Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial
| Autor: | Daniel P Petrylak, Ronald de Wit, Kim N Chi, Alexandra Drakaki, Cora N Sternberg, Hiroyuki Nishiyama, Daniel Castellano, Syed Hussain, Aude Fléchon, Aristotelis Bamias, Evan Y Yu, Michiel S van der Heijden, Nobuaki Matsubara, Boris Alekseev, Andrea Necchi, Lajos Géczi, Yen-Chuan Ou, Hasan Senol Coskun, Wen-Pin Su, Miriam Hegemann, Ivor J Percent, Jae-Lyun Lee, Marcello Tucci, Andrey Semenov, Fredrik Laestadius, Avivit Peer, Giampaolo Tortora, Sufia Safina, Xavier Garcia del Muro, Alejo Rodriguez-Vida, Irfan Cicin, Hakan Harputluoglu, Ryan C Widau, Astra M Liepa, Richard A Walgren, Oday Hamid, Annamaria H Zimmermann, Katherine M Bell-McGuinn, Thomas Powles, Suet-Lai Shirley Wong, Thean Hsiang Tan, Elizabeth Jane Hovey, Timothy Dudley Clay, Siobhan Su Wan Ng, Annemie Rutten, Jean-Pascal Machiels, Herlinde Dumez, Susanna Yee-Shan Cheng, Kim Nguyen Chi, Cristiano Ferrario, Lisa Sengeloev, Niels Viggo Jensen, Constance Thibault, Brigitte Laguerre, Florence Joly, Aude Flechon, Stéphane Culine, Catherine Becht, Günter Niegisch, Michael Stöckle, Marc-Oliver Grimm, Georgios Gakis, Wolfgang Schultze-Seemann, Haralambos Kalofonos, Dimitrios Mavroudis, Christos Papandreou, Vasilis Karavasilis, Janos Révész, Lajos Geczi, Eli Rosenbaum, Raya Leibowitz-Amit, Daniel Kejzman, David Sarid, Giorgio Vittorio Scagliotti, Sergio Bracarda, Francesco Massari, Takahiro Osawa, Naoto Miyajima, Nobuo Shinohara, Fumimasa Fukuta, Chikara Ohyama, Wataru Obara, Shinichi Yamashita, Yoshihiko Tomita, Koji Kawai, Satoshi Fukasawa, Masafumi Oyama, Junji Yonese, Masayoshi Nagata, Motohide Uemura, Kazuo Nishimura, Mutsushi Kawakita, Hiroyuki Tsunemori, Katsuyoshi Hashine, Junichi Inokuchi, Akira Yokomizo, Satoshi Nagamori, Hyo Jin Lee, Se Hoon Park, Sun Young Rha, Yu Jung Kim, Yun-Gyoo Lee, Leticia Vazquez Cortés, Claudia Lorena Urzua Flores, Reinoud J B Blaisse, Fransiscus L G Erdkamp, Maureen J B Aarts, Joanna Wojcik-Tomaszewska, Piotr Tomczak, Bozena Sikora-Kupis, Michael Schenker, Alina Amalia Herzal, Anghel Adrian Udrea, Petr Karlov, Sufia Z Safina, Roman Fomkin, Enrique Grande Pulido, F Xavier García Del Muro, Juan Ignacio Delgado Mignorance, Daniel Castellano Gauna, Alejo Rodríguez-Vida, Yu-Li Su, Chien-Liang Lin, Chia-Chi Lin, Su-Peng Yeh, Irfan Çiçin, Mustafa Erman, Yuksel Urun, Yurii Golovko, Igor Bondarenko, Ivan Sinielnikov, Simon Crabb, Isabel Syndikus, Robert Huddart, Santhanam Sundar, Simon Chowdhury, Naveed Sarwar, Thomas Flaig, Chong Xian Pan, Daniel Petrylak, James Schwarz, Ivor Percent, Jennifer Cultrera, John Hainsworth, Benjamin Herms, William Lawler, Thomas Lowe, Scott Tagawa, Jeanny Aragon-Ching, Ulka Vaishampayan |
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| Přispěvatelé: | UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Service d'oncologie médicale, 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, S, Flechon, A, Bamias, A, Yu, Ey, van der Heijden, M, Matsubara, N, Alekseev, B, Necchi, A, Geczi, L, Ou, Yc, Coskun, H, Su, Wp, Hegemann, M, 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, Widau, Rc, Liepa, Am, Walgren, Ra, Hamid, O, Zimmermann, Ah, Bell-McGuinn, Km, Powles, T, Medical Oncology |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Internationality medicine.medical_treatment Phases of clinical research Docetaxel Kaplan-Meier Estimate Gastroenterology 2ND-LINE THERAPY 0302 clinical medicine Monoclonal Antineoplastic Combined Chemotherapy Protocols Medicine ramucirab Medicine (all) Antibodies Monoclonal General Medicine Middle Aged OPEN-LABEL Prognosis Neoadjuvant Therapy Treatment Outcome 030220 oncology & carcinogenesis Female Taxoids medicine.drug Adult medicine.medical_specialty Metastatic Urothelial Carcinoma Urology Locally advanced BLADDER-CANCER Placebo Antibodies Monoclonal Humanized Risk Assessment Ramucirumab Antibodies Disease-Free Survival Double blind II TRIAL 03 medical and health sciences LUNG-CANCER Aged Carcinoma Transitional Cell Double-Blind Method Humans Neoplasm Invasiveness Neoplasm Staging Proportional Hazards Models Survival Analysis Urinary Bladder Neoplasms Internal medicine BREAST-CANCER In patient Adverse effect Platinum Chemotherapy FACTOR RECEPTOR-2 Settore MED/06 - ONCOLOGIA MEDICA business.industry Carcinoma TRANSITIONAL-CELL-CARCINOMA Surgery Discontinuation Regimen Ramucirumab docetaxel 030104 developmental biology ENDOTHELIAL GROWTH-FACTOR Transitional Cell business FOLLOW-UP |
| Zdroj: | Lancet (London, England), Vol. 390, no.10109, p. 2266-2277 (2017) Lancet, 390(10109), 2266-2277. Elsevier Science Lancet (UK), 390(10109), 2266-2277. Elsevier Ltd. |
| ISSN: | 0140-6736 |
| Popis: | Summary Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. 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 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m 2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. Interpretation To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Funding Eli Lilly and Company. |
| Databáze: | OpenAIRE |
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