Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
Roche Innovation Center New York, Hoffmann-La Roche Inc., USA.
J Hepatol. 2016 Aug;65(2):289-95. doi: 10.1016/j.jhep.2016.04.004. Epub 2016 Apr 13.
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.
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).
Codrituzumab 是一种针对肝细胞癌（HCC）中表达的 Glypican-3（GPC3）的人源化单克隆抗体，与 CD16/FcγRIIIa 相互作用并触发抗体依赖性细胞毒性。在先前接受系统治疗失败的晚期 HCC 患者中，进行了一项随机 II 期试验，比较了 Codrituzumab 与安慰剂的疗效。
先前接受过系统治疗失败、年龄 ⩾18 岁、东部合作肿瘤学组（ECOG）0-1、Child-Pugh A 的晚期 HCC 患者，按 2:1 的比例随机分配接受每两周 1600mg Codrituzumab 或安慰剂。根据 GPC3 免疫组织化学表达将患者分层：2+/3+、1+和 0。主要终点是无进展生存期。次要终点包括总生存期（OS）、耐受性、药代动力学和生物标志物分析中的探索性终点。
共纳入 185 例患者：125 例接受 Codrituzumab，60 例接受安慰剂：中位年龄 64/63 岁，85/75%为男性，46/42%为亚洲人，ECOG 0 65/63%，74/77%有血管侵犯和/或肝外转移。84%/70%的患者之前接受过索拉非尼治疗。药物暴露量为计划剂量的 98.4%，两组不良反应谱相同。Codrituzumab 组与安慰剂组的中位无进展生存期和总生存期分别为：2.6 个月 vs. 1.5 个月（风险比 0.97，p=0.87）和 8.7 个月 vs. 10 个月（风险比 0.96，p=0.82）。基于第 3 天的预测 Ctrough 在第 1 周期的暴露量、外周免疫细胞中高 CD16/FcγRIIIa 和肿瘤中 GPC3 的表达，均与无进展生存期和总生存期延长相关。
在先前接受过治疗的 HCC 患者中，Codrituzumab 并未显示出临床获益。Codrituzumab 更高的药物暴露量或使用 CD16 和 GPC3 作为潜在的生物标志物是否能改善疗效，仍有待解答。
Codrituzumab 是一种针对肝癌蛋白 Glypican-3 的人工合成抗体。在这项临床试验中，Codrituzumab 被发现对肝癌没有效果。但研究提示，更高剂量的 Codrituzumab 或选择 Glypican-3 或其介质 CD16 水平较高的患者可能会改善疗效。
本试验在 ClinicalTrials.gov 注册（NCT01507168）。
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