Daniel P Petrylak1, Ronald de Wit2, Kim N Chi3, Alexandra Drakaki4, Cora N Sternberg5, Hiroyuki Nishiyama6, Daniel Castellano7, Syed Hussain8, Aude Fléchon9, Aristotelis Bamias10, Evan Y Yu11, Michiel S van der Heijden12, Nobuaki Matsubara13, Boris Alekseev14, Andrea Necchi15, Lajos Géczi16, Yen-Chuan Ou17, Hasan Senol Coskun18, Wen-Pin Su19, Miriam Hegemann20, Ivor J Percent21, Jae-Lyun Lee22, Marcello Tucci23, Andrey Semenov24, Fredrik Laestadius25, Avivit Peer26, Giampaolo Tortora27, Sufia Safina28, Xavier Garcia Del Muro29, Alejo Rodriguez-Vida30, Irfan Cicin31, Hakan Harputluoglu32, Ryan C Widau33, Astra M Liepa33, Richard A Walgren33, Oday Hamid33, Annamaria H Zimmermann33, Katherine M Bell-McGuinn33, Thomas Powles34. 1. Yale University School of Medicine, New Haven, CT, USA. Electronic address: daniel.petrylak@yale.edu. 2. Erasmus MC Cancer Institute, Rotterdam, Netherlands. 3. British Columbia Cancer Agency, Vancouver, BC, Canada. 4. David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. 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, UK. 9. Centre Léon Bérard, Lyon, France. 10. National and Kapodistrian University of Athens, Athens, Greece. 11. University of Washington, Seattle, WA, USA. 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; Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan. 20. University Hospital, Tübingen, Germany. 21. Florida Cancer Specialists, Port Charlotte, FL, USA. 22. Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Korea. 23. Division of Medical Oncology, Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy. 24. RBHI Ivanovo Regional Oncology Dispensary, Ivanovo, Russia. 25. Centre Oscar Lambret, Lille, France. 26. Rambam Health Care Campus, Haifa, Israel. 27. University of Verona and Azienda Ospedaliera Universitaria Integrata, Verona, Italy. 28. Tatarstan Regional Cancer Centre, Kazan, Russia. 29. Institut Català d'Oncologia L'Hospitalet, IDIBELL, University of Barcelona, Barcelona, Spain. 30. Hospital del Mar, Barcelona, Spain. 31. Trakya University, Edirne, Turkey. 32. Inonu University, Malatya, Turkey. 33. Eli Lilly and Company, Indianapolis, IN, USA. 34. Barts Cancer Institute, Queen Mary University of London, London, UK.
Abstract
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 allocatedramucirumab 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 allocatedramucirumab 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.
RCT Entities:
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-ahuman 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.
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