2. Academic Validation
  3. Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma

Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma

  • J Hepatol. 2016 Aug;65(2):289-95. doi: 10.1016/j.jhep.2016.04.004.
Ghassan K Abou-Alfa 1,  Oscar Puig 2,  Bruno Daniele 3,  Masatoshi Kudo 4,  Philippe Merle 5,  Joong-Won Park 6,  Paul Ross 7,  Jean-Marie Peron 8,  Oliver Ebert 9,  Stephen Chan 10,  Tung Ping Poon 11,  Massimo Colombo 12,  Takuji Okusaka 13,  Baek-Yeol Ryoo 14,  Beatriz Minguez 15,  Takayoshi Tanaka 16,  Toshihiko Ohtomo 16,  Stacey Ukrainskyj 2,  Frederic Boisserie 2,  Olga Rutman 2,  Ya-Chi Chen 2,  Chao Xu 2,  Eliezer Shochat 17,  Lori Jukofsky 2,  Bernhard Reis 17,  Gong Chen 2,  Laura Di Laurenzio 2,  Ray Lee 2,  Chia-Jui Yen 18
Affiliations

Affiliations

  • 1 Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: abou-alg@mskcc.org.
  • 2 Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
  • 3 G. Rummo Hospital, Benevento, Italy.
  • 4 Kinki University Hospital, Japan.
  • 5 Hopital de la Croix-Rousse, Hepatologie et Gastroenterologie, Lyon, France.
  • 6 National Cancer Center, Republic of Korea.
  • 7 King's College Hospital, United Kingdom.
  • 8 Hopital Purpan, Gastro Enterologie Hepatologie, France.
  • 9 II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Germany.
  • 10 Prince of Wales Hospital, Hong Kong.
  • 11 Queen Mary Hospital, Hong Kong.
  • 12 Fondazione IRCCS Ospedale Maggiore Policlinico, Italy.
  • 13 National Cancer Center Hospital, Japan.
  • 14 Asan Medical Center, Republic of Korea.
  • 15 Liver Unit, Hospital Universitario Vall d́Hebron, Barcelona, Spain.
  • 16 Chugai Pharmaceutical Co. Ltd., Japan.
  • 17 Roche Innovation Center Basel, Hoffmann-La Roche, Switzerland.
  • 18 National Cheng-Kung Univ. Hospital, Taiwan.
PMID: 27085251 DOI: 10.1016/j.jhep.2016.04.004
Abstract

Background & aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Lay summary: 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.

Clinical trial registration: This trial is registered at Clinicaltrials.gov (NCT01507168).

Keywords

CD16; Codrituzumab; Glypican-3; Hepatocellular carcinoma.

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