Memorial Sloan Kettering Cancer Center, New York, New York.
Georgetown University, Lombardi Comprehensive Cancer Center, Washington, D.C.
Clin Cancer Res. 2018 Apr 15;24(8):1816-1823. doi: 10.1158/1078-0432.CCR-17-1922. Epub 2018 Mar 16.
Utomilumab (PF-05082566) is an agonistic mAb that engages the immune costimulatory molecule 4-1BB/CD137. In this first-in-human, phase I, open-label, multicenter, multiple-dose study (NCT01307267) we evaluated safety, tolerability, pharmacokinetics, preliminary clinical activity, and pharmacodynamics of single-agent utomilumab in patients with advanced malignancies. Dose escalation was based on a standard 3+3 design for doses of utomilumab from 0.006 to 0.3 mg/kg every 4 weeks and a time-to-event continual reassessment method for utomilumab 0.6 to 10 mg/kg every 4 weeks. The primary study endpoint was dose-limiting toxicity (DLT) in the first two cycles. Utomilumab demonstrated a well-tolerated safety profile ( = 55). None of the patients experienced a DLT at the dose levels evaluated. The most common treatment-related adverse events were fatigue, pyrexia, decreased appetite, dizziness, and rash (<10% of patients). Only one (1.8%) patient experienced a grade 3-4 treatment-related adverse event (fatigue), and no clinically relevant elevations in transaminases were noted. Utomilumab demonstrated linear pharmacokinetics at doses ranging from 0.006 to 10 mg/kg, with similar safety and pharmacokinetics in anti-drug antibody (ADA)-negative and ADA-positive patients. The overall objective response rate was 3.8% (95% CI, 0.5%-13.0%) in patients with solid tumors and 13.3% in patients with Merkel cell carcinoma, including a complete response and a partial response. Circulating biomarkers support 4-1BB/CD137 engagement by utomilumab and suggest that circulating lymphocyte levels may influence probability of clinical benefit. The favorable safety profile and preliminary antitumor activity demonstrated by utomilumab warrant further evaluation in patients with advanced malignancies. .
乌托米单抗（PF-05082566）是一种激动型单克隆抗体，可与免疫共刺激分子 4-1BB/CD137 结合。在这项首次人体、I 期、开放性、多中心、多剂量研究（NCT01307267）中，我们评估了乌托米单抗单药治疗晚期恶性肿瘤患者的安全性、耐受性、药代动力学、初步临床活性和药效学。剂量递增基于乌托米单抗 0.006 至 0.3mg/kg 每 4 周的标准 3+3 设计和乌托米单抗 0.6 至 10mg/kg 每 4 周的时间事件连续再评估方法。主要研究终点是前两个周期的剂量限制性毒性（DLT）。乌托米单抗表现出良好的耐受性安全性特征（=55）。在所评估的剂量水平下，没有患者发生 DLT。最常见的与治疗相关的不良事件是疲劳、发热、食欲下降、头晕和皮疹（<10%的患者）。只有 1 名（1.8%）患者发生 3-4 级与治疗相关的不良事件（疲劳），未观察到转氨酶的临床相关升高。乌托米单抗在 0.006 至 10mg/kg 的剂量范围内表现出线性药代动力学，在抗药物抗体（ADA）阴性和 ADA 阳性患者中的安全性和药代动力学相似。在实体瘤患者中的总客观缓解率为 3.8%（95%CI，0.5%-13.0%），在 Merkel 细胞癌患者中的客观缓解率为 13.3%，包括完全缓解和部分缓解。循环生物标志物支持乌托米单抗与 4-1BB/CD137 的结合，并表明循环淋巴细胞水平可能影响临床获益的可能性。乌托米单抗表现出良好的安全性特征和初步的抗肿瘤活性，值得在晚期恶性肿瘤患者中进一步评估。
