Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial

Hansjochen Wilke, Kei Muro, Eric Van Cutsem, Sang Cheul Oh, György Bodoky, Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto, Oleg Lipatov, Tae You Kim, David Cunningham, Philippe Rougier, Yoshito Komatsu, Jaffer Ajani, Michael Emig, Roberto Carlesi, David Ferry, Kumari Chandrawansa, Jonathan D. Schwartz, Atsushi Ohtsu

Research output: Contribution to journalArticle

948 Citations (Scopus)

Abstract

Background: VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel. Methods: This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase. Findings: Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5-10·8] vs 7·4 months [95% CI 6·3-8·4], hazard ratio 0·807 [95% CI 0·678-0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]). Interpretation: The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer. Funding: Eli Lilly and Company.

Original languageEnglish
Pages (from-to)1224-1235
Number of pages12
JournalThe Lancet Oncology
Volume15
Issue number11
DOIs
Publication statusPublished - 2014 Jan 1

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Paclitaxel
Stomach
Adenocarcinoma
Placebos
Stomach Neoplasms
Vascular Endothelial Growth Factor Receptor-2
Survival
ramucirumab
Therapeutics
Febrile Neutropenia
Intention to Treat Analysis
South America
Anthracyclines
Leukopenia
Random Allocation
North America
Neutropenia
Platinum
Abdominal Pain
Fatigue

ASJC Scopus subject areas

  • Oncology

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Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW) : A double-blind, randomised phase 3 trial. / Wilke, Hansjochen; Muro, Kei; Van Cutsem, Eric; Oh, Sang Cheul; Bodoky, György; Shimada, Yasuhiro; Hironaka, Shuichi; Sugimoto, Naotoshi; Lipatov, Oleg; Kim, Tae You; Cunningham, David; Rougier, Philippe; Komatsu, Yoshito; Ajani, Jaffer; Emig, Michael; Carlesi, Roberto; Ferry, David; Chandrawansa, Kumari; Schwartz, Jonathan D.; Ohtsu, Atsushi.

In: The Lancet Oncology, Vol. 15, No. 11, 01.01.2014, p. 1224-1235.

Research output: Contribution to journalArticle

Wilke, H, Muro, K, Van Cutsem, E, Oh, SC, Bodoky, G, Shimada, Y, Hironaka, S, Sugimoto, N, Lipatov, O, Kim, TY, Cunningham, D, Rougier, P, Komatsu, Y, Ajani, J, Emig, M, Carlesi, R, Ferry, D, Chandrawansa, K, Schwartz, JD & Ohtsu, A 2014, 'Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial', The Lancet Oncology, vol. 15, no. 11, pp. 1224-1235. https://doi.org/10.1016/S1470-2045(14)70420-6
Wilke, Hansjochen ; Muro, Kei ; Van Cutsem, Eric ; Oh, Sang Cheul ; Bodoky, György ; Shimada, Yasuhiro ; Hironaka, Shuichi ; Sugimoto, Naotoshi ; Lipatov, Oleg ; Kim, Tae You ; Cunningham, David ; Rougier, Philippe ; Komatsu, Yoshito ; Ajani, Jaffer ; Emig, Michael ; Carlesi, Roberto ; Ferry, David ; Chandrawansa, Kumari ; Schwartz, Jonathan D. ; Ohtsu, Atsushi. / Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW) : A double-blind, randomised phase 3 trial. In: The Lancet Oncology. 2014 ; Vol. 15, No. 11. pp. 1224-1235.
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author = "Hansjochen Wilke and Kei Muro and {Van Cutsem}, Eric and Oh, {Sang Cheul} and Gy{\"o}rgy Bodoky and Yasuhiro Shimada and Shuichi Hironaka and Naotoshi Sugimoto and Oleg Lipatov and Kim, {Tae You} and David Cunningham and Philippe Rougier and Yoshito Komatsu and Jaffer Ajani and Michael Emig and Roberto Carlesi and David Ferry and Kumari Chandrawansa and Schwartz, {Jonathan D.} and Atsushi Ohtsu",
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TY - JOUR

T1 - Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW)

T2 - A double-blind, randomised phase 3 trial

AU - Wilke, Hansjochen

AU - Muro, Kei

AU - Van Cutsem, Eric

AU - Oh, Sang Cheul

AU - Bodoky, György

AU - Shimada, Yasuhiro

AU - Hironaka, Shuichi

AU - Sugimoto, Naotoshi

AU - Lipatov, Oleg

AU - Kim, Tae You

AU - Cunningham, David

AU - Rougier, Philippe

AU - Komatsu, Yoshito

AU - Ajani, Jaffer

AU - Emig, Michael

AU - Carlesi, Roberto

AU - Ferry, David

AU - Chandrawansa, Kumari

AU - Schwartz, Jonathan D.

AU - Ohtsu, Atsushi

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background: VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel. Methods: This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase. Findings: Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5-10·8] vs 7·4 months [95% CI 6·3-8·4], hazard ratio 0·807 [95% CI 0·678-0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]). Interpretation: The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer. Funding: Eli Lilly and Company.

AB - Background: VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel. Methods: This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase. Findings: Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5-10·8] vs 7·4 months [95% CI 6·3-8·4], hazard ratio 0·807 [95% CI 0·678-0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]). Interpretation: The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer. Funding: Eli Lilly and Company.

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