2253 - Phase 3 LEAP-011 trial: First-Line Pembrolizumab With Lenvatinib in Patients With Advanced Urothelial Carcinoma Ineligible to Receive Platinum-Based Chemotherapy

Background

Pembrolizumab (pembro) is the standard of care for patients (pts) with locally advanced or metastatic urothelial carcinoma who are cisplatin-ineligible with tumors expressing programmed death ligand 1 (PD-L1) and for pts unable to receive platinum-based chemotherapy regardless of PD-L1 status, based on KEYNOTE-052 (NCT02335424). Lenvatinib is a potent multiple-receptor tyrosine kinase inhibitor that selectively inhibits VEGF, VEGFR1-3, FGFR1-4, PDGFRα, c-kit, and RET and was found to have activity in multiple solid tumors. In KEYNOTE-146 (NCT02501096), the combination of lenvatinib and pembro showed promising efficacy and manageable safety in previously treated pts with advanced urothelial carcinoma, regardless of PD-L1 status.

Trial design

LEAP-011 (NCT03898180) is a randomized, double-blind, multicenter, global, phase 3 trial to test the hypothesis that the addition of lenvatinib to first-line pembro in advanced UC may improve outcomes compared to pembro/placebo. Eligible pts are adults with histologically confirmed locally advanced unresectable or metastatic urothelial carcinoma, that are either cisplatin-ineligible with tumors expressing PD-L1 (combined positive score ≥10), or that are ineligible to receive any platinum-based chemotherapy. Pts have not been previously treated with systemic chemotherapy for advanced urothelial carcinoma, have an ECOG PS score of 0-2, and have tumor tissue for PD-L1 analysis. About 694 pts will be enrolled and randomly assigned 1:1 to receive up to 35 cycles (2 y) of pembro 200 mg IV every 3 weeks with either lenvatinib 20 mg or placebo orally QD. Radiologic assessment will include CT/MRI of the chest, abdomen, or pelvis and bone imaging. Responses will be assessed per RECIST v1.1 by blinded independent central review. Dual primary end points are PFS and OS. Secondary end points are objective response rate, response duration, safety/tolerability, and disease control rate. Tissue-and blood-based biomarkers will be explored. Adverse events (AEs; graded per NCI CTCAE v4.0) will be monitored from randomization through 30 days after last dose of study drug (90 days for serious AEs).

Clinical trial identification

NCT03898180; April 1, 2019.

Editorial acknowledgement

Matthew Grzywacz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

Y. Loriot: Honoraria (self), Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Honoraria (institution): BMS; Honoraria (self), Honoraria (institution): Clovis; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Seattle Genetics; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self), Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Honoraria (institution): Astellas; Honoraria (institution): Exelixis; Honoraria (institution): Nektar; Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Sanofi. A. Balar: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Pfizer/EMD Serono. R. de Wit: Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): Janssen; Advisory / Consultancy: Clovis. J.A. Garcia: Advisory / Consultancy: Merck; Honoraria (self), Research grant / Funding (institution): Eisai. P. Grivas: Advisory / Consultancy: Merck & Co., Genentech, Dendreon, Bayer, Pfizer, Bristol-Myers Squibb, Exelixis, AstraZeneca, Biocept, Clovis Oncology, EMD Serono, Seattle Genetics, Foundation Medicine, Driver Inc., QED Therapeutics, Heron Therapeutics, Janssen; Speaker Bureau / Expert testimony, Educational unbranded activity: Genentech, Bristol-Myers Squibb; Travel / Accommodation / Expenses: AstraZeneca, Clovis Oncology; Research grant / Funding (institution): Merck & Co., Genentech, Bayer, Mirati, Oncogenex, AstraZeneca, Pfizer, Clovis Oncology, Bavarian Nordic, Immunomedics. N. Matsubara: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): BAYER; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): SANOFI; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): MSD; Advisory / Consultancy, Research grant / Funding (self): Roche; Advisory / Consultancy: Lilly; Speaker Bureau / Expert testimony: Chugai; Research grant / Funding (self): Eisai. T.L. Frenkl: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck; Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment, Spouse, employment and travel/accommodations/expenses: Amicus Therapeutics; Leadership role, Spouse, on board of directors for VenatoRx: VenatoRx; Shareholder / Stockholder / Stock options: GSK; Shareholder / Stockholder / Stock options: AstraZeneca. E. Sbar: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: MSD; Shareholder / Stockholder / Stock options: BMS; Shareholder / Stockholder / Stock options: Pfizer. X.C. Jia: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. A.O. Siefker-Radtke: Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: Nektar Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Seattle Genetics; Advisory / Consultancy: Bavarian Nordic. All other authors have declared no conflicts of interest.