title: Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.
abstract: OBJECTIVE
  Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC.
  
  
  METHODS
  Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety.
  
  
  RESULTS
  The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively.
  
  
  CONCLUSIONS
  Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.
authors: Philip J. Johnson, University of Birmingham, Birmingham, United Kingdom; Shukui Qin, Nanjing Bayi Hospital, Nanjing; Jianming Xu, 307 Hospital of PLA, Beijing; Ligong Lu, Guangdong Provincial People's Hospital, Guangdong; Lunan Yan, West China Hospital of Sichuan University, Chengdu; Ronnie T.P. Poon, University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China; Joong Won Park, Center for Liver Cancer, National Cancer Center, Goyang; Jeong Heo, Pusan National University School of Medicine, Pusan; Kwang Hyub Han, Yonsei University College of Medicine; Seung Woon Paik, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Won Young Tak, Kyungpook National University Hospital, Daegu, Republic of Korea; Jean-Luc Raoul, Institut Paoli Calmettes, Marseille; Eveline Boucher, Central Eugene Marquis, Rennes Cedex, Rennes; Thomas Decaens, Hôpital Henri Mondor, University of Paris-Est, and INSERM, Creteil Cedex, Creteil, France; Philip A. Philip, Karmanos Cancer Center, Detroit, MI; David Liu, Rana Ezzeddine, Ian Walters, Bristol-Myers Squibb, Princeton, NJ; Chih-Hung Hsu, Ann-Lii Cheng, National Taiwan University Hospital; Yee Chao, Cancer Center, Taipei Veterans General Hospital, Taipei; Tsung-Hui Hu, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung; Long-Bin Jeng, China Medical University Hospital, Taichung, Taiwan, Republic of China; Jorge Robles-Aviña, High Specialty Central South Hospital, Mexico City, Mexico; Masatoshi Kudo, Kinki University School of Medicine, Osaka, Japan; Abhasnee Sobhonslidsuk, Ramathibodi Hospital, Bangkok, Thailand; Dmitriy Komov, N.N. Blokhin Cancer Research Center, Moscow, Russia.
authors: Philip J
authors: PJ
authors: Johnson
authors: Shukui
authors: S
authors: Qin
authors: Joong-Won
authors: JW
authors: Park
authors: Ronnie T P
authors: RT
authors: Poon
authors: Jean-Luc
authors: JL
authors: Raoul
authors: Philip A
authors: PA
authors: Philip
authors: Chih-Hung
authors: CH
authors: Hsu
authors: Tsung-Hui
authors: TH
authors: Hu
authors: Jeong
authors: J
authors: Heo
authors: Jianming
authors: J
authors: Xu
authors: Ligong
authors: L
authors: Lu
authors: Yee
authors: Y
authors: Chao
authors: Eveline
authors: E
authors: Boucher
authors: Kwang-Hyub
authors: KH
authors: Han
authors: Seung-Woon
authors: SW
authors: Paik
authors: Jorge
authors: J
authors: Robles-Aviña
authors: Masatoshi
authors: M
authors: Kudo
authors: Lunan
authors: L
authors: Yan
authors: Abhasnee
authors: A
authors: Sobhonslidsuk
authors: Dmitry
authors: D
authors: Komov
authors: Thomas
authors: T
authors: Decaens
authors: Won-Young
authors: WY
authors: Tak
authors: Long-Bin
authors: LB
authors: Jeng
authors: David
authors: D
authors: Liu
authors: Rana
authors: R
authors: Ezzeddine
authors: Ian
authors: I
authors: Walters
authors: Ann-Lii
authors: AL
authors: Cheng
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D000077157:Sorafenib; D015996:Survival Rate; D014227:Triazines / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D014227:Triazines; D009536:Niacinamide; D000077157:Sorafenib; C509922:brivanib; D000409:Alanine