title: Safety and efficacy of tigatuzumab plus sorafenib as first-line therapy in subjects with advanced hepatocellular carcinoma: A phase 2 randomized study.
abstract: OBJECTIVE
  Tigatuzumab is a humanized monoclonal antibody that acts as a death receptor-5 agonist and exerts tumour necrosis factor-related apoptosis-inducing ligand-like activity. In this phase II study, safety and tolerability of the combination of tigatuzumab and sorafenib was evaluated in patients with advanced hepatocellular carcinoma.
  
  
  METHODS
  Adults with advanced hepatocellular carcinoma, measurable disease, and an Eastern Cooperative Oncology Group performance score⩽1 were enrolled. Eligible subjects were randomly assigned 1:1:1 to tigatuzumab (6 mg/kg loading, 2 mg/kg/week maintenance) plus sorafenib 400 mg twice daily; tigatuzumab (6 mg/kg loading, 6 mg/kg/week maintenance) plus sorafenib 400 mg twice daily; or sorafenib 400 mg twice daily. The primary end point was time to progression. Secondary end points included overall survival and safety.
  
  
  RESULTS
  163 subjects were randomized to treatment. Median time to progression was 3.0 months in the tigatuzumab 6/2 mg/kg combination group (p=0.988 vs. sorafenib), 3.9 months in the tigatuzumab 6/6 mg/kg combination group (p=0.586 vs. sorafenib), and 2.8 months in the sorafenib alone group. Median overall survival was 12.2 months in the tigatuzumab 6/6 mg/kg combination group (p=0.659 vs. sorafenib), vs. 8.2 months in both other treatment groups (p=0.303, tigatuzumab 6/2 mg/kg combination vs. sorafenib). The most common treatment-emergent adverse events were palmar-plantar erythrodysesthesia syndrome, diarrhea, and decreased appetite.
  
  
  CONCLUSIONS
  Tigatuzumab combined with sorafenib vs. sorafenib alone in adults with advanced hepatocellular carcinoma did not meet its primary efficacy end point, although tigatuzumab plus sorafenib is well tolerated in hepatocellular carcinoma.
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: alcheng@ntu.edu.tw.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.affiliation: Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC, USA.
authors.forename: Aiwu Ruth
authors.initials: AR
authors.lastname: He
authors.affiliation: Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: Ho Yeong
authors.initials: HY
authors.lastname: Lim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Baek-Yeol
authors.initials: BY
authors.lastname: Ryoo
authors.affiliation: Chang Gung Medical Foundation-Kaohsiung, Kaohsiung, Taiwan.
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Hung
authors.affiliation: Chang Gung Medical Foundation-Linkuo, Taoyaun, Taiwan.
authors.forename: I-Shyan
authors.initials: IS
authors.lastname: Sheen
authors.affiliation: Japan Red Cross Musashino Hospital, Tokyo, Japan.
authors.forename: Namiki
authors.initials: N
authors.lastname: Izumi
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: TaShara
authors.initials: T
authors.lastname: Austin
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Greenberg
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Shiratori
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center and Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA; Department of Biostatistics, Bioinformatics, and Biomathematics, Lombardi Comprehensive Cancer Center and Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Beckman
authors.affiliation: Kinki University Hospital, Osaka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D040262:Receptors, Vascular Endothelial Growth Factor; D012189:Retrospective Studies; D000077157:Sorafenib; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; C552861:tigatuzumab; D009536:Niacinamide; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Advanced hepatocellular carcinoma; CS-1008; Combination therapy; Monoclonal antibody; Sorafenib; Tigatuzumab