Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer
Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer
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DOI：
10.1200/jco.2016.67.9761
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发表时间：
2016-09-10
影响因子：
45.3
通讯作者：
Segal, Neil H.
中科院分区：
文献类型：
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作者：
Massard, Christophe;Gordon, Michael S.;Segal, Neil H.
目的探讨结合程序性细胞死亡配体-1 （PD-L1）的人单克隆抗体durvalumab的安全性和有效性，以及PD-L1表达在晚期尿路上皮性膀胱癌（UBC）患者临床反应中的作用。方法一项1/2期多中心、开放标签的研究正在对不能手术或转移性实体瘤患者进行研究。我们在此报告UBC扩展队列的结果。Durvalumab （MEDI4736，每2周10mg /kg）静脉注射长达12个月。主要终点是安全性，客观缓解率（ORR，确认）是关键的次要终点。通过对预处理肿瘤活检的探索性分析，将PD-L1阳性定义为>= 25%的肿瘤细胞或肿瘤浸润免疫细胞表达膜PD-L1。结果共61例患者（pd - l1阳性40例，pd - l1阴性21例）得到治疗，其中93.4%的患者既往接受过一种或多种晚期疾病治疗（中位随访时间为4.3个月）。最常见的治疗相关不良事件（ae）是疲劳（13.1%）、腹泻（9.8%）和食欲下降（8.2%）。3例患者发生3级治疗相关不良事件（4.9%）；没有与治疗相关的4级或5级ae。一例与治疗相关的AE（急性肾损伤）导致治疗中断。在42例反应可评估的患者中，ORR为31.0% (95% CI， 17.6至47.1)，pd - l1阳性亚组的ORR为46.4% (95% CI， 27.5至66.1)，pd - l1阴性亚组的ORR为0% （95% CI， 0.0至23.2）。13例应答患者中有12例正在进行应答，中位应答持续时间尚未达到（范围，4.1+至49.3+周）。结论durvalumab在pd - l1阳性的UBC患者中具有可控的安全性和有意义的临床活性，其中许多患者进行了大量预处理。
PurposeTo investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC).MethodsA phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1-positive as >= 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1.ResultsA total of 61 patients (40 PD-L1-positive, 21 PD-L1-negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1-positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1-negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks).ConclusionDurvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, many of whom were heavily pretreated.