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

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, diarrhea, 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 signaling as a potential new therapeutic treatment option for patients with urothelial carcinoma.

FUNDING: Eli Lilly and Company.

LANCET. 2017 September 12 [Epub ahead of print]

Daniel P Petrylak, MD,1 Ronald de Wit, PhD,2 Kim N Chi, MD,3 Alexandra Drakaki, PhD,4 Cora N Sternberg, MD,5 Hiroyuki Nishiyama, PhD,6 Daniel Castellano, MD,7 Syed Hussain, MD,8 Aude Fléchon, MD,9 Aristotelis Bamias, PhD,10 Evan Y Yu, MD,11 Michiel S van der Heijden, MD,12 Nobuaki Matsubara, MD,13 Boris Alekseev, PhD,14 Andrea Necchi, MD,15 Lajos Géczi, PhD,16 Yen-Chuan Ou, PhD,17 Hasan Senol Coskun, MD,18 Wen-Pin Su, PhD,19,20 Miriam Hegemann, MD,21 Ivor J Percent, MD,22 Jae-Lyun Lee, PhD,23 Marcello Tucci, MD,24 Andrey Semenov, PhD,25 Fredrik Laestadius, MD,26 Avivit Peer, MD,27 Giampaolo Tortora, PhD,28 Sufia Safina, MD,29 Xavier Garcia del Muro, PhD,30 Alejo Rodriguez-Vida, MD,31 Irfan Cicin, MD,32 Hakan Harputluoglu, MD,33 Ryan C Widau, PhD,34 Astra M Liepa, PharmD,34 Richard A Walgren, PhD,34 Oday Hamid, PharmD,34 Annamaria H Zimmermann, MS,34 Katherine M Bell-McGuinn, PhD,34 Thomas Powles, MD35 for the RANGE study Investigators

1. Yale School of Medicine, New Haven, Connecticut 
2. Erasmus MC Cancer Institute, Rotterdam, Netherlands
3. British Columbia Cancer Agency, Vancouver, BC, Canada
4. David Geffen School of Medicine, UCLA, Los Angeles, California
5. San Camillo and Forlanini Hospitals, Rome, Italy
6. University of Tsukuba, Tsukuba, Ibaraki, Japan
7. Hospital Universitario 12 de Octubre (CiberOnc), Madrid, Spain
8. Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom
9. Centre Léon Bérard, Lyon, France
10. National and Kapodistrian University of Athens, Athens, Greece
11. University of Washington, Seattle, Washington
12. Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
13. National Cancer Centre Hospital East, Chiba, Japan
14. PA Herzen Moscow Oncological Research Institute, Moscow, Russia
15. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
16. National Institute of Oncology, Budapest, Hungary
17. Taichung Veterans General Hospital, Taichung, Taiwan
18. Akdeniz University School of Medicine, Antalya, Turkey
19. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
20. Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan
21. University Hospital, Tübingen, Germany
22. Florida Cancer Specialists, Port Charlotte, Florida
23. Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Korea
24. Division of Medical Oncology, Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Turin, Italy
25. RBHI Ivanovo Regional Oncology Dispensary, Ivanovo, Russia
26. Centre Oscar Lambret, Lille, France
27. Rambam Health Care Campus, Haifa, Israel
28. University of Verona and Azienda Ospedaliera Universitaria Integrata, Verona, Italy
29. Tatarstan Regional Cancer Centre, Kazan, Russia
30. Institut Català d'Oncologia L'Hospitalet, IDIBELL, University of Barcelona, Barcelona, Spain
31. Hospital del Mar, Barcelona, Spain
32. Trakya University, Edirne, Turkey
33. Inonu University, Malatya, Turkey
34. Eli Lilly and Company, Indianapolis, Indiana 
35. Barts Cancer Institute, Queen Mary University of London, London, United Kingdom

The Lancet volume 390, issue 10109, P2266-2277; DOI:https://doi.org/10.1016/S0140-6736(17)32365-6
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