Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis
Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis
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DOI：
10.1038/s41591-020-0918-0
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发表时间：
2020-06-01
期刊：
影响因子：
82.9
通讯作者：
Sullivan, Ryan J.
中科院分区：
文献类型：
--
作者：
Brastianos, Priscilla K.;Lee, Eudocia Quant;Sullivan, Ryan J.
越来越多的转移性癌症患者发展为软脑膜播散性疾病(LMD)，存活率很低(1-3)。我们在实体肿瘤患者和LMD()患者中进行了一项培溴利珠单抗的2期单臂研究。患者每3周静脉注射200毫克培溴利珠单抗，直到病情明确进展或出现不可接受的毒性。主要终点是3个月的总存活率(OS3)。次要目标包括毒性、应答率和对颅内外疾病进展的时间。使用Simon两阶段设计来比较无效假设OS3为18%和替代方案为43%。20名患者-17名乳腺癌患者，2名肺癌患者和1名卵巢癌患者-被纳入预先指定的评估组，他们至少接受了一剂培溴利珠单抗。存活患者的中位随访时间为6.3个月(2.2~12.5个月)。出现一种(或更多)3级或以上不良事件的患者比例为40%，最常见的是高血糖(n=6)、恶心(n=7)和呕吐(n=7)。这项研究达到了主要终点，因为20名患者中有12名(OS3，0.60；90%可信区间，0.39-0.78)在登记后3个月仍活着。培溴利珠单抗是安全可行的，在LMD患者中显示出良好的活性。需要进一步的研究来确定哪些LMD患者可以受益于培溴利珠单抗。
An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal(1-3). We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (). Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. The primary endpoint was rate of overall survival at 3 months (OS3). Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Twenty patients-17 with breast cancer, two with lung cancer and one with ovarian cancer-were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. The median follow-up of surviving patients was 6.3 months (range, 2.2-12.5 months). The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39-0.78) patients were alive at 3 months after enrollment. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab.