title: Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.
abstract: BACKGROUND
  VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib.
  
  
  METHODS
  In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347.
  
  
  RESULTS
  Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression.
  
  
  CONCLUSIONS
  Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable.
  
  
  BACKGROUND
  Eli Lilly and Co.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. Electronic address: azhu@partners.org.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.affiliation: Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.affiliation: Asan Medical Center, University of Ulsan School of Medicine, Seoul, South Korea.
authors.forename: Baek-Yeol
authors.initials: BY
authors.lastname: Ryoo
authors.affiliation: National Cheng Kung University Hospital, Tainan City, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: The University of Hong Kong, Hong Kong.
authors.forename: Ronnie
authors.initials: R
authors.lastname: Poon
authors.affiliation: Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Pastorelli
authors.affiliation: Hopital Saint-Andre, Bordeaux, France.
authors.forename: Jean-Frederic
authors.initials: JF
authors.lastname: Blanc
authors.affiliation: Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea.
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
authors.affiliation: California Pacific Medical Center, San Francisco, CA, USA.
authors.forename: Ari D
authors.initials: AD
authors.lastname: Baron
authors.affiliation: Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil.
authors.forename: Tulio Eduardo Flesch
authors.initials: TE
authors.lastname: Pfiffer
authors.affiliation: National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.affiliation: University Hospital in Motol, Prague, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kubackova
authors.affiliation: University Hospital Cancer Center, Frankfurt, Germany.
authors.forename: Jorg
authors.initials: J
authors.lastname: Trojan
authors.affiliation: Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Sastre
authors.affiliation: Royal Marsden Hospital, Surrey, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Chau
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Chang
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Paolo B
authors.initials: PB
authors.lastname: Abada
authors.affiliation: Eli Lilly and Company, Bridgewater, NJ, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Stemline Therapeutics Inc, New York, NY, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schwartz
authors.affiliation: Kinki University School of Medicine, Osaka-Sayama City, Osaka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016001:Confidence Intervals; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018579:Patient Selection; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D012074:Remission Induction; D000077157:Sorafenib; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D000096662:Ramucirumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009536:Niacinamide; D010671:Phenylurea Compounds; D000077157:Sorafenib; D000096662:Ramucirumab