Phase III LEAP-011 trial: First-line pembrolizumab with lenvatinib in patients with advanced urothelial carcinoma ineligible to receive platinum-based chemotherapy

Abstract

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 PDL1 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).