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 journalArticle

48 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 - Nov 18 2017

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docetaxel
Platinum
Placebos
Carcinoma
Therapeutics
Disease-Free Survival
Vascular Endothelial Growth Factor Receptor-2
Research Personnel
ramucirumab
Sepsis

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

@article{ae5a3cb7654548a0ad6b1a8d9b300f43,
title = "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",
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.",
author = "{RANGE study investigators} and Petrylak, {Daniel P.} and {de Wit}, Ronald and Chi, {Kim N.} and Alexandra Drakaki and Sternberg, {Cora N.} and Hiroyuki Nishiyama and Daniel Castellano and Syed Hussain and Aude Fl{\'e}chon and Aristotelis Bamias and Yu, {Evan Y.} and {van der Heijden}, {Michiel S.} and Nobuaki Matsubara and Boris Alekseev and Andrea Necchi and Lajos G{\'e}czi and Ou, {Yen Chuan} and Coskun, {Hasan Senol} and Su, {Wen Pin} and Miriam Hegemann and Percent, {Ivor J.} and Lee, {Jae Lyun} and Marcello Tucci and Andrey Semenov and Fredrik Laestadius and Avivit Peer and Giampaolo Tortora and Sufia Safina and {del Muro}, {Xavier Garcia} and Alejo Rodriguez-Vida and Irfan Cicin and Hakan Harputluoglu and Widau, {Ryan C.} and Liepa, {Astra M.} and Walgren, {Richard A.} and Oday Hamid and Zimmermann, {Annamaria H.} and Bell-McGuinn, {Katherine M.} and Thomas Powles and Wong, {Suet Lai Shirley} and Tan, {Thean Hsiang} and Hovey, {Elizabeth Jane} and Clay, {Timothy Dudley} and Ng, {Siobhan Su Wan} and Annemie Rutten and Machiels, {Jean Pascal} and Herlinde Dumez and Cheng, {Susanna Yee Shan} and Cristiano Ferrario and Junichi Inokuchi",
year = "2017",
month = "11",
day = "18",
doi = "10.1016/S0140-6736(17)32365-6",
language = "English",
volume = "390",
pages = "2266--2277",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "10109",

}

TY - JOUR

T1 - Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE)

T2 - a randomised, double-blind, phase 3 trial

AU - RANGE study investigators

AU - Petrylak, Daniel P.

AU - de Wit, Ronald

AU - Chi, Kim N.

AU - Drakaki, Alexandra

AU - Sternberg, Cora N.

AU - Nishiyama, Hiroyuki

AU - Castellano, Daniel

AU - Hussain, Syed

AU - Fléchon, Aude

AU - Bamias, Aristotelis

AU - Yu, Evan Y.

AU - van der Heijden, Michiel S.

AU - Matsubara, Nobuaki

AU - Alekseev, Boris

AU - Necchi, Andrea

AU - Géczi, Lajos

AU - Ou, Yen Chuan

AU - Coskun, Hasan Senol

AU - Su, Wen Pin

AU - Hegemann, Miriam

AU - Percent, Ivor J.

AU - Lee, Jae Lyun

AU - Tucci, Marcello

AU - Semenov, Andrey

AU - Laestadius, Fredrik

AU - Peer, Avivit

AU - Tortora, Giampaolo

AU - Safina, Sufia

AU - del Muro, Xavier Garcia

AU - Rodriguez-Vida, Alejo

AU - Cicin, Irfan

AU - Harputluoglu, Hakan

AU - Widau, Ryan C.

AU - Liepa, Astra M.

AU - Walgren, Richard A.

AU - Hamid, Oday

AU - Zimmermann, Annamaria H.

AU - Bell-McGuinn, Katherine M.

AU - Powles, Thomas

AU - Wong, Suet Lai Shirley

AU - Tan, Thean Hsiang

AU - Hovey, Elizabeth Jane

AU - Clay, Timothy Dudley

AU - Ng, Siobhan Su Wan

AU - Rutten, Annemie

AU - Machiels, Jean Pascal

AU - Dumez, Herlinde

AU - Cheng, Susanna Yee Shan

AU - Ferrario, Cristiano

AU - Inokuchi, Junichi

PY - 2017/11/18

Y1 - 2017/11/18

N2 - 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.

AB - 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.

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U2 - 10.1016/S0140-6736(17)32365-6

DO - 10.1016/S0140-6736(17)32365-6

M3 - Article

VL - 390

SP - 2266

EP - 2277

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10109

ER -