title: Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma.
abstract: The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC).
  
  
  
  Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS).
  
  
  
  The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival.
  
  
  
  Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC.
  
  
  
  ClinicalTrials.gov, NCT01210495.
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea ykkang@amc.seoul.kr.
authors.forename: Y-K
authors.initials: YK
authors.lastname: Kang
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: T
authors.initials: T
authors.lastname: Yau
authors.affiliation: National Cancer Center/Center for Liver Cancer, Goyang-si.
authors.forename: J-W
authors.initials: JW
authors.lastname: Park
authors.affiliation: Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: H Y
authors.initials: HY
authors.lastname: Lim
authors.affiliation: Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: T-Y
authors.initials: TY
authors.lastname: Lee
authors.affiliation: Department of Hepatology, Sasaki Foundation Kyoundo Hospital, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Obi
authors.affiliation: State Key Laboratory in Oncology of South China, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong.
authors.forename: S L
authors.initials: SL
authors.lastname: Chan
authors.affiliation: Nanjing Bayi Hospital, Nanjing, China.
authors.forename: Sk
authors.initials: S
authors.lastname: Qin
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa.
authors.forename: R D
authors.initials: RD
authors.lastname: Kim
authors.affiliation: Pfizer Inc, Collegeville.
authors.forename: M
authors.initials: M
authors.lastname: Casey
authors.affiliation: Pfizer Inc, New York.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Pfizer Inc, New York.
authors.forename: H
authors.initials: H
authors.lastname: Bhattacharyya
authors.affiliation: Pfizer Oncology, San Diego, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Williams
authors.affiliation: Pfizer srl, Milan, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Valota
authors.affiliation: Pfizer Inc, Collegeville.
authors.forename: D
authors.initials: D
authors.lastname: Chakrabarti
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Hospital, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kudo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077784:Axitinib; D006528:Carcinoma, Hepatocellular / Q000401:mortality* / Q000628:therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007191:Indazoles / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000401:mortality* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D010166:Palliative Care / Q000379:methods* / Q000639:trends; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome
chemical_list: D007093:Imidazoles; D007191:Indazoles; D000077784:Axitinib
keywords: antiangiogenic therapy; axitinib; best supportive care; hepatocellular carcinoma