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

详细信息    查看全文

• 作者：Ghassan K. Abou-Alfa¹ ; ² ; ^{abou-alg@mskcc.org" class="auth_mail" title="E-mail the corresponding author} ; Oscar Puig³ ; Bruno Daniele⁴ ; Masatoshi Kudo⁵ ; Philippe Merle⁶ ; Joong-Won Park⁷ ; Paul Ross⁸ ; Jean-Marie Peron⁹ ; Oliver Ebert¹⁰ ; Stephen Chan¹¹ ; Tung Ping Poon¹² ; Massimo Colombo¹³ ; Takuji Okusaka¹⁴ ; Baek-Yeol Ryoo¹⁵ ; Beatriz Minguez¹⁶ ; Takayoshi Tanaka¹⁷ ; Toshihiko Ohtomo¹⁷ ; Stacey Ukrainskyj³ ; Frederic Boisserie³ ; Olga Rutman³ ; Ya-Chi Chen³ ; Chao Xu³ ; Eliezer Shochat¹⁸ ; Lori Jukofsky³ ; Bernhard Reis¹⁸ ; Gong Chen³ ; Laura Di Laurenzio³ ; Ray Lee³ ; Chia-Jui Yen¹⁹
• 关键词：Hepatocellular carcinoma ; Codrituzumab ; Glypican-3 ; CD16
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：65
• 期：2
• 页码：289-295
• 全文大小：792 K

文摘

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 C_trough 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).