Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Abstract

Purpose: To determine the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of lenvatinib in patients with advanced hepatocellular carcinoma (HCC).Experimental Design: This multicenter, open-label, phase I, dose-escalation study included patients aged 20 to 80 years, refractory to standard therapy, and stratified by hepatic function measured using Child-Pugh (CP) scores: CP-A (score, 5-6) and CP-B (score, 7-8). Lenvatinib was administered continually once daily for 4-week cycles. MTD was defined as the maximum dose associated with 1 dose-limiting toxicity (DLT) occurring in cycle 1 among 6 patients.Results: In total, 20 patients (9 in CP-A and 11 in CP-B) were enrolled. The MTD was 12 and 8 mg once daily in CP-A and CP-B, respectively; DLTs included proteinuria, hepatic encephalopathy, and hyperbilirubinemia. The most common grade 3 toxicities included hypertension in CP-A and hyperbilirubinemia in CP-B. Lenvatinib plasma concentration at 24 hours after administration (C 24 h ) for 12 mg once daily was higher in patients with HCC than in patients with other solid tumors shown in a previous phase I study, but C 24 h for 25 mg once daily lenvatinib was comparable. After lenvatinib treatment, the number of circulating endothelial and c-Kit þ cells decreased and the levels of interleukin (IL)-6, IL10, granulocyte-colony stimulating factor, and vascular endothelial growth factor increased (P < 0.05). Partial responses were observed in 3 patients and tumor shrinkage occurred in 14 patients. Conclusions: Lenvatinib (12 mg once daily) demonstrated preliminary efficacy with manageable toxicity and is the recommended dose for phase II studies in patients with HCC and CP-A.

Chemotherapy for hepatocellular carcinoma: current status and future perspectives

“…Lenvatinib is an orally active inhibitor of multiple receptor tyrosine kinases, VEGFR 1-3, FGFR 1-4, PDGFRα, Rearranged during Transfection (RET), and KIT (18,20,21). The drug was shown in a Phase II trial to exert promising antitumor efficacy in both advanced HCC patients who received it as first-line therapy and as second-line treatment (21), with a response rate of 23.9%, median time to progression of 9.4 months, and median survival time of 18.3 months.…”

Lenvatinib in Advanced Hepatocellular Carcinoma

“…A daily dose of 24 mg was initially determined based on the results of a phase I trial for the treatment of solid tumors and other subsequent studies in other types of cancer; however, the dose was reduced to 12 mg after another phase I trial addressing the effect of lenvatinib metabolism on liver function in HCC patients [13]. …”

Lenvatinib May Drastically Change the Treatment Landscape of Hepatocellular Carcinoma

“…A phase I trial in patients with Child-Pugh A and B HCC was conducted for that purpose. Based on the results, the recommended dose was set at 12 mg/day for Child-Pugh A patients and 8 mg/day for Child-Pugh B patients [20].…”