Preclinical study for antitumor mechanism of lenvatinib and clinical studies for hepatocellular carcinoma

Abstract

Lenvatinib is an oral multikinase inhibitor that targets VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT. The preclinical studies of lenvatinib for hepatocellular carcinoma (HCC) suggest that lenvatinib exerts the potent antitumor effect on the basis of the inhibitory actions on VEGF and FGF-induced tumor angiogenesis and on FGF-induced tumor cell growth. Phase I and II trials were conducted in Japan and Korea evaluating the maximal tolerated dose, efficacy, and safety of lenvatinib for HCC patients and have produced promising results. Considering the relationship between body weight, AUC and dose in HCC patients, the recommended starting dose was determined to be 8 mg/day for patients weighing lower than 60 kg and 12 mg/day for patients of 60 kg and higher. A phase III REFLECT study have demonstrated that the non-inferiority of lenvatinib to sorafenib in overall survival was confirmed and that lenvatinib was significantly superior to sorafenib in the analysis of progression-free survival and response rate. Based on these results, lenvatinib has been approved for the treatment of patients with unresectable HCC in Japan, US, EU and others this year. Clinical studies of lenvatinib combination therapy with transarterial chemoembolization (TACE) and with immune checkpoint inhibitors are currently on-going. Because of the potent antitumor effect, lenvatinib may change treatment strategy for HCC patients in the future.