Rota Caremoli Elena, Labianca Roberto
Cancer Center Azienda Ospedaliera Papa Giovanni XXIII - Unit of Medical Oncology , Piazza OMS 1, 24127 Bergamo , Italy +39 035 267 3694, +39 035 267 3691 ; +39 035 267 4985 ;
Expert Opin Investig Drugs. 2014 Nov;23(11):1563-74. doi: 10.1517/13543784.2014.949339.
Sorafenib is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). Sorafenib is an oral multikinase inhibitor that blocks several receptors involved in tumor cell proliferation and angiogenesis. The hepatocyte-growth factor/mesenchymal-epithelial transition (MET) factor pathway represents another emerging target in HCC. Tivantinib (ARQ 197) is an oral, selective small MET tyrosine kinase inhibitor with antitumor activity, especially in MET-high patients. Recent clinical data exhibit promising activity in HCC.
This article reviews the preclinical and clinical data of tivantinib (published and ongoing trials), focusing on development in advanced HCC. Comments regarding the failure of trials with nonspecific drugs reported in the past 2 years are also included.
A randomized Phase II trial in second-line HCC showed a significant improvement in time to progression with tivantinib treatment in MET-high patients. Tivantinib remains in clinical development and has not yet been approved for any indication. A Phase III study in MET-high HCC is ongoing in a second-line setting, after sorafenib failure. In case of a survival benefit, tivantinib might become the first treatment for selected patients, based on MET status as a predictor. Therefore, there is a need for identifying HCC molecular subclasses and for developing a trial design based on molecular biomarkers.
索拉非尼是唯一被批准用于治疗晚期肝细胞癌（HCC）的药物。索拉非尼是一种口服多激酶抑制剂，可阻断多种参与肿瘤细胞增殖和血管生成的受体。肝细胞生长因子/间充质-上皮转化（MET）因子通路是HCC中另一个新出现的靶点。替凡替尼（ARQ 197）是一种口服的、选择性的小分子MET酪氨酸激酶抑制剂，具有抗肿瘤活性，尤其在MET高表达的患者中。近期临床数据显示其在HCC治疗中具有良好前景。
本文回顾了替凡替尼的临床前和临床数据（已发表及正在进行的试验），重点关注其在晚期HCC治疗中的进展。还包括对过去两年报道的非特异性药物试验失败情况的评论。
一项针对二线HCC的随机II期试验表明，替凡替尼治疗可使MET高表达患者的疾病进展时间显著延长。替凡替尼仍在进行临床研发，尚未获批用于任何适应症。在索拉非尼治疗失败后的二线治疗中，一项针对MET高表达HCC的III期研究正在进行。如果能证明其具有生存获益，基于MET状态作为预测指标，替凡替尼可能成为特定患者的首选治疗药物。因此，有必要识别HCC分子亚类并基于分子生物标志物制定试验设计。
