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

• Published in: The Lancet (British edition) 2017-11, Vol.390 (10109), p.2266-2277
• Main Authors: Petrylak, Daniel P, de Wit, Ronald, Sternberg, Cora N, Nishiyama, Hiroyuki, Castellano, Daniel, Matsubara, Nobuaki, Alekseev, Boris, Necchi, Andrea, Géczi, Lajos, Ou, Yen-Chuan, Coskun, Hasan Senol, Su, Wen-Pin, Hegemann, Miriam, Percent, Ivor J, Lee, Jae-Lyun, Tucci, Marcello, Tortora, Giampaolo, Safina, Sufia, Rodriguez-Vida, Alejo, Harputluoglu, Hakan, Widau, Ryan C, Liepa, Astra M, Hamid, Oday, Zimmermann, Annamaria H, Bell-McGuinn, Katherine M, Wong, Suet-Lai Shirley, Hovey, Elizabeth Jane, Ng, Siobhan Su Wan, Dumez, Herlinde, Cheng, Susanna Yee-Shan, Jensen, Niels Viggo, Laguerre, Brigitte, Culine, Stéphane, Becht, Catherine, Niegisch, Günter, Grimm, Marc-Oliver, Gakis, Georgios, Schultze-Seemann, Wolfgang, Mavroudis, Dimitrios, Révész, Janos, Geczi, Lajos, Rosenbaum, Eli, Kejzman, Daniel, Peer, Avivit, Sarid, David, Bracarda, Sergio, Massari, Francesco, Osawa, Takahiro, Shinohara, Nobuo, Fukuta, Fumimasa, Obara, Wataru, Tomita, Yoshihiko, Kawai, Koji, Oyama, Masafumi, Nagata, Masayoshi, Uemura, Motohide, Nishimura, Kazuo, Kawakita, Mutsushi, Inokuchi, Junichi, Yokomizo, Akira, Park, Se Hoon, Rha, Sun Young, Kim, Yu Jung, Flores, Claudia Lorena Urzua, Blaisse, Reinoud J B, van der Heijden, Michiel S, Aarts, Maureen J B, Wojcik-Tomaszewska, Joanna, Tomczak, Piotr, Sikora-Kupis, Bozena, Safina, Sufia Z, Semenov, Andrey, Fomkin, Roman, Del Muro, F Xavier García, Lin, Chien-Liang, Yeh, Su-Peng, Çiçin, Irfan, Erman, Mustafa, Golovko, Yurii, Bondarenko, Igor, Powles, Thomas, Syndikus, Isabel, Huddart, Robert, Sundar, Santhanam, Chowdhury, Simon, Drakaki, Alexandra, Petrylak, Daniel, Schwarz, James, Percent, Ivor, Hainsworth, John, Herms, Benjamin, Tagawa, Scott, Vaishampayan, Ulka
• Format: Article
• Language: English
• Subjects: Adult; Aged; Angiogenesis; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Bladder cancer; Cancer; Cancer therapies; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - mortality; Carcinoma, Transitional Cell - pathology; Chemotherapy; Clinical medicine; Clinical trials; Cytotoxicity; Disease-Free Survival; Docetaxel; Double-Blind Method; Double-blind studies; Evidence-based medicine; Female; Humans; Immunotherapy; Internationality; Kaplan-Meier Estimate; Ligands; Male; Medical prognosis; Metastases; Metastasis; Middle Aged; Monoclonal antibodies; Neoadjuvant Therapy - methods; Neoplasm Invasiveness - pathology; Neoplasm Staging; Oncology; Patients; Platinum; Prognosis; Proportional Hazards Models; Ramucirumab; Risk Assessment; Survival Analysis; Targeted cancer therapy; Taxoids - administration & dosage; Treatment Outcome; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - mortality; Urinary Bladder Neoplasms - pathology; Urothelial carcinoma; Vascular endothelial growth factor
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(17)32365-6

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. 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/m2 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. 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 discont