Tivantinib for the treatment of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with a poor prognosis due to late diagnosis in the majority of cases. Physicians are frequently confronted with patients who are not eligible for curative or locoregional treatments any more. In this scenario, the multi-tyrosine kinase inhibitor sorafenib remains the only systemic first-line treatment option providing modest survival benefit compared to placebo with significant but for most patients acceptable adverse effects. Areas covered: Tivantinib was the first antiproliferative agent to be been applied in a phase III trial based on receptor overexpression analyses after disease progression on sorafenib. While phase I and II trials with tivantinib in second line showed encouraging results, a recent press release announced that the METIV-HCC phase III study of tivantinib in HCC did not meet its primary endpoint of improving overall survival. Expert commentary: Evidence for antiangiogenetic therapy inducing tumor hypoxia leading to overexpression of proliferative genes, including cMET, underlines the potential of tivantinib as second-line treatment. However, as the mechanism of action of tivantinib through cMET inhibition has recently been questioned by several groups, identification of alternative proliferative markers or targets is mandatory.

Cantharidic acid induces apoptosis through the p38 MAPK signaling pathway in human hepatocellular carcinoma

“…Hepatocellular carcinoma (HCC) is the second leading causes of cancer in Taiwan . Several new therapeutic strategies, such as tyrosine kinase inhibitors and c‐Met inhibitors, have been employed to improve the efficacy of treatment for HCC, but the grim reality is that patients are diagnosed with HCC only at advanced stages . Moreover, because resection is possible in only 30% of cases, this tumor type is associated with high lethality .…”

Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond

“…The receptor tyrosine kinase c-MET has emerged as a possible therapeutic target in HCC and other cancers, with aberrant expression of the receptor promoting cellular proliferation and metastasis observed in numerous cancers [96]. However, tivantinib, a selective oral c-MET inhibitor, failed to meet its primary endpoint of improved OS over placebo in its pivotal phase 3 METIV-HCC trial, in which patients with advanced HCC with high MET expression were evaluated in the secondline setting [97,98]. While reasons for its failure are unclear, it has been speculated that the efficacy of tivantinib may be c-MET independent and therefore the patient selection based on c-MET expression was inappropriate [98].…”

“…However, tivantinib, a selective oral c-MET inhibitor, failed to meet its primary endpoint of improved OS over placebo in its pivotal phase 3 METIV-HCC trial, in which patients with advanced HCC with high MET expression were evaluated in the secondline setting [97,98]. While reasons for its failure are unclear, it has been speculated that the efficacy of tivantinib may be c-MET independent and therefore the patient selection based on c-MET expression was inappropriate [98]. Cabozantinib is a multikinase inhibitor which targets c-MET but also VEGFRs, AXL, RET, KIT, and FLT3 [99].…”

Molecular diagnosis and therapy of hepatocellular carcinoma: achievements and challenges

“…Tivantinib as the first drug was used to a phase III trial grounded in receptor overexpression analyses after disease progression on sorafenib in HCC [71] . Lenvatinib as an oral multikinase inhibitor for differentiated thyroid cancer and renal cell cancer treatment initially was approved.…”

“…Phase III c-MET [71] Improved OS and PFS [71] HCC: hepatocellular carcinoma; OS: overall survival; ORR: objective response rate; PFS: progression-free survival; TKI: tyrosine kinase inhibitor; TTP: time to progression…”