1. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial
- Author
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Koji Kawai, Satoshi Nagamori, Katherine M Bell-McGuinn, Cristiano Ferrario, Wen Pin Su, Isabel Syndikus, Aude Flechon, Georgios Gakis, Timothy Dudley Clay, Leticia Vazquez Cortés, Ronald de Wit, Florence Joly, Bozena Sikora-Kupis, Sergio Bracarda, Astra M. Liepa, Annemie Rutten, Daniel P. Petrylak, Su Peng Yeh, Annamaria Zimmermann, Sameera R. Wijayawardana, Mutsushi Kawakita, Siobhan Ng, Thean Hsiang Tan, Chikara Ohyama, Yu Jung Kim, Yuriy Golovko, Dimitrios Mavroudis, Jian Ri Li, Reinoud J. B. Blaisse, Mustafa Erman, Francesca Russo, Catherine Becht, Anghel Adrian Udrea, Robert Huddart, Syed A. Hussain, Fransiscus L.G. Erdkamp, Satoshi Fukasawa, Francesco Massari, Motohide Uemura, Boris Alekseev, Irfan Cicin, Se Hoon Park, Marcello Tucci, Lajos Géczi, Maureen J.B. Aarts, Yu Li Su, Fumimasa Fukuta, Hyo Jin Lee, Wolfgang Schultze-Seemann, Alexandra Drakaki, Hakan Harputluoglu, Xavier Garcia del Muro, Santhanam Sundar, Avivit Peer, Herlinde Dumez, William E. Lawler, Juan Ignacio Delgado Mignorance, Naveed Sarwar, Jeanny B. Aragon-Ching, Benjamin T. Herms, Fredrik Laestadius, Nobuaki Matsubara, Ivan Sinielnikov, Cora N. Sternberg, Hiroyuki Nishiyama, Piotr Tomczak, Brigitte Laguerre, Rebecca R. Hozak, Vasilis Karavasilis, Christina A. Schwentner, Hiroyuki Tsunemori, Masayoshi Nagata, Igor Bondarenko, Andrea Necchi, Yen Chuan Ou, Scott T. Tagawa, Constance Thibault, Richard A. Walgren, Akira Yokomizo, Evan Y. Yu, Alejo Rodriguez-Vida, Sufia Safina, Ulka N. Vaishampayan, János Révész, Aristotelis Bamias, Jae-Lyun Lee, Chien Liang Lin, Thomas W. Flaig, Roman Fomkin, Petr Alexandrovich Karlov, Joanna Wojcik-Tomaszewska, Junichi Inokuchi, Wataru Obara, Haralambos Kalofonos, John D. Hainsworth, Marc-Oliver Grimm, Thomas Eugene Lowe, Pablo Gajate Borau, Simon J. Crabb, Lisa Sengeloev, Junji Yonese, Simon Chowdhury, Elizabeth Jane Hovey, Daniel Castellano, Peter Istvan Acs, Chia-Chi Lin, Claudia Lorena Urzua Flores, Jean-Pascal Machiels, Kim N. Chi, Takahiro Osawa, Nobuo Shinohara, Daniel Kejzman, Günter Niegisch, David Sarid, Yuksel Urun, Yun Gyoo Lee, Oday Hamid, Alina Amalia Herzal, Michael Schenker, Eli Rosenbaum, Enrique Grande, Raya Leibowitz-Amit, Naoto Miyajima, Michiel S. van der Heijden, Shinichi Yamashita, Susanna Yee Shan Cheng, Kazuo Nishimura, Sun Young Rha, Thomas Powles, Hasan Şenol Coşkun, Jens Bedke, Ivor J. Percent, Christos Papandreou, James K. Schwarz, Masafumi Oyama, Giorgio V. Scagliotti, Chong-Xian Pan, Yoshihiko Tomita, Giampaolo Tortora, Stéphane Culine, Suet Lai Shirley Wong, Andrey Semenov, Jennifer L. Cultrera, Niels Viggo Jensen, Michael Stöckle, Katsuyoshi Hashine, Medical Oncology, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Centre du cancer, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Medische Oncologie (9), Petrylak, Dp, de Wit, R, Chi, Kn, Drakaki, A, Sternberg, Cn, Nishiyama, H, Castellano, D, Hussain, Sa, Flechon, A, Bamias, A, Yu, Ey, van der Heijden, M, Matsubara, N, Alekseev, B, Necchi, A, Geczi, L, Ou, Yc, Coskun, H, Su, Wp, Bedke, J, Gakis, G, Percent, Ij, Lee, Jl, Tucci, M, Semenov, A, Laestadius, F, Peer, A, Tortora, G, Safina, S, del Muro, Xg, Rodriguez-Vida, A, Cicin, I, Harputluoglu, H, Tagawa, St, Vaishampayan, U, Aragon-Ching, Jb, Hamid, O, Liepa, Am, Wijayawardana, S, Russo, F, Walgren, Ra, Zimmermann, Ah, Hozak, Rr, Bell-McGuinn, Km, Powles, T, and Graduate School
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Male ,0301 basic medicine ,MULTICENTER ,Docetaxel ,Gastroenterology ,ANGIOGENESIS ,VINFLUNINE ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Neoplasm Metastasis ,education.field_of_study ,CHEMOTHERAPY ,Middle Aged ,OPEN-LABEL ,Prognosis ,Survival Rate ,Oncology ,030220 oncology & carcinogenesis ,Female ,medicine.drug ,EXPRESSION ,Urologic Neoplasms ,medicine.medical_specialty ,BEVACIZUMAB ,Population ,BLADDER-CANCER ,Neutropenia ,Antibodies, Monoclonal, Humanized ,Placebo ,Ramucirumab ,03 medical and health sciences ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Neoplasm Invasiveness ,education ,Survival rate ,Aged ,Platinum ,Salvage Therapy ,Carcinoma, Transitional Cell ,business.industry ,medicine.disease ,ATEZOLIZUMAB ,030104 developmental biology ,ENDOTHELIAL GROWTH-FACTOR ,business ,Febrile neutropenia ,Follow-Up Studies - Abstract
Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
- Published
- 2020
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