ESMO 2017: RANGE: A randomized, double-blind, placebo controlled phase 3 study of docetaxel with or without ramucirumab in platinum refractory advanced or metastatic urothelial carcinoma
In a previous randomized phase II study of platinum-refractory metastatic urothelial carcinoma, ramucirumab plus docetaxel significantly improved median progression-free survival (PFS) over docetaxel alone (5.4 vs 2.8 months; HR, 0.389; 95% CI, 0.235-0.643), with no unexpected toxicities [1]. To confirm these results, the authors conducted a randomized phase III trial (RANGE) in a similar patient population.
In this randomized, double-blind, phase III trial, patients with progressive advanced or metastatic urothelial carcinoma during or after platinum-based chemotherapy were enrolled. Key inclusion criteria included progression ≤14 months after platinum chemotherapy and ECOG performance status 0 or 1. Additional prior treatment with one immune checkpoint inhibitor was permitted. Patients were randomized 1:1 to receive docetaxel 75 mg/m2 with ramucirumab 10 mg/kg or placebo on day 1 of a 21-day cycle until disease progression or other discontinuation criteria. The primary endpoint was investigator-assessed PFS; 331 PFS events from the first 437 randomized patients provided 90% power to detect statistical significance, assuming a hazard ratio (HR) of 0.70 with a 2-sided alpha of 0.05. Secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and quality of life as assessed with the EORTC QLQ-C30 and EQ-5D-5L. Radiographic assessment with RECIST v1.1 occurred at baseline and every 6 weeks for the first year, and then every 12 weeks thereafter.
There were 530 patients randomized to ramucirumab plus docetaxel (n = 263) or placebo plus docetaxel (n = 267). Baseline characteristics were well-balanced between the two groups, including Bellmunt risk factors (liver metastases, hemoglobin <10 g/dL, ECOG performance status >0, and time since previous therapy <3 months). Median follow-up duration in the full intention to treat population was 5.0 months (IQR 2.3-8.9). Investigator assessed PFS was significantly prolonged in patients treated with ramucirumab plus docetaxel versus placebo plus docetaxel (median, 4.1 vs 2.8 months; HR, 0.757; 95% CI, 0.607-0.943). A blinded central analysis demonstrated consistent PFS results (HR, 0.672; 95% CI, 0.536-0.842). Subgroup analyses for PFS favored ramucirumab plus docetaxel for most scenarios. ORR in the first 437 ITT population was 24.5% (95%CI, 18.8-30.3) in the ramucirumab plus docetaxel arm and 14.0% (95% CI, 9.4-18.6) in the placebo plus docetaxel arm. At this point in follow-up, OS data are immature. Mean scores for global quality of life were relatively unchanged over time, with no differences between treatment arms. Grade ≥3 adverse events were reported at a similar frequency in both arms with no unexpected toxicities; neutropenia was the most common grade ≥3 adverse events (15% ramucirumab arm vs 14% placebo arm).
Dr. Petrylak concluded with several take-home points, (i) RANGE is the first phase III study to demonstrate a PFS advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma (HR 0.757), (ii) ORR was higher in the ramucirumab plus docetaxel arm, (iii) the combination of ramucirumab and docetaxel did not result in significant additive compromise to quality of life when compared to placebo plus docetaxel, (iv) the combination of ramucirumab and docetaxel is a new treatment option for patients with platinum-refractory advanced urothelial carcinoma.
Reference:
1. Petrylak DP, Tagawa ST, Kohli M, et al. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: An open-label, three-arm, randomized controlled phase II trial. J Clin Oncol 2016;34(13):1500-1509.
Speaker: Daniel P. Petrylak, Yale Cancer Center, New Haven, United States of America
Co-Authors: K. N. Chi (Vancouver, Canada) A. Drakaki (Los Angeles, United States of America) C. N. Sternberg (Rome, Italy) R. De Wit (Rotterdam, Netherlands) H. Nishiyama (Tsukuba, Japan) E. Y. Yu (Seattle, United States of America) D. Castellano (Madrid, Spain)
S. Hussain (Liverpool, United Kingdom) I. J. Percent (Port Charlotte, United States of America)
A. Fléchon (Lyon, France) A. Bamias (Athens, Greece) M. S. Van der Heijden (Amsterdam, Netherlands) N. Matsubara (Chiba, Japan) B. Alekseev (Moscow, Russian Federation) R. A. Walgren (Indianapolis, United States of America) O. Hamid (Indianapolis, United States of America) A. H. Zimmermann (Indianapolis, United States of America) K. M. Bell-Mcguinn (Indianapolis, United States of America) T. Powles (London, United Kingdom)
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain