Tivantinib (ARQ197) in hepatocellular carcinoma

Porta, Camillo; Giglione, Palma; Ferrari, Alessandra; Reversi, F.; Liguigli, Wanda; Imarisio, Ilaria; Ganini, Carlo

doi:10.1586/14737140.2015.1050383

Cited by 16 publications

(18 citation statements)

References 49 publications

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“…The METIV-HCC trial initially started patients on 240 mg BID; however, the dose was decreased to 120 mg BID in response to a higher than expected incidence of neutropenia 54. However, it should be noted that the METIV-HCC trial used a different formulation of tivantinib than the Santoro et al Phase II trial 23. Once the dose was decreased to 120 mg BID, a safety analysis showed that a dose of 120 mg BID of the new formulation resulted in an incidence of neutropenia similar to that seen at a dose of 240 mg in the Phase II trial 55.…”

Section: Dosing and Toxicitymentioning

confidence: 98%

“…When HGF binds to c-MET, there is activation of multiple metabolic pathways, including the mitogen-activated protein kinase, protein kinase B, mammalian target of rapamycin, phophatidylinositol 3-kinase and focal adhesion kinase, which can lead to tumor growth, proliferation, cell invasion and distant metastasis (Figure 1). 19–21 Upregulation of the c-MET pathway is found in multiple cancers, including HCC, where it is present 20–40% of the time and is associated with increased risk for metastases and poor prognosis 22,23. HGF is also over-expressed in HCC, which results in increased hepatic regeneration and suppression of hepatocyte apoptosis 24,25.…”

Section: Development and Pharmacologymentioning

confidence: 99%

“…Significant challenges to this alternative hypothesis have been raised. Notably, in vivo studies have not documented evidence of neurotoxicity, which is known to be a major adverse effect of microtubule inhibitors 23. Similarly, tivantinib has demonstrated only minimal, if any, response in patients who have tumors with low levels of MET expression, while those tumors with high levels of MET have had the most profound responses to the drug 33,34…”

Section: Development and Pharmacologymentioning

confidence: 99%

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Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: the evidence to date

Pievsky¹,

Pyrsopoulos

2016

JHC

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Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer-related death in the United States and carries a very poor prognosis, with a median survival time of <50% at 1 year for advanced disease. To date, sorafenib is the only therapy approved by the Food and Drug Administration for the treatment of advanced HCC. Tivantinib (ARQ-197), a non-ATP competitive inhibitor of cellular mesenchymal–epithelial transcription factor (c-MET), has shown a survival benefit in patients with advanced HCC who have failed or are intolerant to sorafenib in Phase I and II trials. Those patients who have tumors with high concentrations of MET (MET-high) appear to derive the greatest benefit from tivantinib therapy. Currently, two large randomized double-blind placebo-controlled Phase III trials (METIV-HCC [NCT01755767] and JET-HCC [NCT02029157]) are evaluating tivantinib in patients with MET-high advanced HCC, with the primary end points of overall survival and progression-free survival, respectively. This study reviews the evidence for the use of tivantinib in advanced HCC. Specific topics addressed include the pharmacology, dosing, toxicity, and biomarkers associated with tivantinib use.

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Section: Dosing and Toxicitymentioning

confidence: 98%

Section: Development and Pharmacologymentioning

confidence: 99%

Section: Development and Pharmacologymentioning

confidence: 99%

See 1 more Smart Citation

Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: the evidence to date

Pievsky¹,

Pyrsopoulos

2016

JHC

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“…Tivantinib is an oral, ATP-independent inhibitor of MET, binding to its inactive form [16, 17]; its anti-MET effect was confirmed by several groups, though some also suggested additional targets [18-20], including a weak non-specific anti-tubulin activity [21-23]. However, neurotoxicity, a hallmark of tubulin inhibitors, has not been reported in over 2000 patients treated with tivantinib to date, even at doses much higher than the therapeutic one [8, 24-28].…”

Section: Introductionmentioning

confidence: 99%

Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib

et al. 2016

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ARQ 197-215 was a randomized placebo-controlled phase II study testing the MET inhibitor tivantinib in second-line hepatocellular carcinoma (HCC) patients. It identified tumor MET as a key biomarker in HCC.Aim of this research was to study the prognostic and predictive value of tumor (MET, the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) and circulating (MET, hepatocyte growth factor [HGF], alpha-fetoprotein [AFP], vascular endothelial growth factor [VEGF]) biomarkers in second-line HCC. Tumor MET-High status was centrally assessed by immunohistochemistry. Circulating biomarkers were centrally analyzed on serum samples collected at baseline and every 4-8 weeks, using medians as cut-off to determine High/Low status. Tumor MET, tested in 77 patients, was more frequently High after (82%) versus before (40%) sorafenib. A significant interaction (p = 0.04) between tivantinib and baseline tumor MET in terms of survival was observed. Baseline circulating MET and HGF (102 patients) High status correlated with shorter survival (HR 0.61, p = 0.03, and HR 0.60, p = 0.02, respectively), while the association between AFP (104 patients) or VEGF (103 patients) status and survival was non-significant.Conclusions: Tumor MET levels were higher in patients treated with sorafenib. Circulating biomarkers such as MET and HGF may be prognostic in second-line HCC. These results need to be confirmed in larger randomized clinical trials.

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“…Tivantinib, an orally selective MET inhibitor is a second-line treatment in advanced HCC patients where MET tumor overexpression is high. Phase III clinical trials (ARQ 197-A-U303, NCT01755767) with Tivantinib is currently undergoing with 60% of overall survival as interim analysis has been planned as the end point criteria (Porta et al, 2015). Brivanib (antiangiogenicagent) and linifanib (multikinase inhibitor; phase III clinical trial) although showed marked antitumoral effects as second-line therapy did not show improvement against placebo and was halted for further phase III trial respectively (Cainap et al, 2015; Llovet etal., 2013) Erlotinib (EGFR inhibitor) and sorafenib combination therapy was unsuccessful as first-line therapy (Zhu, Rosmorduc, et al, 2015).…”

Section: Current Treatment Modalities For Hepatocellular Carcinomamentioning

confidence: 99%

Recent advances in hepatocellular carcinoma therapy

Dutta

Mahato

2017

Pharmacology & Therapeutics

233

169

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Hepatocellular carcinoma (HCC), also called malignant hepatoma, is one of the deadliest cancers due to its complexities, reoccurrence after surgical resection, metastasis and heterogeneity. Incidence and mortality of HCC are increasing in Western countries and are expected to rise as a consequence of the obesity epidemic. Multiple factors trigger the initiation and progression of HCC including chronic alcohol consumption, viral hepatitis B and C infection, metabolic disorders and age. Although Sorafenib is the only FDA approved drug for the treatment of HCC, numerous treatment modalities such as transcatheter arterial chemoembolization/transarterial chemoembolization (TACE), radiotherapy, locoregional therapy and chemotherapy have been tested in the clinics. Polymeric nanoparticles, liposomes, and micelles carrying small molecules, proteins, peptides and nucleic acids have attracted great attention for the treatment of various cancers including HCC. Herein, we discuss the pathogenesis of HCC in relation to its various recent treatment methodologies using nanodelivery of monoclonal antibodies (mAbs), small molecules, miRNAs and peptides. Synopsis of recent clinical trials of mAbs and peptide drugs has been presented with a broad overview of the pathogenesis of the disease and treatment efficacy.

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Tivantinib (ARQ197) in hepatocellular carcinoma

Cited by 16 publications

References 49 publications

Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: the evidence to date

Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: the evidence to date

Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib

Recent advances in hepatocellular carcinoma therapy

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