title: Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma.
abstract: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy.
  
  
  
  Patients with advanced HCC who had failed prior systemic therapy, ⩾18years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis.
  
  
  
  185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p=0.87), and 8.7 vs. 10 (hazard ratios 0.96, p=0.82). Projected Ctrough at cycle 3day 1 based exposure, high CD16/FcγRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival.
  
  
  
  Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions.
  
  
  
  Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome.
  
  
  
  This trial is registered at Clinicaltrials.gov (NCT01507168).
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: abou-alg@mskcc.org.
authors.forename: Ghassan K
authors.initials: GK
authors.lastname: Abou-Alfa
authors.affiliation: Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Puig
authors.affiliation: G. Rummo Hospital, Benevento, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Daniele
authors.affiliation: Kinki University Hospital, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Hopital de la Croix-Rousse, Hepatologie et Gastroenterologie, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Merle
authors.affiliation: National Cancer Center, Republic of Korea.
authors.forename: Joong-Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: King's College Hospital, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Ross
authors.affiliation: Hopital Purpan, Gastro Enterologie Hepatologie, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Peron
authors.affiliation: II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Ebert
authors.affiliation: Prince of Wales Hospital, Hong Kong.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.affiliation: Queen Mary Hospital, Hong Kong.
authors.forename: Tung Ping
authors.initials: TP
authors.lastname: Poon
authors.affiliation: Fondazione IRCCS Ospedale Maggiore Policlinico, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Colombo
authors.affiliation: National Cancer Center Hospital, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.affiliation: Asan Medical Center, Republic of Korea.
authors.forename: Baek-Yeol
authors.initials: BY
authors.lastname: Ryoo
authors.affiliation: Liver Unit, Hospital Universitario Vall d́Hebron, Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Minguez
authors.affiliation: Chugai Pharmaceutical Co. Ltd., Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Chugai Pharmaceutical Co. Ltd., Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ohtomo
authors.affiliation: Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Ukrainskyj
authors.affiliation: Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Boisserie
authors.affiliation: Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Rutman
authors.affiliation: Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Roche Innovation Center Basel, Hoffmann-La Roche, Switzerland.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Shochat
authors.affiliation: Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Jukofsky
authors.affiliation: Roche Innovation Center Basel, Hoffmann-La Roche, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Reis
authors.affiliation: Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Di Laurenzio
authors.affiliation: Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
authors.forename: Ray
authors.initials: R
authors.lastname: Lee
authors.affiliation: National Cheng-Kung Univ. Hospital, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
mesh_terms: D061067:Antibodies, Monoclonal, Humanized; D006528:Carcinoma, Hepatocellular; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D053673:Glypicans; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053673:Glypicans; C000619938:codrituzumab
keywords: CD16; Codrituzumab; Glypican-3; Hepatocellular carcinoma