Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?

Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeuti...

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Autores principales:	Shankun Zhao, Weizhou Wu, Hao Jiang, Lei Ma, Chengyi Pan, Chong Jin, Jinggang Mo, Liezhi Wang, Kunpeng Wang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	tivantinib MET inhibitor hepatocellular carcinoma therapeutic effect adverse event Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/f4e0d617edab4fcba36128a345c3c5df
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spelling	oai:doaj.org-article:f4e0d617edab4fcba36128a345c3c5df2021-11-04T11:50:33ZSelective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?1664-322410.3389/fimmu.2021.731527https://doaj.org/article/f4e0d617edab4fcba36128a345c3c5df2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.731527/fullhttps://doaj.org/toc/1664-3224Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the “ClinicalTrials.gov” for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.Shankun ZhaoWeizhou WuHao JiangLei MaChengyi PanChong JinJinggang MoLiezhi WangKunpeng WangFrontiers Media S.A.articletivantinibMET inhibitorhepatocellular carcinomatherapeutic effectadverse eventImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tivantinib MET inhibitor hepatocellular carcinoma therapeutic effect adverse event Immunologic diseases. Allergy RC581-607
spellingShingle	tivantinib MET inhibitor hepatocellular carcinoma therapeutic effect adverse event Immunologic diseases. Allergy RC581-607 Shankun Zhao Weizhou Wu Hao Jiang Lei Ma Chengyi Pan Chong Jin Jinggang Mo Liezhi Wang Kunpeng Wang Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?
description	Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the “ClinicalTrials.gov” for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.
format	article
author	Shankun Zhao Weizhou Wu Hao Jiang Lei Ma Chengyi Pan Chong Jin Jinggang Mo Liezhi Wang Kunpeng Wang
author_facet	Shankun Zhao Weizhou Wu Hao Jiang Lei Ma Chengyi Pan Chong Jin Jinggang Mo Liezhi Wang Kunpeng Wang
author_sort	Shankun Zhao
title	Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?
title_short	Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?
title_full	Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?
title_fullStr	Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?
title_full_unstemmed	Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?
title_sort	selective inhibitor of the c-met receptor tyrosine kinase in advanced hepatocellular carcinoma: no beneficial effect with the use of tivantinib?
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/f4e0d617edab4fcba36128a345c3c5df
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Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?

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