title: Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial.
abstract: Transarterial chemoembolization (TACE) is the current standard of treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). Brivanib, a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor signaling, may improve the effectiveness of TACE when given as an adjuvant to TACE. In this multinational, randomized, double-blind, placebo-controlled, phase III study, 870 patients with TACE-eligible HCC were planned to be randomly assigned (1:1) after the first TACE to receive either brivanib 800 mg or placebo orally once-daily. The primary endpoint was overall survival (OS). Secondary endpoints included time to disease progression (TTDP; a composite endpoint based on development of extrahepatic spread or vascular invasion, deterioration of liver function or performance status, or death), time to extrahepatic spread or vascular invasion (TTES/VI), rate of TACE, and safety. Time to radiographic progression (TTP) and objective response rate were exploratory endpoints. The trial was terminated after randomization of 502 patients (brivanib, 249; placebo, 253) when two other phase III studies of brivanib in advanced HCC patients failed to meet OS objectives. At termination, median follow-up was approximately 16 months. Intention-to-treat analysis showed no improvement in OS with brivanib versus placebo (median, 26.4 [95% confidence interval {CI}: 19.1 to not reached] vs. 26.1 months [19.0-30.9]; hazard ratio [HR]: 0.90 [95% CI: 0.66-1.23]; log-rank P=0.5280). Brivanib improved TTES/VI (HR, 0.64 [95% CI: 0.45-0.90]), TTP (0.61 [0.48-0.77]), and rate of TACE (0.72 [0.61-0.86]), but not TTDP (0.94 [0.72-1.22]) versus placebo. Most frequent grade 3-4 adverse events included hyponatremia (brivanib, 18% vs. placebo, 5%) and hypertension (13% vs. 3%).
  
  
  CONCLUSIONS
  In this study, brivanib as adjuvant therapy to TACE did not improve OS.
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.forename: Guohong
authors.initials: G
authors.lastname: Han
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.forename: Jean-Frederic
authors.initials: JF
authors.lastname: Blanc
authors.forename: Lunan
authors.initials: L
authors.lastname: Yan
authors.forename: Jijin
authors.initials: J
authors.lastname: Yang
authors.forename: Ligong
authors.initials: L
authors.lastname: Lu
authors.forename: Won-Young
authors.initials: WY
authors.lastname: Tak
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yu
authors.forename: Joon-Hyeok
authors.initials: JH
authors.lastname: Lee
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Lin
authors.forename: Changping
authors.initials: C
authors.lastname: Wu
authors.forename: Tawesak
authors.initials: T
authors.lastname: Tanwandee
authors.forename: Guoliang
authors.initials: G
authors.lastname: Shao
authors.forename: Ian B
authors.initials: IB
authors.lastname: Walters
authors.forename: Christine
authors.initials: C
authors.lastname: Dela Cruz
authors.forename: Valerie
authors.initials: V
authors.lastname: Poulart
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D016461:Chemoembolization, Therapeutic; D017024:Chemotherapy, Adjuvant; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D017211:Treatment Failure; D014227:Triazines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D014227:Triazines; D042461:Vascular Endothelial Growth Factor A; C509922:brivanib; D000409:Alanine