Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer
Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer
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DOI：
10.1016/j.lungcan.2007.12.011
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发表时间：
2008-07-01
期刊：
影响因子：
5.3
通讯作者：
Klein, Jerry
中科院分区：
文献类型：
--
作者：
Greco, F. Anthony;Bonomi, Philip;Klein, Jerry
背景资料：mapatumumab（针对TRAIL-RI的激动性人单克隆抗体）的临床前药理学特性表明，该抗体降低细胞活力，在体外诱导多种类型癌细胞的细胞死亡，抑制或减少实体瘤异种移植模型中的肿瘤生长，并可在某些模型中诱导显著的肿瘤消退。mapatumumab的受体TRAIL-R1在NSCLC细胞上表达。这种药理学的配置文件表明，mapatumumab可能有治疗益处，在治疗NSCLC.Methods：这2期多中心研究的目的是评估的疗效，安全性和耐受性mapatumumab在晚期非小细胞肺癌（NSCLC）患者先前治疗至少1铂为基础的方案。每例患者接受mapatumumab的剂量为10毫克/公斤静脉注射（IV），每21天在没有疾病progression.Results：共32例复发性或难治性IIIB或IV期或复发性NSCLC患者入组。患者接受过中位3种既往治疗方案（范围1-7）。在本研究中，患者对Mapatumumab耐受良好，未因不良事件而停药。报告的最常见不良事件（不考虑相关性）为疲乏、咳嗽、恶心、呼吸困难、便秘和呕吐。实验室分析显示，在研究患者中没有明显的肝或肾毒性证据。没有患者产生抗mapatumumab抗体。本研究中观察到的血浆mapatumumab浓度与基于I期药代动力学结果的预测暴露量一致。根据RECIST标准，32例接受治疗的患者均未出现缓解。9例患者（29%）病情稳定（SD）。结论：在一组接受过大量预治疗的NSCLC患者中，没有证明mapatumumab的客观单药活性，但该药物安全且耐受性良好。基于这种有利的安全性特征，以及与常用于治疗NSCLC的药物联合使用的潜在协同作用的临床前证据，未来有必要对mapatumumab与化疗联合使用进行评估。(c)2008爱思唯尔爱尔兰有限公司保留所有权利。
Background: Preclinical pharmacological properties of mapatumumab (agonistic human monoclonal antibody to TRAIL-RI) suggest that this antibody reduces cell viability, induces cell death in many types of cancer cell tines in vitro, inhibits or reduces tumor growth in xenograft models of solid tumors, and can induce significant tumor regression in some models. The receptor for mapatumumab, TRAIL-R1, is expressed on NSCLC cell tines. This pharmacologic profile suggests that mapatumumab may have therapeutic benefit in the treatment of NSCLC.Methods: This Phase 2 multi-center study was designed to evaluate the efficacy, safety, and tolerability of mapatumumab in patients with advanced non-small cell lung cancer (NSCLC) previously treated with at least 1 platinum-based regimen. Each patient was to receive mapatumumab at a dose of 10 mg/kg administered intravenously (IV) every 21 days in absence of disease progression.Results: A total of 32 patients with relapsed or refractory Stage IIIB or IV or recurrent NSCLC were enrolled. Patients had received a median of 3 previous therapeutic regimens (range 1-7). Mapatumumab was well tolerated by the patients in this study with no discontinuations due to adverse events. The most common adverse events reported, regardless of relationship, were fatigue, cough, nausea, dyspnea, constipation, and vomiting. Laboratory analyses revealed no appreciable evidence of hepatic or renal toxicity among the study patients. No patients developed anti-mapatumumab antibodies. The plasma mapatumumab concentrations observed in this study were consistent with the predicted exposures, based on Phase 1 pharmacokinetic results. None of the 32 treated patients showed a response according to the RECIST criteria. Nine patients (29%) had stable disease (SD).Conclusion: In a group of heavily pretreated NSCLC patients, no objective single agent activity of mapatumumab was demonstrated, but the drug was safe and well tolerated. Based on this favorable safety profile, and preclinical evidence of potential synergy in combination with agents commonly used to treat NSCLC, future evaluation of mapatumumab in combination with chemotherapy is warranted. (c) 2008 Elsevier Ireland Ltd. All rights reserved.