RANGE: A randomized, double-blind, placebo-controlled phase 3 study of docetaxel (DOC) with or without ramucirumab (RAM) in platinum-refractory advanced or metastatic urothelial carcinoma

Abstract

Background: Limited treatment options are available for patients (pts) with platinumrefractory 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. Methods: 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 RAM10 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. Results: 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≥3AE (15% RAMarm vs 14% PL arm). Mean scores for global quality of life were relatively unchanged over time, with no differences between arms. Conclusions: 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.