Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study
Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study
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DOI：
10.1016/s1470-2045(17)30007-4
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发表时间：
2017-02-01
期刊：
影响因子：
51.1
通讯作者：
O'Donnell, Peter H.
中科院分区：
文献类型：
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作者：
Plimack, Elizabeth R.;Bellmunt, Joaquim;O'Donnell, Peter H.
背景PD-1及其配体在尿路上皮癌中表达，研究结果表明，抑制PD-1通路具有临床益处。我们的目的是评估安全性和活性的抗PD-1抗体pembrolizumab在局部晚期或转移性尿路上皮cancer.Methods这项研究的一部分，非随机，多队列，开放标签，1b期KEYNOTE-012篮子试验。我们从美国和以色列的8家医院招募了18岁及以上的患者，这些患者经组织学或细胞学确诊为局部晚期或转移性尿路上皮癌，包括肾盂癌、输尿管癌、膀胱癌或尿道癌。要求患者在肿瘤细胞或肿瘤间质中检测到至少1%的PD-L1表达，如通过免疫组织化学测定的。患者每2周一次静脉注射10 mg/kg pembrolizumab，直至疾病进展、不可接受的毒性效应或研究结束（即治疗24个月）。主要终点为安全性和总体缓解（根据实体瘤疗效评价标准[RECIST]第1.1版定义），由设盲的独立中心审查进行评估。在接受一剂或多剂帕博利珠单抗的患者中评估了安全性（所有接受治疗的患者人群）;在接受帕博利珠单抗、基线时有可测量疾病、有一次或多次基线后扫描或因疾病进展或治疗相关不良事件而停药的患者中评估了活性（全分析集）。本研究已在ClinicalTrials注册。在2013年5月14日至2013年12月10日期间，115名患者接受了组织预筛选，作为两部分同意过程的一部分。61例（53%）患者为PD-L1阳性，其中33例入组本研究。所有入组患者均接受了至少一剂帕博利珠单抗，并被纳入安全性分析。27例患者组成了全分析集，认为其活动性可评估。6例患者不可评估：3例在首次基线后扫描前因非治疗相关不良事件停用研究药物，2例在首次基线后扫描前退出，1例在基线时无可测量疾病。最常见的治疗相关不良事件是疲劳（33例患者中的6例[18%]）和外周水肿（4例[12%]）。5例（15%）患者发生了11例3级治疗相关不良事件;没有一例事件发生在1例以上患者中。3例（9%）患者发生了5起严重的治疗相关不良事件。中位随访13个月（范围1-26，IQR 5-23）后，27例可评估患者中有7例（26% [95% CI 11-46]）达到总体缓解，其中3例（11% [2-29]）完全缓解和4例（15% [4-34]）部分缓解。在研究期间发生的四例死亡（心脏骤停、肺炎、败血症和蛛网膜下腔出血）中，没有一例被认为与治疗相关。解释帕博利珠单抗在晚期尿路上皮癌患者中显示出抗肿瘤活性和可接受的安全性，支持正在进行的帕博利珠单抗在该人群中的2期和3期研究。
Background PD-1 and its ligands are expressed in urothelial cancer, and fi ndings have shown that inhibition of the PD-1 pathway has clinical benefi t. We aimed to assess the safety and activity of an anti-PD-1 antibody pembrolizumab in patients with locally advanced or metastatic urothelial cancer.Methods This study was part of the non-randomised, multi-cohort, open-label, phase 1b KEYNOTE-012 basket trial. We enrolled patients aged 18 years and older with a histologically or cytologically confi rmed diagnosis of locally advanced or metastatic urothelial cancer, including cancers of the renal pelvis, ureter, bladder, or urethra, from eight hospitals in the USA and Israel. Patients were required to have at least 1% PD-L1 expression detected on the tumour cells or in tumour stroma, as determined by immunohistochemistry. Patients were given 10 mg/kg intravenous pembrolizumab every 2 weeks until disease progression, unacceptable toxic eff ects, or the end of the study (ie, 24 months of treatment). Primary endpoints were safety and overall response (defi ned by Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1), as assessed by a masked, independent central review. Safety was assessed in patients who received one or more doses of pembrolizumab (all-patients-as-treated population); activity was assessed in patients who received pembrolizumab, had measurable disease at baseline, and had one or more post-baseline scans, or discontinued because of progressive disease or treatment-related adverse events (full analysis set). This study is registered with ClinicalTrials. gov, number NCT01848834, and is no longer enrolling patients; follow-up is ongoing.Findings Between May 14, 2013, and Dec 10, 2013, 115 patients were tissue pre-screened as part of a two-part consent process. 61 (53%) patients were PD-L1 positive, of whom 33 were enrolled in this study. All enrolled patients received at least one dose of pembrolizumab and were included in the safety analyses. 27 patients comprised the full analysis set and were deemed assessable for activity. Six patients were not assessable: three discontinued study drug because of a non-treatment-related adverse event before the fi rst post-baseline scan, two withdrew before the fi rst post-baseline scan, and one had no measurable disease at baseline. The most common treatment-related adverse events were fatigue (six [18%] of 33 patients) and peripheral oedema (4 [12%]). Five (15%) patients had 11 grade 3 treatment-related adverse events; no single event occurred in more than one patient. Three (9%) patients experienced fi ve serious treatment-related adverse events. After median follow-up of 13 months (range 1-26, IQR 5-23), an overall response was achieved in seven (26% [95% CI 11-46]) of 27 assessable patients, with three (11% [2-29]) complete and four (15% [4-34]) partial responses. Of the four deaths that occurred during the study (cardiac arrest, pneumonia, sepsis, and subarachnoid haemorrhage), none were deemed treatment related.Interpretation Pembrolizumab showed anti-tumour activity and acceptable safety in patients with advanced urothelial cancer, supporting ongoing phase 2 and 3 studies of pembrolizumab in this population.