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MET inhibitors for treatment of advanced hepatocellular carcinoma: A review.

ABSTRACT: The current standard treatment option for advanced hepatocellular carcinoma (HCC) is sorafenib, but its clinical benefit is modest. In spite of many attempts, few drugs can provide any significant improvement of survival as the first- or second-line therapy of choice in phase III randomized controlled trials. Recently, the subgroup analysis of a phase II randomized controlled trial has shown that tivantinib, a selective MET inhibitor, can significantly improve the overall survival in patients with MET-positive advanced HCC after the failure or intolerance of a prior systemic therapy. These findings enlighten the role of MET inhibitors in the treatment of advanced HCC. In this paper, we review all ongoing and completed clinical trials regarding this topic. As for the first-line therapy of advanced HCC, INC280 and foretinib are being evaluated in 2 phase II single-arm trials; and MSC2156119J and golvatinib plus sorafenib are being compared with sorafenib alone in 2 phase II randomized controlled trials. As for the second-line therapy of advanced HCC, tivantinib and cabozantinib are being compared with placebo in 2 phase III randomized controlled trials.

SUBMITTER: Qi XS

PROVIDER: S-EPMC4427665 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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MET inhibitors for treatment of advanced hepatocellular carcinoma: A review.

Qi Xing-Shun XS Guo Xiao-Zhong XZ Han Guo-Hong GH Li Hong-Yu HY Chen Jiang J

World journal of gastroenterology 20150501 18

The current standard treatment option for advanced hepatocellular carcinoma (HCC) is sorafenib, but its clinical benefit is modest. In spite of many attempts, few drugs can provide any significant improvement of survival as the first- or second-line therapy of choice in phase III randomized controlled trials. Recently, the subgroup analysis of a phase II randomized controlled trial has shown that tivantinib, a selective MET inhibitor, can significantly improve the overall survival in patients wi ...[more]

PMID: 25987766

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Project description:Background:Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis. First-line sorafenib has been the standard of care for a decade, but the treatment landscape is expanding. This review provides a practical overview of current and future systemic treatment options for advanced HCC and their place in clinical practice. Summary:First-line sorafenib and lenvatinib have shown to improve the survival of patients with advanced HCC. In the second line, regorafenib provides benefit for patients who previously tolerated sorafenib. Anti-PD1 antibodies, nivolumab and pembrolizumab, recently became available for second-line use in the US. Ramucirumab (for patients with ?-fetoprotein [AFP] levels ?400) and cabozantinib present potential future second-line treatment options. Combinations of systemic and locoregional treatment, such as radiofrequency ablation or selective internal radiotherapy, require further research. Precision medicine has not yet been translated into clinical practice, as the most common driver mutations (TERT promoter, CTNNB1, TP53, and ARID1A mutations) have not yet been shown to be suitable therapeutic targets. However, our growing understanding of signaling pathways and efforts in drug development are expected to pave the way for precision medicine in HCC in the future. Evaluating the place for the current and novel systemic treatment options in clinical practice can be challenging due to the diverse toxicity profiles of the treatment options and characteristics of the patient population. Sorafenib data elucidate the effect patient characteristics (such as the performance score, Child-Pugh class, AFP, etiology of the underlying disease, and level of macrovascular invasion and extrahepatic spread) may have on outcomes in advanced stages. Key Messages:Lenvatinib is expected to join sorafenib as a preferred first-line treatment in advanced HCC. In the second line, the treatment of choice, regorafenib, is soon expected to be accompanied by cabozantinib and ramucirumab in patients with AFP ?400 ng/mL, whereas nivolumab and pembrolizumab present second-line alternatives in the US.

Project description:BackgroundMultikinase inhibitors (MKIs) have been shown to improve survival in patients with hepatocellular carcinoma (HCC) compared with placebo. Distinct from other MKIs, cabozantinib has inhibitory activity for both AXL and MET. This review considers the literature elucidating the role of AXL and MET in HCC progression, treatment resistance, and immunomodulation. A systematic search of the PubMed database was conducted on November 16, 2020, and identified a total of 174 search results. A further 36 potentially relevant articles were identified based on the authors' knowledge. After initial screening by title/abstract, 159 underwent full-text screening and we identified 69 original research articles reporting empirical data from in vitro or in vivo models of HCC evaluating the effects of manipulating AXL or MET signaling on tumorigenic behavior.SummaryAXL expression is highly correlated with HCC progression and outcomes and has been reported to be involved in transforming growth factor-β and the regulation of PI3K/AKT, ERK/MAPK, and CCN proteins. MET protein expression is increased in HCC with the highest histological grade and has been reported to be involved in the regulation of PI3K/AKT, PLCγ/DAG/PKC, and MAPK/ERK signaling. Both AXL and MET are key regulators of sorafenib resistance in HCC. In terms of immunomodulation, there are data to indicate that AXL and MET interact with the immune components of the tumor microenvironment and promote tumorigenesis and treatment resistance. In addition, AXL was found to play a potential role in the development of a protumorigenic neutrophil phenotype in HCC. Combined inhibition of MET and programmed cell death protein resulted in additive reduction of HCC cell growth.Key messagesAXL and MET play key roles in HCC progression, treatment resistance, and immunomodulation. Continued development of drugs that target these receptor tyrosine kinases appears likely to represent a useful strategy to improve outcomes for patients with HCC.

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MET inhibitors for treatment of advanced hepatocellular carcinoma: A review.

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MET inhibitors for treatment of advanced hepatocellular carcinoma: A review.

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