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
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DOI：
10.1016/j.jhep.2016.04.004
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发表时间：
2016-08-01
影响因子：
25.7
通讯作者：
Yen, Chia-Jui
中科院分区：
文献类型：
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作者：
Abou-Alfa, Ghassan K.;Puig, Oscar;Yen, Chia-Jui
背景与目的：Codrituzumab是一种人源化的抗GPC3的单抗，在肝细胞癌中表达，它与CD16/FccRIIIa相互作用，引发抗体依赖性的细胞毒作用。Codrituzumab和安慰剂在一项随机的II期试验中被用于先前系统治疗失败的晚期肝细胞癌患者。方法：早期系统治疗失败，东方合作肿瘤组(ECOG)0-1，Child-Pugh A的晚期肝癌患者被随机分为2：1和两周一次的Codrituzumab 1600 mg和安慰剂。根据GPC3免疫组织化学表达对患者进行分层：2+/3+、1+和0。主要终点是无进展生存期。结果：有血管侵犯和/或肝外转移的185例患者中，125例接受可屈曲珠单抗治疗，60例接受安慰剂治疗：中位年龄/63，男性85/75%，亚洲46/42%，ECOG 0.65/63%，74/77%。84%/70%的患者有索拉非尼的先证者。药物暴露是计划剂量的98.4%，两组之间的不良事件情况相同。与安慰剂组相比，Codrituzumab组几个月的中位无进展存活率和总存活率分别为：2.6比1.5(风险比0.97，p=0.87)和8.7比10(风险比0.96，p=0.82)。外周免疫细胞CD16/FccRIIIa的高表达以及肿瘤中GPC3的表达均与延长无进展生存期和总生存期有关。结论：Codrituzumab在既往治疗的肝细胞癌患者中未显示出临床益处。更高的Codrituzumab药物暴露或使用CD16和GPC3作为潜在的生物标记物是否会改善结果仍是未回答的问题。Lay概要：Codrituzumab是一种针对一种名为glypcan-3的肝癌蛋白的人造抗体。在这项临床试验中，没有发现codrituzumab对肝癌有效。然而，有人建议，大剂量的codrituzumab或选择Glypcan-3或其介体CD16水平高的患者可能会改善预后。(C)2016年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FccRIIIa 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 extrahepatic 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/FccRIIIa 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. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.