title: Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study.
abstract: BACKGROUND
  Angiogenesis is an important therapeutic target in colorectal carcinoma. Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2. We assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) for metastatic colorectal cancer in patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
  
  
  METHODS
  Between Dec 14, 2010, and Aug 23, 2013, we enrolled patients into the multicentre, randomised, double-blind, phase 3 RAISE trial. Eligible patients had disease progression during or within 6 months of the last dose of first-line therapy. Patients were randomised (1:1) via a centralised, interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression, unacceptable toxic effects, or death. Randomisation was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01183780.ld
  
  
  RESULTS
  We enrolled 1072 patients (536 in each group). Median overall survival was 13·3 months (95% CI 12·4-14·5) for patients in the ramucirumab group versus 11·7 months (10·8-12·7) for the placebo group (hazard ratio 0·844 95% CI 0·730-0·976; log-rank p=0·0219). Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI. Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia (203 [38%] of 529 patients in the ramucirumab group vs 123 [23%] of 528 in the placebo group, with febrile neutropenia incidence of 18 [3%] vs 13 [2%]), hypertension (59 [11%] vs 15 [3%]), diarrhoea (57 [11%] vs 51 [10%]), and fatigue (61 [12%] vs 41 [8%]).
  
  
  CONCLUSIONS
  Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma. No unexpected adverse events were identified and toxic effects were manageable.
  
  
  BACKGROUND
  Eli Lilly.
authors: Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address: jtabernero@vhio.net.
authors: Josep
authors: J
authors: Tabernero
authors: Department of Gastroenterology, National Cancer Centre Hospital East, Chiba, Japan.
authors: Takayuki
authors: T
authors: Yoshino
authors: Rocky Mountain Cancer Center/US Oncology, Denver, CO, USA.
authors: Allen Lee
authors: AL
authors: Cohn
authors: Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors: Radka
authors: R
authors: Obermannova
authors: Department of Oncology, Szent László Hospital, Budapest, Hungary.
authors: Gyorgy
authors: G
authors: Bodoky
authors: Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla, RTICC, Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, Spain.
authors: Rocio
authors: R
authors: Garcia-Carbonero
authors: Prof Dr Ion Chiricuta Institute of Oncology and UMF Iuliu Hatieganu, Cluj-Napoca, Romania.
authors: Tudor-Eliade
authors: TE
authors: Ciuleanu
authors: West Clinic, Memphis, TN, USA.
authors: David C
authors: DC
authors: Portnoy
authors: University Hospitals Gasthuisberg, Leuven, Belgium.
authors: Eric
authors: E
authors: Van Cutsem
authors: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors: Axel
authors: A
authors: Grothey
authors: University Hospital Motol, Prague, Czech Republic.
authors: Jana
authors: J
authors: Prausová
authors: Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors: Pilar
authors: P
authors: Garcia-Alfonso
authors: Shizuoka Cancer Centre, Shizuoka, Japan.
authors: Kentaro
authors: K
authors: Yamazaki
authors: Southern Medical Day Care Centre, Wollongong, NSW, Australia.
authors: Philip R
authors: PR
authors: Clingan
authors: Medical Oncology 1, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.
authors: Sara
authors: S
authors: Lonardi
authors: Department of Oncology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea.
authors: Tae Won
authors: TW
authors: Kim
authors: Eli Lilly Canada, Toronto, ON, Canada.
authors: Lorinda
authors: L
authors: Simms
authors: Eli Lilly, Indianapolis, IN, USA.
authors: Shao-Chun
authors: SC
authors: Chang
authors: Eli Lilly and Company, Bridgewater, NJ, USA.
authors: Federico
authors: F
authors: Nasroulah
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D000096662:Ramucirumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002166:Camptothecin; D005472:Fluorouracil; D002955:Leucovorin; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000096662:Ramucirumab