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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

2017; Elsevier BV; Volume: 390; Issue: 10109 Linguagem: Inglês

10.1016/s0140-6736(17)32365-6

1474-547X

Daniel P. Petrylak, Ronald de Wit, Kim N., Alexandra Drakaki, Cora N. Sternberg, Hiroyuki Nishiyama, Daniel Castellano, Syed A. Hussain, Aude Fléchon, Aristotelis Bamias, Evan Y. Yu, Michiel S. van der Heijden, Nobuaki Matsubara, B. Yа. Alekseev, Andrea Necchi, Lajos Géczi, Yen‐Chuan Ou, Hasan Şenol Çoşkun, Wen-Pin Su, Miriam Hegemann, Ivor Percent, Jae‐Lyun Lee, Marcello Tucci, Andrey Semenov, Fredrik Laestadius, Avivit Peer, Giampaolo Tortora, Sufia Safina, Xavier García del Muro, Alejo Rodríguez‐Vida, İrfan Çiçin, Hakan Harputluoğlu, 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 Hovey, Timothy Clay, Siobhan Ng, Annemie Rutten, Jean‐Pascal Machiels, Herlinde Dumez, Susanna Y. Cheng, Kim Nguyen, Cristiano Ferrario, Lisa Sengeloev, Niels Viggo Jensen, Constance Thibault, Brigitte Laguerre, Fredrik Laestadius, Florence Joly, Aude Fléchon, Stéphane Culine, Catherine Becht, Günter Niegisch, Michael Stöckle, Marc‐Oliver Grimm, Georgios Gakis, Wolfgang Schultze‐Seemann, Haralabos P. Kalofonos, Dimitriοs Mavroudis, Christos N. Papandreou, Vasilios Karavasilis, Aristotelis Bamias, János Révész, Lajos Géczi, Eli Rosenbaum, Raya Leibowitz‐Amit, Daniel Kejzman, Avivit Peer, David Sarid, Giorgio V. Scagliotti, Cora N. Sternberg, Giampaolo Tortora, Sergio Bracarda, Andrea Necchi, Francesco Massari, Takahiro Osawa, Naoto Miyajima, Nobuo Shinohara, Fumimasa Fukuta, Chikara Οhyama, Wataru Obara, Shinichi Yamashita, Yoshihiko Tomita, Koji Kawai, Satoshi Fukasawa, Nobuaki Matsubara, Masafumi Oyama, Junji Yonese, Masayoshi Nagata, Motohide Uemura, Kazuo Nishimura, Mutsushi Kawakita, Hiroyuki Tsunemori, Katsuyoshi Hashine, Junichi Inokuchi, Akira Yokomizo, Satoshi Nagamori, Jae‐Lyun Lee, Hyo Jin Lee, Se Hoon Park, Sun Young Rha, Yu Jung Kim, Yun‐Gyoo Lee, Leticia Vazquez Cortés, Claudia Lorena Urzua Flores, R.J.B. Blaisse, Michiel S. van der Heijden, Ronald de Wit, F. Erdkamp, Maureen J.B. Aarts, Joanna Wójcik-Tomaszewska, Piotr Tomczak, Bożena Sikora-Kupis, Michael Schenker, Alina Amalia Herzal, Anghel Adrian Udrea, Petr Karlov, Sufia Safina, B. Yа. Alekseev, Andrey Semenov, Р Н Фомкин, Enrique Grande Pulido, Francisco Xavier García del Muro, Juan Ignacio Delgado Mignorance, D. Castellano Gauna, Alejo Rodríguez‐Vida, Yu‐Li Su, Yen‐Chuan Ou, Chien-Liang Lin, Wen-Pin Su, Chia‐Chi Lin, Su‐Peng Yeh, İrfan Çiçin, Hakan Harputluoğlu, Mustafa Erman, Hasan Şenol Çoşkun, Yüksel Ürün, Yurii Golovko, Igor Bondarenko, Ivan Sinielnikov, Thomas Powles, Simon J. Crabb, Isabel Syndikus, Robert Huddart, Santhanam Sundar, Simon Chowdhury, Naveed Sarwar, Alexandra Drakaki, Thomas W. Flaig, Chong Xian Pan, Daniel P. Petrylak, James K. Schwarz, Ivor Percent, Jennifer L. Cultrera, John D. Hainsworth, Benjamin Herms, William Lawler, T. E. Lowe, Scott T. Tagawa, Jeanny B. Aragon‐Ching, Ulka N. Vaishampayan,

Cancer Immunotherapy and Biomarkers

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/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. 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.