부산대학교 도서관

To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/S0140-6736(17)32365-6 Byline: Prof Daniel P Petrylak, MD [daniel.petrylak@yale.edu] (a,*), Prof Ronald de Wit, PhD (b), Prof Kim N Chi, MD (c), Alexandra Drakaki, PhD (d), Prof Cora N Sternberg, MD (e), Prof Hiroyuki Nishiyama, PhD (f), Daniel Castellano, MD (g), Prof Syed Hussain, MD (h), Aude Flechon, MD (i), Prof Aristotelis Bamias, PhD (j), Prof Evan Y Yu, MD (k), Prof Michiel S van der Heijden, MD (l), Nobuaki Matsubara, MD (m), Prof Boris Alekseev, PhD (n), Andrea Necchi, MD (o), Lajos Geczi, PhD (p), Prof Yen-Chuan Ou, PhD (q), Prof Hasan Senol Coskun, MD (r), Prof Wen-Pin Su, PhD (s,t), Miriam Hegemann, MD (u), Ivor J Percent, MD (v), Prof Jae-Lyun Lee, PhD (w), Marcello Tucci, MD (x), Andrey Semenov, PhD (y), Fredrik Laestadius, MD (z), Avivit Peer, MD (aa), Prof Giampaolo Tortora, PhD (ab), Sufia Safina, MD (ac), Xavier Garcia del Muro, PhD (ad), Alejo Rodriguez-Vida, MD (ae), Prof Irfan Cicin, MD (af), Prof Hakan Harputluoglu, MD (ag), Ryan C Widau, PhD (ah), Astra M Liepa, PharmD (ah), Richard A Walgren, PhD (ah), Oday Hamid, PharmD (ah), Annamaria H Zimmermann, MS (ah), Katherine M Bell-McGuinn, PhD (ah), Prof Thomas Powles, MD (ai), 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, Fredrik Laestadius, Florence Joly, Aude Flechon, Stephane Culine, Catherine Becht, Gunter Niegisch, Michael Stockle, Marc-Oliver Grimm, Georgios Gakis, Wolfgang Schultze-Seemann, Haralambos Kalofonos, Dimitrios Mavroudis, Christos Papandreou, Vasilis Karavasilis, Aristotelis Bamias, Janos Revesz, Lajos Geczi, Eli Rosenbaum, Raya Leibowitz-Amit, Daniel Kejzman, Avivit Peer, David Sarid, Giorgio Vittorio Scagliotti, Cora N Sternberg, Giampaolo Tortora, Sergio Bracarda, Andrea Necchi, Francesco Massari, Takahiro Osawa, Naoto Miyajima, Nobuo Shinohara, Fumimasa Fukuta, Chikara Ohyama, 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 Cortes, Claudia Lorena Urzua Flores, Reinoud J B Blaisse, Michiel S van der Heijden, Ronald de Wit, 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, Boris Alekseev, Andrey Semenov, Roman Fomkin, Enrique Grande Pulido, F Xavier Garcia Del Muro, Juan Ignacio Delgado Mignorance, Daniel Castellano Gauna, Alejo Rodriguez-Vida, Yu-Li Su, Yen-Chuan Ou, Chien-Liang Lin, Wen-Pin Su, Chia-Chi Lin, Su-Peng Yeh, Irfan Cicin, Hakan Harputluoglu, Mustafa Erman, Hasan Senol Coskun, Yuksel Urun, Yurii Golovko, Igor Bondarenko, Ivan Sinielnikov, Thomas Powles, Simon Crabb, Isabel Syndikus, Robert Huddart, Santhanam Sundar, Simon Chowdhury, Naveed Sarwar, Alexandra Drakaki, 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 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.sup.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. Author Affiliation: (a) Yale University School of Medicine, New Haven, CT, USA (b) Erasmus MC Cancer Institute, Rotterdam, Netherlands (c) British Columbia Cancer Agency, Vancouver, BC, Canada (d) David Geffen School of Medicine, UCLA, Los Angeles, CA, USA (e) San Camillo and Forlanini Hospitals, Rome, Italy (f) University of Tsukuba, Tsukuba, Ibaraki, Japan (g) Hospital Universitario 12 de Octubre (CiberOnc), Madrid, Spain (h) Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK (i) Centre Leon Berard, Lyon, France (j) National and Kapodistrian University of Athens, Athens, Greece (k) University of Washington, Seattle, WA, USA (l) Netherlands Cancer Institute--Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (m) National Cancer Centre Hospital East, Chiba, Japan (n) PA Herzen Moscow Oncological Research Institute, Moscow, Russia (o) Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (p) National Institute of Oncology, Budapest, Hungary (q) Taichung Veterans General Hospital, Taichung, Taiwan (r) Akdeniz University School of Medicine, Antalya, Turkey (s) Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan (t) Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan (u) University Hospital, Tubingen, Germany (v) Florida Cancer Specialists, Port Charlotte, FL, USA (w) Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Korea (x) Division of Medical Oncology, Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy (y) RBHI Ivanovo Regional Oncology Dispensary, Ivanovo, Russia (z) Centre Oscar Lambret, Lille, France (aa) Rambam Health Care Campus, Haifa, Israel (ab) University of Verona and Azienda Ospedaliera Universitaria Integrata, Verona, Italy (ac) Tatarstan Regional Cancer Centre, Kazan, Russia (ad) Institut Catala d'Oncologia L'Hospitalet, IDIBELL, University of Barcelona, Barcelona, Spain (ae) Hospital del Mar, Barcelona, Spain (af) Trakya University, Edirne, Turkey (ag) Inonu University, Malatya, Turkey (ah) Eli Lilly and Company, Indianapolis, IN, USA (ai) Barts Cancer Institute, Queen Mary University of London, London, UK * Correspondence to: Prof Daniel P Petrylak, Yale School of Medicine, New Haven, CT 06520, USA (footnote)[Dagger] A full list of investigators is provided in the