title: Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma.
abstract: Angiogenesis inhibition by the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor sorafenib provides survival benefit in hepatocellular carcinoma (HCC); however, angiogenic escape from sorafenib may occur due to angiogenesis-associated fibroblast growth factor receptor (FGFR) pathway activation. In addition to VEGFR and PDGFR, dovitinib inhibits FGFR. Frontline oral dovitinib (500 mg/day, 5 days on, 2 days off; n = 82) versus sorafenib (400 mg twice daily; n = 83) was evaluated in an open-label, randomized phase 2 study of Asian-Pacific patients with advanced HCC. The primary and key secondary endpoints were overall survival (OS) and time to tumor progression (TTP) as determined by a local investigator, respectively. Patients included in the study were ineligible for surgical and/or locoregional therapies or had disease progression after receiving these therapies. The median OS (95% confidence interval [CI]) was 8.0 (6.6-9.1) months for dovitinib and 8.4 (5.4-11.3) months for sorafenib. The median TTP (95% CI) per investigator assessment was 4.1 (2.8-4.2) months and 4.1 (2.8-4.3) months for dovitinib and sorafenib, respectively. Common any-cause adverse events included diarrhea (62%), decreased appetite (43%), nausea (41%), vomiting (41%), fatigue (35%), rash (34%), and pyrexia (30%) for dovitinib and palmar-plantar erythrodysesthesia syndrome (66%) and decreased appetite (31%) for sorafenib. Subgroup analysis revealed a significantly higher median OS for patients in the dovitinib arm who had baseline plasma soluble VEGFR1 (sVEGFR1) and hepatocyte growth factor (HGF) below median levels versus at or above the median levels (median OS [95% CI]: sVEGFR1, 11.2 [9.0-13.8] and 5.7 [4.3-7.0] months, respectively [P = .0002]; HGF, 11.2 [8.9-13.8] and 5.9 [5.0-7.6] months, respectively [P = 0.0002]).
  
  
  
  Dovitinib was well tolerated, but activity was not greater than sorafenib as a frontline systemic therapy for HCC. Based on these data, no subsequent phase 3 study has been planned. (Hepatology 2016;64:774-784).
authors.affiliation: National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.affiliation: Chiangmai University, Chiangmai, Thailand.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Thongprasert
authors.affiliation: Samsung Medical Center, Seoul, South Korea.
authors.forename: Ho Yeong
authors.initials: HY
authors.lastname: Lim
authors.affiliation: Srinagarind Hospital, Khon Kaen, Thailand.
authors.forename: Wattana
authors.initials: W
authors.lastname: Sukeepaisarnjaroen
authors.affiliation: Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Tsai-Shen
authors.initials: TS
authors.lastname: Yang
authors.affiliation: Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Cheng-Chung
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yee
authors.initials: Y
authors.lastname: Chao
authors.affiliation: Prince of Wales Hospital and The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Chan
authors.affiliation: Kinki University School of Medicine, Osaka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.affiliation: National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Asan Medical Center, Seoul, South Korea.
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.affiliation: Sir Run Run Shaw Hospital, Zhejiang University Medical College, Zhejiang, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Pan
authors.affiliation: Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Numata
authors.affiliation: Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Han
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ.
authors.forename: Binaifer
authors.initials: B
authors.lastname: Balsara
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Ana-Marie
authors.initials: AM
authors.lastname: Rodriguez
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ.
authors.forename: Yongyu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Queen Mary Hospital, Pok Fu Lam, Hong Kong.
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D045744:Cell Line, Tumor; D005202:Asia, Eastern / Q000453:epidemiology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008875:Middle Aged; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015363:Quinolones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077157:Sorafenib; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D015415:Biomarkers; D010671:Phenylurea Compounds; D015363:Quinolones; D009536:Niacinamide; D000077157:Sorafenib