1080\/14737140.2019.1643239","article-title":"Capmatinib for the treatment of non-small cell lung cancer","volume":"19","author":"Vansteenkiste","year":"2019","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1200\/JCO.2018.77.7326","article-title":"Phase Ib\/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With EGFR-Mutated, MET Factor\u2013Dysregulated Non\u2013Small-Cell Lung Cancer","volume":"36","author":"Wu","year":"2018","journal-title":"JCO"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1093\/annonc\/mdy334","article-title":"PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers","volume":"29","author":"Sabari","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e441","DOI":"10.1016\/j.cllc.2018.03.010","article-title":"MET Expression in Advanced Non-Small-Cell Lung Cancer: Effect on Clinical Outcomes of Chemotherapy, Targeted Therapy, and Immunotherapy","volume":"19","author":"Reis","year":"2018","journal-title":"Clin. Lung Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.lungcan.2016.11.011","article-title":"The race to target MET exon 14 skipping alterations in non-small cell lung cancer: The Why, the How, the Who, the Unknown, and the Inevitable","volume":"103","author":"Reungwetwattana","year":"2017","journal-title":"Lung Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1080\/13543784.2018.1462336","article-title":"C-MET inhibitors for advanced non-small cell lung cancer","volume":"27","author":"Pasquini","year":"2018","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e13","DOI":"10.1016\/j.jtho.2019.07.027","article-title":"Capmatinib and Osimertinib Combination Therapy for EGFR-Mutant Lung Adenocarcinoma","volume":"15","author":"Gautschi","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ctrv.2017.10.003","article-title":"Does c-Met remain a rational target for therapy in patients with EGFR TKI-resistant non-small cell lung cancer?","volume":"61","author":"Wu","year":"2017","journal-title":"Cancer Treat Rev."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Colinet, B., Van Meerbeeck, J.P., Cuppens, T., and Vansteenkiste, J.F. (2020). Osimertinib in patients with advanced\/metastatic epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer-the Belgian ASTRIS data. Acta Clin. Belg, 1\u20138.","DOI":"10.1080\/17843286.2019.1708125"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"104938","DOI":"10.1016\/j.ejps.2019.05.016","article-title":"Preclinical pharmacokinetics, disposition, and translational pharmacokinetic\/pharmacodynamic modeling of savolitinib, a novel selective cMet inhibitor","volume":"136","author":"Gu","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_44","unstructured":"(2020, January 16). Home-ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/6\/1918\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:40:45Z","timestamp":1760175645000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/6\/1918"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,19]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["jcm9061918"],"URL":"https:\/\/doi.org\/10.3390\/jcm9061918","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,19]]}}}