LBA4_PR - RANGE: a randomized, double-blind, placebo-controlled phase 3 study of docetaxel (DOC) with or without ramucirumab (RAM) in platinum-refractory adv...

Date 10 September 2017
Event ESMO 2017 Congress
Session Presidential Symposium II
Topics Anti-Cancer Agents & Biologic Therapy
Urothelial Cancers
Genitourinary Cancers
Presenter Daniel Petrylak
Citation Annals of Oncology (2017) 28 (suppl_5): v605-v649. 10.1093/annonc/mdx440
Authors D.P. Petrylak1, K.N. Chi2, A. Drakaki3, C.N. Sternberg4, R. de Wit5, H. Nishiyama6, E.Y. Yu7, D. Castellano8, S. Hussain9, I.J. Percent10, A. Fléchon11, A. Bamias12, M.S. van der Heijden13, N. Matsubara14, B. Alekseev15, R.A. Walgren16, O. Hamid16, A.H. Zimmermann16, K.M. Bell-Mcguinn16, T. Powles17
  • 1Medical Oncology, Yale University School of Medicine, 06520-8032 - New Haven/US
  • 2Medicine, BC Cancer Agency, Vancouver/CA
  • 3Medicine And Urology, UCLA Medical Center, Los Angeles/US
  • 4Department Of Oncology, San Camillo and Forlanini Hospitals, 156 - Rome/IT
  • 5Oncology, Erasmus MC Cancer Institute, Rotterdam/NL
  • 6Oncology, University of Tsukuba, Tsukuba/JP
  • 7Medicine, University of Washington, Seattle/US
  • 8Medical Oncology, University Hospital 12 De Octubre, 28041 - Madrid/ES
  • 9Oncology, University of Liverpool, Liverpool/GB
  • 10Oncology, Florida Cancer Specialists, Port Charlotte/US
  • 11Oncology, Centre Léon Bérard, Lyon/FR
  • 12Therapeutics Oncology, National and Kapodistrian University of Athens, Athens/GR
  • 13Molecular Carcinogenesis, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam/NL
  • 14Oncology, National Cancer Center Hospital East, 277-8577 - Chiba/JP
  • 15Oncology, P.A. Herzen Moscow Oncological Research Institute, 125284 - Moscow/RU
  • 16Oncology, Eli Lilly and Company, 46285 - Indianapolis/US
  • 17Medical Oncology, Barts Cancer Institute, Queen Mary University of London, London/GB

Abstract

Background

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.

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 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.

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 ≥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.

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.

Clinical trial identification

NCT02426125

Legal entity responsible for the study

Eli Lilly and Company

Funding

Eli Lilly and Company

Disclosure

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.