title: 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.
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/m(2) 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.
  
  
  RESULTS
  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%]).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Eli Lilly and Company.
authors.affiliation: Department of Medical Oncology/Haematology, Kliniken Essen-Mitte, Germany. Electronic address: h.wilke@kliniken-essen-mitte.de.
authors.forename: Hansjochen
authors.initials: H
authors.lastname: Wilke
authors.affiliation: Aichi Cancer Center Hospital, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Muro
authors.affiliation: University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Korea University Guro Hospital, Seoul, South Korea.
authors.forename: Sang-Cheul
authors.initials: SC
authors.lastname: Oh
authors.affiliation: St László Hospital, Department of Oncology, Budapest Gastrointestinal Medical Oncology, Budapest, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Bodoky
authors.affiliation: National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Clinical Trial Promotion Department, Chiba Cancer Center, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hironaka
authors.affiliation: Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan.
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Sugimoto
authors.affiliation: Republican Clinical Oncology Dispensary, Ufa, Russia.
authors.forename: Oleg
authors.initials: O
authors.lastname: Lipatov
authors.affiliation: Seoul National University Cancer Hospital, Seoul, South Korea.
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: Centre Hospitalier Universitaire Georges Pompidou Assistance Publique-Hôpitaux de Paris, Université Paris V, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rougier
authors.affiliation: Hokkaido University Hospital Cancer Center, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Komatsu
authors.affiliation: University of Texas M D Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jaffer
authors.initials: J
authors.lastname: Ajani
authors.affiliation: Eli Lilly Deutschland, Bad Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Emig
authors.affiliation: Eli Lilly Italia, Sesto Fiorentino, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Carlesi
authors.affiliation: New Cross Hospital, Wolverhampton, UK.
authors.forename: David
authors.initials: D
authors.lastname: Ferry
authors.affiliation: Eli Lilly and Company, Bridgewater, NJ, USA.
authors.forename: Kumari
authors.initials: K
authors.lastname: Chandrawansa
authors.affiliation: Stemline Therapeutics, New York, NY, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schwartz
authors.affiliation: Gastrointestinal, Oncology, National Cancer Center Hospital East, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016001:Confidence Intervals; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004943:Esophagogastric Junction / Q000473:pathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D011379:Prognosis; D016016:Proportional Hazards Models; D012074:Remission Induction / Q000379:methods*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome; D000096662:Ramucirumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017239:Paclitaxel; D000096662:Ramucirumab