ASCO 2018: A Subgroup Analysis of the East Asia Population in RANGE

Chicago, IL (UroToday.com) At last year’s ESMO Clinical Congress in Madrid, Spain, Daniel Petrylak, MD, and colleagues presented the first results of RANGE, a phase III randomized controlled trial assessing docetaxel with or without ramucirumab in platinum refractory advanced or metastatic urothelial carcinoma [1]. For this trial, 530 patients were randomized to ramucirumab plus docetaxel (n = 263) or placebo plus docetaxel (n = 267). Over a median follow-up in the intention to treat (ITT) population of 5.0 months (IQR 2.3-8.9), the 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). 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 the 2018 ASCO annual meeting, Nobuaki Matsubara, MD, and colleagues presented results of the RANGE phase III trial specific to patients from East Asia. 

Key inclusion criteria for RANGE included progression ≤14 months after platinum chemotherapy and ECOG performance status 0 or 1. Additionally, prior treatment with one immune checkpoint inhibitor was permitted. Patients in the ITT population 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. Patients from East Asia (n=110) received docetaxel 60 mg/m2 rather than 75 mg/m2. The primary endpoint was investigator-assessed PFS and secondary endpoints included ORR, overall survival, safety, and quality of life (QOL).

Among enrolled patients, more patients from East Asia had primary upper tract tumors and fewer bladder tumors compared to the ITT population. The median PFS among East Asian patients per investigator assessment was 3.02 months for patients receiving ramucirumab plus docetaxel compared to 2.99 for docetaxel plus placebo (HR 0.928, 95%CI 0.597-1.444). When using blinded central review, median PFS was 3.32 months for patients receiving ramucirumab plus docetaxel compared to 2.69 for docetaxel plus placebo (HR 0.793, 95%CI 0.513-1.225). 
InvestigatorAssessment RANGEstudy
Although these results favored ramucirumab plus docetaxel, they were not statistically significant, whereas both outcomes showed significantly improved PFS for ramucirumab plus docetaxel in the ITT population. The remaining comparisons between the East Asian and the ITT population are as follows:
Comparisons EastAsian ITT populations
The most common grade ≥3 adverse events in the East Asian population was neutropenia and leukopenia, and observed at a similar frequency in both arms. Mean scores for global QOL in East Asian population remained essentially stable over time without a clear difference between arms. 

The results of RANGE specific to the East Asian population demonstrate a non-statistically significant trend towards improved PFS for patients receiving ramucirumab plus docetaxel with a reduced docetaxel dose of 60 mg/m2. However, these results do not completely recapitulate the results of the ITT population, which demonstrated statistically significant differences between arms for both investigator and centrally-blinded PFS assessment at a docetaxel dose of 75 mg/m2. Whether differences in PFS between the two populations are secondary to a reduced docetaxel dose in the East Asian population or an inherently different disease biology remains to be elucidated. 
Clinical trial information: NCT02426125

References: 
1. Petrylak DP, Chi KN, Drakaki A, et al. RANGE: A randomized, double-blind, placebo controlled phase 3 study of docetaxel with or without ramucirumab in platinum refractory advanced or metastatic urothelial carcinoma. ESMO 2017, abstr LBA4.

Presented by: Nobuaki Matsubara, MD, National Cancer Center Hospital East, Chiba, Japan

Co-Authors: Daniel Peter Petrylak, Hiroyuki Nishiyama, Wen-Pin Su, Jae-Lyun Lee, Jian-Ri Li, Richard A. Walgren, Oday Hamid, Annamaria Zimmermann, Katherine M Bell-McGuinn, Ling Gao, Gosuke Homma, Ikuo Yana, Thomas Powles; National Cancer Center Hospital East, Chiba, Japan; Yale School of Medicine, New Haven, CT; University of Tsukuba, Tsukuba, Japan; National Cheng Kung University (NCKU) Hospital, Tainan, Taiwan; University of Ulsan College of Medicine/ Asan Medical Center, Seoul, Korea, Republic of (South); Taichung Veterans General Hospital, Taichung, Taiwan; Eli Lilly and Company, Indianapolis, IN; Eli Lilly and Company, Branchburg, NJ; Eli Lilly and Company Japan K.K., Kobe, Japan; Barts Cancer Institute, Queen Mary University of London, London, United Kingdom


Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the 2018 ASCO annual meeting - Chicago, IL, USA

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