814P - 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

ABSTRACT 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). The 3-arm randomised Ph 2 comparing PFS of L plus E and L alone versus E alone is ongoing. 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. 4 DLTs were observed: G3 nausea and vomiting (1 pt) and G2 mucositis (1 pt) at 24 mg; G3 elevated CPK at 18 mg; G3 abdominal pain at 12 mg. The MTD was L 18 mg plus E 5 mg. Median duration of tx was 14.5 wk (range 1-68, 7/20 (35%) pts ongoing). The most common tx-related adverse events (AEs), all grades were fatigue 45% (G3, 5%); mucosal inflammation 40%; proteinuria 35% (G3, 10%); diarrhoea 30% (G3, 5%); rash 30%; hypertension 25%; nausea, vomiting each 25% (each G3 5%); constipation, decreased appetite, epistaxis each 20%. There was 1 G4 related AE of hypercholesterolemia. PR was observed in 6/18 (33%) pts in the MTD and lower dosing cohorts. Durable stable disease (≥23 wk) or PR were achieved in 8/16 (50%) pts with postbaseline tumor assessments (and 3 pts ongoing with SD Conclusions Lenvatinib 18 mg in combination with everolimus 5 mg appeared to be safe when administered to multiply pretreated patients with advanced RCC in this Ph 1b part. The PRs observed and response durability warrant further evaluation in this refractory population during the ongoing Ph 2 part of the study. Disclosure A.M. Molina: A. Molina discloses research funding from EISAI and Novartis. J. Larkin: J. Larkin has received honoraria from EISAI. A. Gold: A. Gold is an employee of Eisai, Inc. C. Andresen: C. Andresen is an employee of Eisai, Inc. K. Wood: K. Wood is an employee of EISAI, Ltd. R.J. Motzer: R. Motzer discloses research funding from EISAI and Novartis, both >$10,000. M.D. Michaelson: Dr. Michaelson discloses institutional research funding from: EISAI, Pfizer, Abbott, GlaxoSmithKline, Genentech Consultant or advisory role (UNCOMPENSATED): Pfizer, EISAI. All other authors have declared no conflicts of interest.