Limited treatment options are available for patients (pts) with platinum-refractory advanced or metastatic urothelial carcinoma (UC). In a previous randomized phase 2 study (NCT01282463) of platinum-refractory metastatic UC, RAM plus DOC significantly improved median progression-free survival (PFS) over DOC (5.4 vs 2.8 months; HR, 0.389; 95% CI, 0.235-0.643; P = 0.0002) with no unexpected toxicities. To confirm these results, we conducted a randomized phase 3 trial in a similar pt population.
In this randomized, double-blind, phase 3 trial, pts with progressive advanced or metastatic UC during or after platinum-based chemotherapy were enrolled. Additional prior treatment with 1 immune checkpoint inhibitor was permitted. Pts were randomized (1:1) to receive DOC 75 mg/m2 with RAM 10 mg/kg or placebo (PL) on day 1 of a 21-day cycle until disease progression or other discontinuation criteria. Primary endpoint was investigator-assessed PFS, analyzed in the first 437 randomized (intention-to-treat, ITT) pts. Secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and quality of life as assessed with the EORTC QLQ-C30. Radiographic assessment occurred every 6 weeks.
530 pts were randomized to RAM plus DOC (n = 263) or PL plus DOC (n = 267). PFS was significantly prolonged in pts treated with RAM plus DOC versus PL plus DOC (median, 4.1 vs 2.8 months; HR, 0.757; 95% CI, 0.607-0.943; p = 0.0118). A blinded central analysis demonstrated consistent PFS results (HR, 0.672; 95% CI, 0.536-0.842; p = 0.0005). ORR in the first 437 ITT population was 24.5% (95% CI, 18.8-30.3) in the RAM arm and 14.0% (95% CI, 9.4-18.6) in the PL arm. OS data are immature. Grade ≥3 adverse events (AEs) were reported at a similar frequency in both arms with no unexpected toxicities; neutropenia was the most common grade ≥3 AE (15% RAM arm vs 14% PL arm). Mean scores for global quality of life were relatively unchanged over time, with no differences between arms.
RAM plus DOC is the first regimen in a phase 3 study to show superior PFS over chemotherapy in pts with platinum-refractory advanced UC.
Clinical trial identification
Legal entity responsible for the study
Eli Lilly and Company
Eli Lilly and Company
K.N. Chi: Clinical trial costs from Eli Lilly and Company, during the conduct of the study. C.N. Sternberg: Personal fees for participating in an advisory board and institutional research funding from Eli Lilly and Company, during the conduct of the study. R. de Wit: Grant support or personal fees from Lilly, Merck, Roche and Sanofi. E.Y. Yu: Honorarium and institutional research funding from Eli Lilly and Company A. Fléchon: Personal fees and non-financial support from Janssen, Novartis, Astellas, Sanofi, Roche, MSD, Pfizer, Ipsen, Bayer, Astra Zeneca, outside the submitted work; . M.S. van der Heijden: Personal fees from Roche/Genentech, AstraZeneca, Astellas, BMS, and grants from Astellas, outside the submitted work. N. Matsubara: Honoraria from MSD, AstraZeneca, Eisai, Ono, Kissei, Sanofi Taiho, Takeda, Chugai, Novartis, Bayer Yakuhin, Pfizer Japan, Merck Serono Co., Janssen; research funding from Shionogi, Bayer Yakuhin, Janssen, Chugai, Eli Lilly Japan, Eisai, MSD R.A. Walgren, O. Hamid, A.H. Zimmermann, K.M. Bell-Mcguinn: Employee and shareholder of Eli Lilly and Company T. Powles: Honoraria from Roche, Merck, AstraZeneca, BMS, Lilly, Pfizer; and research funding from Roche and AstraZeneca. All other authors have declared no conflicts of interest.