First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors
First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors
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DOI：
10.1093/annonc/mdx002
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发表时间：
2017-04-01
影响因子：
50.5
通讯作者：
Burris, H. A.
中科院分区：
文献类型：
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作者：
Bang, Y. J.;Giaccone, G.;Burris, H. A.
背景：马吉妥昔单抗是一种抗HER2抗体，它以更高的亲和力与CD16A的低亲和力和高亲和力形式结合，CD16A是一种Fc受体，对抗体依赖的细胞介导的细胞毒性（ADCC）作用于肿瘤细胞至关重要。一项1期研究旨在评估马吉妥昔单抗在HER2过表达癌症患者中的毒性特征、最大耐受剂量（MTD）、药代动力学和抗肿瘤活性。
患者和方法：HER2阳性乳腺癌或胃癌患者，或其他HER2过表达的癌症患者，且无标准治疗方法，接受马吉妥昔单抗静脉输注治疗，剂量为每4周中的3周给予0.1 - 6.0 mg/kg（方案A）或每3周一次（10 - 18 mg/kg）（方案B）。
结果：66名患者接受了马吉妥昔单抗治疗（34名患者采用方案A，32名患者采用方案B）。两种方案均未达到MTD。治疗耐受性良好，主要为1级和2级毒性，包括全身性症状，如发热、恶心、贫血、腹泻和疲劳。在60名可评估疗效的患者中，分别有7名（12%）患者观察到确认的部分缓解，30名（50%）患者病情稳定；这些患者中有26名（70%）之前接受过HER2靶向治疗。在超过一半（23名中有18名，78%）可评估疗效的乳腺癌患者中观察到肿瘤缩小，包括持久（>30周）的缓解者。对患者外周血单个核细胞样本的体外分析证实，与曲妥珠单抗相比，马吉妥昔单抗具有更强的支持ADCC的能力。
结论：马吉妥昔单抗耐受性良好，具有有前景的单药活性。马吉妥昔单抗作为单药以及与其他治疗药物联合的进一步开发工作正在进行中。
Background: Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas.Patients and methods: Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1-6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10-18 mg/kg) (Regimen B).Results: Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as pyrexia, nausea, anemia, diarrhea, and fatigue. Among 60 response-evaluable patients, confirmed partial responses and stable disease were observed in 7 (12%) and 30 (50%) patients, respectively; 26 (70%) of these patients had received prior HER2-targeted therapy. Tumor reductions were observed in over half (18/23, 78%) of response-evaluable patients with breast cancer including durable (>30 weeks) responders. Ex vivo analyses of patient peripheral blood mononuclear cell samples confirmed the ability of margetuximab to support enhanced ADCC compared with trastuzumab.Conclusions: Margetuximab was well-tolerated and has promising single-agent activity. Further development efforts of margetuximab as single agent and in combination with other therapeutic agents are ongoing.