title: Ramucirumab as Second-Line Treatment in Patients With Advanced Hepatocellular Carcinoma: Analysis of REACH Trial Results by Child-Pugh Score.
abstract: OBJECTIVE
  REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential ramucirumab survival benefit, severity of liver disease, and baseline α-fetoprotein (αFP).
  
  
  OBJECTIVE
  To assess treatment effects and tolerability of ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial.
  
  
  METHODS
  Randomized, double-blind, phase 3 trial of ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis; 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8).
  
  
  METHODS
  Ramucirumab (8 mg/kg) or placebo intravenously plus best supportive care every 2 weeks.
  
  
  METHODS
  Overall survival (OS), defined as time from randomization to death from any cause.
  
  
  RESULTS
  In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80; 95% CI, 0.63-1.02; P = .06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline αFP levels of 400 ng/mL (to convert ng/mL to μg/L, multiply by 1.0) or more, a ramucirumab OS benefit was significant for a score of Child-Pugh 5 (HR, 0.61; 95% CI, 0.43-0.87; P = .01) and Child-Pugh 6 (HR, 0.64; 95% CI, 0.42-0.98; P = .04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment-emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6.
  
  
  CONCLUSIONS
  In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline αFP levels of 400 ng/mL or more, a ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline αFP levels of 400 ng/mL or more.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01140347.
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.affiliation: California Pacific Medical Center, San Francisco.
authors.forename: Ari David
authors.initials: AD
authors.lastname: Baron
authors.affiliation: Otto von Guericke University of Magdeburg, Magdeburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Malfertheiner
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Masatoshi
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authors.lastname: Kudo
authors.affiliation: Saga-Ken Medical Centre Koseikan, Saga, Japan.
authors.forename: Seiji
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authors.lastname: Kawazoe
authors.affiliation: Surgery Department CHU Estaing, Clermond Ferrand, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Pezet
authors.affiliation: Evangelisches Krankenhaus Bielefeld, Bielefeld, Germany.
authors.forename: Florian
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authors.lastname: Weissinger
authors.affiliation: Policlinico Sant' Orsola-Malpighi, Bologna, Italy.
authors.forename: Giovanni
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authors.lastname: Brandi
authors.affiliation: Catholic University of Sacred Heart, Rome, Italy.
authors.forename: Carlo A
authors.initials: CA
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authors.affiliation: Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takuji
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authors.lastname: Okusaka
authors.affiliation: National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.
authors.forename: Yoshiyuki
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authors.lastname: Wada
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Baek-Yeol
authors.initials: BY
authors.lastname: Ryoo
authors.affiliation: Gangnam Severance Hospital, Seoul, South Korea.
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Cho
authors.affiliation: Yonsei Cancer Center, Cancer Metastasis Research Center, Yonsei University College of Medicine, Shinchon-Dong, South Korea.
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan17National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Li
authors.affiliation: National Cheng Kung University Hospital, Tainan City, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Kuan-Der
authors.initials: KD
authors.lastname: Lee
authors.affiliation: Eli Lilly and Company, Bridgewater, New Jersey.
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Chang
authors.affiliation: AstraZeneca Pharmaceuticals, Wilmington, Delaware.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Paolo B
authors.initials: PB
authors.lastname: Abada
authors.affiliation: Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Chau