A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC)

Abstract

PurposeLenvatinib is an oral multi-targeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRβ, RET, and KIT. Everolimus is an oral mammalian target of rapamycin inhibitor approved for advanced renal cell carcinoma (RCC). This phase 1b study assessed safety, maximum tolerated dose (MTD), and preliminary antitumor activity of lenvatinib plus everolimus in metastatic RCC (mRCC) patients.MethodsPatients with advanced unresectable or mRCC and Eastern Cooperative Oncology Group performance status 0–1 were eligible (number of prior treatments not restricted). Starting dose was lenvatinib 12 mg once daily with everolimus 5 mg once daily administered continuously in 28-day cycles using a conventional 3 + 3 dose-escalation design. At the MTD, additional patients were enrolled in an expansion cohort.ResultsTwenty patients (mean 58.4 years) received lenvatinib [12 mg (n = 7); 18 mg (n = 11); 24 mg (n = 2)] plus everolimus 5 mg. MTD was established as once daily lenvatinib 18 mg plus everolimus 5 mg. The most common treatment-related treatment-emergent adverse events (all dosing cohorts) were fatigue 60 % (Grade ≥3: 10 %), mucosal inflammation 50 %, proteinuria (Grade ≥3: 15 %), diarrhea (Grade ≥3: 10 %), vomiting (Grade ≥3: 5 %), hypertension, and nausea, each 40 %. In MTD and lowest-dose cohorts (n = 18), best responses of partial response and stable disease were achieved in 6 (33 %) and 9 (50 %) patients, respectively.ConclusionsLenvatinib 18 mg combined with everolimus 5 mg was associated with manageable toxicity consistent with individual agents and no new safety signals. Observed activity warrants further evaluation of the combination in advanced RCC patients.

Preclinical trial of the multi-targeted lenvatinib in combination with cellular immunotherapy for treatment of renal cell carcinoma

“…A previous study demonstrated that the MTD and recommended phase II dose in this phase I experiment was confirmed to be 18 mg lenvatinib in combination with 5 mg everolimus once daily for treatment of RCC (12). In the present study, cellular immunotherapy and targeted therapy was introduced to treat RCC in a xenograft murine model.…”

“…The upregulation of hypoxia-inducible factor 1 target genes, such as VEGF, has been implicated in RCC (12). Additionally, genetic alterations resulting in the constitutive activation of cellular immunotherapy signaling pathways have been reported to be associated with RCC (14).…”

“…Lenvatinib, which targets the VEGFR1-3, FGFR1-4, PDGFR-β, RET and KIT pathways, has also demonstrated clinical benefit in RCC (11). A previous study indicated that lenvatinib combined with everolimus significantly extended overall survival compared with everolimus alone in patients with metastatic RCC (12).…”

A review on pharmacophoric designs of antiproliferative agents

“…This is presently in phase I clinical trials for solid tumors. Further clinical trials on combination of E-3810-paclitaxel have been completed recently (Bello et al, 2013;Molina et al, 2014). A phase I study to evaluate the safety, tolerability and ADME profile of orally administered CUDC-101 in cancer patients has been carried out and currently is in active stage.…”

Combination therapy for metastatic renal cell carcinoma

“…In contrast to the lack of feasibility of combinations of VEGF receptor TKIs and mTOR inhibitors, the combination of lenvatinib 18 mg daily and everolimus 5 mg daily was demonstrated to be feasible with manageable toxicities in a phase I trial (14). These results led to a randomized, open-label phase II trial by Motzer et al, in which 153 patients with advanced or metastatic, clear-cell RCC who had been treated with one line of VEGF inhibitor with progressive disease within 9 months of discontinuing the VEGF inhibitor were randomized in a 1:1:1 ratio to a continuous daily regimen of either lenvatinib (24 mg/day), everolimus (10 mg/day) or lenvatinib plus everolimus (18 and 5 mg/day, respectively) (15).…”