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

RANGE study investigators

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)2266-2277
Number of pages12
JournalThe Lancet
Volume390
Issue number10109
DOIs
Publication statusPublished - 2017 Nov 18

Bibliographical note

Funding Information:
DPP reports grants from Eli Lilly and Company, during the conduct of the study; personal fees from Bayer, Bellicum, Dendreon, Sanofi-Aventis, Johnson & Johnson, Exelixis, Ferring, Millennium, Medivation, Pfizer, Roche Laboratories, and Tyme pharmaceuticals, outside the submitted work; grants from Oncogenix, Progenics, Johnson & Johnson, Merck, Millennium, Dendreon, Sanofi-Aventis, Agensys, Eli Lilly and Company, and Roche Laboratories, outside the submitted work; and ownership interest/investment from Bellicum and Tyme, outside the submitted work. RdW reports personal fees from Eli Lilly and Company, during the conduct of the study; and personal fees from Merck, Roche, and Sanofi, outside the submitted work. KNC reports institutional funding from Eli Lilly and Company, during the conduct of the study. CNS reports personal fees from Eli Lilly and Company, BMS, Merck/Pfizer, and Clovis, outside the submitted work. SH reports personal fees from Roche, Merck, AstraZeneca, Pierre Fabre, and Bayer, outside the submitted work. AF reports personal fees from AstraZeneca, MSD, Pierre Fabre, Pfizer, and Roche, outside the submitted work. AB reports personal fees from AstraZeneca and BMS, outside the submitted work; and grants and personal fees from Roche, outside the submitted work. EYY reports grants and personal fees from Eli Lilly and Company, during the conduct of the study; grants and personal fees from Agensys, Astellas, Bayer, Dendreon, Genentech/Roche, and Merck, outside the submitted work; and personal fees from AstraZeneca, Churchill Pharmaceuticals, EMD Serono, Ferring, Janssen, Medivation, Sanofi, Seattle Genetics, Tolmar, and Tokai, outside the submitted work. MSvdH reports personal fees from Roche/Genentech, AstraZeneca/Medimmune, and BMS, outside the submitted work; and grants and personal fees from Astellas, outside the submitted work. AN reports grants, personal fees, and non-financial support from Roche, during the conduct of the study; grants and personal fees from Merck and AstraZeneca, during the conduct of the study; and personal fees from Seattle Genetics and Bayer, during the conduct of the study. MT reports personal fees from Astellas, Sanofi, Bayer, and Janssen, outside the submitted work. AP reports consultancy fees from MSD, Bayer, BMS, Janssen, Astellas, Novartis, Roche, AstraZeneca, and Pfizer, outside the submitted work. XGdM reports personal fees from Pfizer, BMS, Eli Lilly and Company, Pharmamar, Novartis, Ipsen, and Roche, outside the submitted work. RCW, AML, OH, AHZ, and KMB-M are employees and shareholders at Eli Lilly and Company. RAW is an employee, shareholder, and has a patent pending (CA2961295A1) at Eli Lilly and Company. TP reports grants and research funding from Roche, outside the submitted work; grants from AstraZeneca, outside the submitted work; and personal fees from Roche, Merck, AstraZeneca, BMS, Eli Lilly and Company, and Pfizer, outside the submitted work. AD, HN, DC, NM, BA, LG, Y-CO, HSC, W-PS, MH, IJP, J-LL, AS, FL, GT, SS, AR-V, IC, and HH declare no competing interests.

Funding Information:
This study was funded by Eli Lilly and Company. We thank the patients, their families, and study personnel across all sites for participating in this study. Writing and editorial assistance were funded by Eli Lilly and Company.

Publisher Copyright:
© 2017 Elsevier Ltd

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this