Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial
Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial
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DOI：
10.1016/s0140-6736(14)60958-2
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发表时间：
2014-09-20
期刊：
影响因子：
168.9
通讯作者：
Daud, Adil
中科院分区：
文献类型：
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作者：
Robert, Caroline;Ribas, Antoni;Daud, Adil
背景：抗程序性死亡受体-1(PD-1)抗体pembrolizumab在不同剂量和方案下对黑色素瘤患者显示出很强的抗肿瘤活性。我们比较了每3周2 mg/kg和10 mg/kg剂量的培溴利珠单抗治疗难治性晚期黑色素瘤患者的疗效和安全性。方法在一项开放的、国际化的、多中心的1期扩大队列试验中，晚期黑色素瘤患者(年龄18岁)在至少两次ipilimumab剂量后进展的患者被随机分配到计算机生成的配置表(1：1最终比例)中，静脉注射培溴珠单抗每3周2 mg/kg或每3周10 mg/kg，直到疾病进展、无法耐受的毒性或同意停药。主要终点采用RECIST实体瘤反应评估标准(RECIST，Version 1.1)通过独立的中心评审评估总体反应率(ORR)。分析是在完全分析集上进行的(所有在基线上有可测量疾病的接受治疗的患者)。这项研究在ClinicalTrials.gov上注册，编号NCT01295827。发现173名患者服用培溴利珠单抗2 mg/kg(n=89)或10 mg/kg(n=84)。中位随访时间为8个月。两种剂量的ORR分别为2 mg/kg组81例患者中21例和10 mg/kg组76例患者中的20例(差异0%，95%CI-14至13；p=0.96)。治疗耐受性良好，2 mg/kg和10 mg/kg组的安全性相似，没有与药物有关的死亡。在2 mg/kg和10 mg/kg组中，最常见的任何级别的药物相关不良事件是乏力(29[33%]比31[37%])、瘙痒(23[26%]比16[19%])和皮疹(16[18%]比15[18%])。在2 mg/kg培溴利珠单抗组中，有5名患者(3%)报告了3级疲劳，这是超过1名患者中唯一报告的与药物相关的3-4级不良反应。解释结果表明，对于几乎没有有效治疗选择的患者，每3周服用2 mg/kg或10 mg/kg的培溴利珠单抗可能是一种有效的治疗方法。
Background The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma.Methods In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged >= 18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827.Findings 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses-21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0.96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient.Interpretation The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options.