title: Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.
abstract: BACKGROUND
  Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy.
  
  
  METHODS
  In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973.
  
  
  RESULTS
  Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care.
  
  
  CONCLUSIONS
  Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC.
  
  
  BACKGROUND
  Eli Lilly.
authors.affiliation: David Geffen School of Medicine at UCLA/Translational Research in Oncology-US Network, Los Angeles, CA, USA. Electronic address: egaron@mednet.ucla.edu.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Garon
authors.affiliation: Institute of Oncology Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania.
authors.forename: Tudor-Eliade
authors.initials: TE
authors.lastname: Ciuleanu
authors.affiliation: Instituto Nacional de Cancerologia (INCAN), Mexico City, Mexico.
authors.forename: Oscar
authors.initials: O
authors.lastname: Arrieta
authors.affiliation: Tata Memorial Centre, Mumbai, India.
authors.forename: Kumar
authors.initials: K
authors.lastname: Prabhash
authors.affiliation: Oncology Unit GPP, Sotiria General Hospital, Athens School of Medicine, Athens, Greece.
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Syrigos
authors.affiliation: Ege University School of Medicine, Izmir, Turkey.
authors.forename: Tuncay
authors.initials: T
authors.lastname: Goksel
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Chemotherapy, N N Blokhin Cancer Research Center, Moscow, Russia.
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.affiliation: Centro de Investigaciones Clínicas, Clínica Viedma, Argentina.
authors.forename: Ruben Dario
authors.initials: RD
authors.lastname: Kowalyszyn
authors.affiliation: Wojewódzkie Centrum Onkologii, Gdansk, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Pikiel
authors.affiliation: Chemotherapy Department, John Paul II Hospital, Krakow, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Czyzewicz
authors.affiliation: Pavlov State Medical University, St Petersburg, Russia.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Orlov
authors.affiliation: Charing Cross Hospital, London, UK.
authors.forename: Conrad R
authors.initials: CR
authors.lastname: Lewanski
authors.affiliation: Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Medical Oncology, San Gerardo Hospital, Monza, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bidoli
authors.affiliation: Cancer Center of Kansas, Wichita, KS, USA.
authors.forename: Shaker
authors.initials: S
authors.lastname: Dakhil
authors.affiliation: St Jansdal Hospital, Herderwijk, Netherlands.
authors.forename: Steven
authors.initials: S
authors.lastname: Gans
authors.affiliation: Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea.
authors.forename: Joo-Hang
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Institute of Oncology, Bucharest, Romania.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Grigorescu
authors.affiliation: City Clinical Oncology Dispensary, St Petersburg, Russia.
authors.forename: Nina
authors.initials: N
authors.lastname: Karaseva
authors.affiliation: LungenClinic Grosshansdorf, German Center for Lung Research (DZL), Grosshansdorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.affiliation: Istituto Toscano Tumori, Livorno, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.affiliation: ImClone Systems, Eli Lilly, Bridgewater, NJ, USA.
authors.forename: Ekaterine
authors.initials: E
authors.lastname: Alexandris
authors.affiliation: Eli Lilly, Indianapolis, IN, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sashegyi
authors.affiliation: ImClone Systems, Eli Lilly, Bridgewater, NJ, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Yurasov
authors.affiliation: Léon-Bérard Cancer Centre, Lyon, France.
authors.forename: Maurice
authors.initials: M
authors.lastname: Pérol
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D000077143:Docetaxel; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010919:Placebos; D010984:Platinum; D011788:Quality of Life; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D000096662:Ramucirumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077143:Docetaxel; D010919:Placebos; D010984:Platinum; D043823:Taxoids; D000096662:Ramucirumab