A phase Ib clinical trial of the multitargeted kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC).

Abstract

358 Background: Lenvatinib (L) is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR 1-4, RET, KIT, and PDGFβ. Everolimus (E) is an oral mTOR inhibitor approved for RCC. This Phase (Ph) 1b/2 study investigates the combination of L plus E in RCC patients (pts) (NCT01136733). The Ph 1b component reported here assessed safety, tolerability, and maximum tolerated dose (MTD). Methods: Pts with advanced unresectable or metastatic RCC, ECOG PS 0-1, age ≥18 y, were eligible for Ph 1b. Pts received L plus E, daily, in 28-day cycles. A standard 3+3 dose-escalation design with expansion cohort was used to identify the MTD. Results: 20 pts (M/F: 14/6; median age: 59 y [range 46-72]; median of 2 prior therapeutic regimens [range 0-5]; 17/20 pts [85%] had received prior anti-VEGF treatment (tx); 7/20 pts [35%] had also received prior mTOR-targeted tx) were treated at 3 dose levels of L (12 mg [n=7]; 18 mg [n=11]; 24 mg [n=2]) in combination with E 5 mg. DLTs were observed in 4 pts: G3 nausea and vomiting (1 pt) and G2 mucositis (1 pt) with 24 mg; G3 elevated creatinine phosphokinase, G2 fatigue, and G1 reflux with 18 mg; G3 abdominal pain with 12 mg. The MTD was L 18 mg plus E 5 mg. Median duration of tx was 19 wk (range 1-68, 6/20 (30%) pts ongoing). The most common tx-related adverse events (AEs), all grades, were fatigue 50% (G3, 5%); diarrhea 40% (G3, 10%); mucosal inflammation 40%; proteinuria 40% (G3, 10%); decreased appetite 35%; nausea, vomiting each 35% (each G3 5%); hypertension 35%; rash 30%; dry skin, epistaxis, weight decreased, constipation, edema peripheral (G3 5%), each 20%. There was 1 G4 tx-related AE of hypercholesterolemia. In the MTD and lower-dose cohorts, partial response (PR) was observed in 6/18 (33%) pts; durable stable disease (SD) (≥23 wk) or PR were achieved in 11/18 (61%) pts. Median PFS was 442 days (approx. 15 mos) in MTD and lower-dose cohorts. Conclusions: Lenvatinib 18 mg in combination with everolimus 5 mg appeared to be well tolerated when administered to multiply pretreated patients with advanced RCC in this Ph1b study. The PRs observed and SD durability warrant further evaluation in this refractory population during the ongoing Ph 2 part of the study. Clinical trial information: NCT01136733.