Abstract: 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.

Keywords: tivantinib, ARQ-197, hepatocellular carcinoma, met inhibitor 

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Liver cancer is the second most common cause of cancer-related death worldwide, the fifth most common cancer among men and the ninth most common cancer among women.1 Hepatocellular carcinoma (HCC) is responsible for ~90% of primary liver cancers.2 In the United States, HCC is the fastest rising cause of cancer-related death, and its incidence has nearly tripled since the 1980s.3,4 Despite increased focus and research, the overall prognosis for HCC remains poor. Curative modalities, such as liver transplant, resection and radiofrequency ablation, do exist when HCC is diagnosed early; however, only ~15% of patients are eligible for such treatments (Table 1).3,5,6 The majority of patients are diagnosed with advanced-stage HCC, for which the median survival time is <50% at 1 year and only 12% at 5 years.7,8 Chemotherapy is rarely used for the treatment of HCC due to its minimal success rate of 10–20% and high levels of toxicity.2

The only therapy currently approved by the Food and Drug Administration (FDA) for the treatment of advanced HCC is sorafenib, a tyrosine kinase inhibitor that has been shown to decrease cell proliferation and tumor angiogenesis.9,10 While sorafenib represents a major advancement in the treatment of HCC, its effects are modest, with the SHARP trial demonstrating an increase in overall survival from 7.9 months to 10.7 months and an increase from 2.8 months to 5.5 months in the median time to radiological progression.10 It demonstrated even less robust benefits in the Asia-Pacific trial, with overall survival in the treatment group of 6.5 months and median time to radiological progression of 2.8 months.9 Furthermore, after experiencing an initial response to treatment, most HCC patients develop a decrease in efficacy with sorafenib.11 Many novel therapies are currently under investigation in clinical trials. In a recently published Phase III trial, regorafenib, an oral multikinase inhibitor, has demonstrated an increase in median overall survival (10.6 months vs. 7.8 months) and an increase in median progression-free survival (PFS; 3.1 months vs. 1.5 months) compared to placebo in patients with advanced HCC who have progressed on sorafenib.12 To date, however, there are no FDA-approved second-line or salvage therapies for those patients who progress with or are intolerant to sorafenib.13

One of the most promising new therapies under investigation is tivantinib (ARQ 197), which has demonstrated positive results in early-phase clinical trials as a second-line agent for multiple solid tumors. This review focuses on tivantinib and its therapeutic profile in the management of HCC.