title: Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study.
abstract: OBJECTIVE
  Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib.
  
  
  METHODS
  In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety.
  
  
  RESULTS
  Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%).
  
  
  CONCLUSIONS
  In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.
authors: Josep M. Llovet and Charissa Chang, Icahn School of Medicine at Mount Sinai, New York, NY; Josep M. Llovet and Jordi Bruix, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) -Hospital Clinic, University of Barcelona, Barcelona, Spain; Thomas Decaens, University of Paris-Est, and Institut National de la Santé et de la Recherche Médicale, Creteil; Jean-Luc Raoul, Institut Paoli Calmette, Marseille; Eveline Boucher, Service d'Oncologie Médicale, Central Eugene Marquis, Rennes; Eric Assenat, Hôpital Saint Eloi, Montpellier; Valerie Boige, Institut Gustave Roussy, Villejuif; Philippe Mathurin, Hôpital Claude Huriez, Lille; Laetitia Fartoux, Hôpital Saint Antoine, Paris; Jean-Frederic Blanc, Saint-Andre Hospital, Bordeaux, France; Masatoshi Kudo, Kinki University School of Medicine, Osaka, Japan; Yoon-Koo Kang, Asan Medical Center; Ho-Yeong Lim, Samsung Medical Center, Seoul; Won-Young Tak, Kyungpook National University Hospital, Daegu; Joong-Won Park, National Cancer Center, Goyang, Republic of Korea; Deng-Yn Lin, Chang Gung Memorial Hospital and Chang Gung University; Yee Chao, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China; Ronnie T. Poon, University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China; Morris Sherman, Toronto General Hospital, Toronto, Ontario, Canada; Richard S. Finn, University of California at Los Angeles, Los Angeles, CA; and Rana Ezzeddine, David Liu, and Ian Walters, Bristol-Myers Squibb, Wallingford, CT.
authors: Josep M
authors: JM
authors: Llovet
authors: Thomas
authors: T
authors: Decaens
authors: Jean-Luc
authors: JL
authors: Raoul
authors: Eveline
authors: E
authors: Boucher
authors: Masatoshi
authors: M
authors: Kudo
authors: Charissa
authors: C
authors: Chang
authors: Yoon-Koo
authors: YK
authors: Kang
authors: Eric
authors: E
authors: Assenat
authors: Ho-Yeong
authors: HY
authors: Lim
authors: Valerie
authors: V
authors: Boige
authors: Philippe
authors: P
authors: Mathurin
authors: Laetitia
authors: L
authors: Fartoux
authors: Deng-Yn
authors: DY
authors: Lin
authors: Jordi
authors: J
authors: Bruix
authors: Ronnie T
authors: RT
authors: Poon
authors: Morris
authors: M
authors: Sherman
authors: Jean-Frédéric
authors: JF
authors: Blanc
authors: Richard S
authors: RS
authors: Finn
authors: Won-Young
authors: WY
authors: Tak
authors: Yee
authors: Y
authors: Chao
authors: Rana
authors: R
authors: Ezzeddine
authors: David
authors: D
authors: Liu
authors: Ian
authors: I
authors: Walters
authors: Joong-Won
authors: JW
authors: Park
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; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000009:adverse effects*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D016879:Salvage Therapy; 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