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

Ghassan K. Abou-Alfa, Oscar Puig, Bruno Daniele, Masatoshi Kudo, Philippe Merle, Joong Won Park, Paul Ross, Jean Marie Peron, Oliver Ebert, Stephen Chan, Tung Ping Poon, Massimo Colombo, Takuji Okusaka, Baek Yeol Ryoo, Beatriz Minguez, Takayoshi Tanaka, Toshihiko Ohtomo, Stacey Ukrainskyj, Frederic Boisserie, Olga RutmanYa Chi Chen, Chao Xu, Eliezer Shochat, Lori Jukofsky, Bernhard Reis, Gong Chen, Laura Di Laurenzio, Ray Lee, Chia Jui Yen

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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, ⩾18 years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600 mg 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 3 day 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).

Original languageEnglish
Pages (from-to)289-295
Number of pages7
JournalJournal of Hepatology
Volume65
Issue number2
DOIs
Publication statusPublished - 2016 Aug 1

All Science Journal Classification (ASJC) codes

  • Hepatology

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    Abou-Alfa, G. K., Puig, O., Daniele, B., Kudo, M., Merle, P., Park, J. W., Ross, P., Peron, J. M., Ebert, O., Chan, S., Poon, T. P., Colombo, M., Okusaka, T., Ryoo, B. Y., Minguez, B., Tanaka, T., Ohtomo, T., Ukrainskyj, S., Boisserie, F., ... Yen, C. J. (2016). Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma. Journal of Hepatology, 65(2), 289-295. https://doi.org/10.1016/j.jhep.2016.04.004