Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study

OBJECTIVES: To assess the tolerability, safety, pharmacokinetics and antitumor activities of lenvatinib, an oral inhibitor of multiple receptor tyrosine kinases, in combination with everolimus, an inhibitor of mammalian target of rapamycin, in Japanese patients with advanced or metastatic renal cell carcinoma after disease progression with vascular endothelial growth factor-targeted therapy. METHODS: Lenvatinib 18 mg and everolimus 5 mg once daily were administered on 28-day continuous cycles until disease progression or unacceptable toxicity. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 4.03, and tumor response was assessed according to the Response Evaluation Criteria in Solid Tumor version 1.1. Pharmacokinetics sampling was carried out during the first cycle. RESULTS: Seven patients with clear cell renal cell carcinoma received this combination treatment. Dose-limiting toxicity was not observed. The most commonly observed adverse events were thrombocytopenia and decreased appetite (100%), followed by hypertriglyceridaemia and palmar-plantar erythrodysesthesia syndrome (86%). The most common grade 3 adverse event was lymphopenia (43%). No grade 4 or 5 adverse events occurred. The steady-state mean areas under the concentration-time curves of lenvatinib and everolimus were 3220 and 401 ng·h/mL, respectively. Five patients (71%) had partial response, and one (14%) had stable disease. CONCLUSIONS: Lenvatinib 18 mg and everolimus 5 mg once daily are well tolerated and manageable, and their combined administration has no significant effect on either drug's pharmacokinetics. Overall, this combination therapy shows encouraging antitumor activity in Japanese patients with renal cell carcinoma.