Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non -randomised, open -label, phase 2 trial
Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non -randomised, open -label, phase 2 trial
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DOI：
10.1016/s1470-2045(20)30111-x
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发表时间：
2020-05-01
期刊：
影响因子：
51.1
通讯作者：
Kluger, Harriet M.
中科院分区：
文献类型：
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作者：
Goldberg, Sarah B.;Schalper, Kurt A.;Kluger, Harriet M.
背景我们在非小细胞肺癌(NSCLC)或黑色素瘤未经治疗的脑转移患者中进行了Pembrolizumab的2期试验，以确定PD-1受体阻滞剂在中枢神经系统的活性。中期结果之前已经发表过，现在我们报告对全部NSCLC队列的最新分析。方法这是一项来自耶鲁大学癌症中心(CT，美国)的开放式第二阶段研究。符合条件的患者为年龄至少18岁的IV期非小细胞肺癌患者，至少有一个5-20 mm的脑转移，以前没有接受过治疗或在以前的放射治疗后进展，没有神经系统症状或需要皮质类固醇，以及东方合作肿瘤组的表现状态不到两个。实体肿瘤的改良反应评估标准(MRECIST)用于评估中枢神经系统疾病；参与不需要全身疾病。培溴利珠单抗10 mg/kg静脉滴注，每2周1次。患者分为两组：队列1为PD-L1表达至少为1%的患者，队列2为PD-L1低于1%或无法评估的患者。主要终点是患者达到脑转移反应(根据mRECIST的部分反应或完全反应)的比例。对所有接受治疗的患者进行了反应和安全终点分析。这项研究已向临床试验注册，NCT02085070。2014年3月31日至2018年5月21日期间，42名患者接受了治疗。中位随访时间8.3个月(IQR 4.5~26.2)。队列1中37例患者中有11例(29.7%[95%可信区间15.9~47.0])出现脑转移反应。与治疗相关的3-4级不良事件包括两名肺炎患者，以及一名分别有躯体症状、结肠炎、肾上腺功能不全、高血糖和低钾血症的患者。42例患者中有6例(14%)发生了与治疗相关的严重不良事件，包括肺炎(n=2)、急性肾损伤、结肠炎、低钾血症和肾上腺功能不全(n=1)。没有与治疗相关的死亡。解释培溴利珠单抗对PD-L1表达至少1%的非小细胞肺癌脑转移瘤具有活性，对选定的未经治疗的脑转移瘤患者是安全的。NSCLC合并中枢神经系统疾病患者的免疫治疗有待进一步研究。版权所有(C)2020爱思唯尔有限公司。保留所有权利。
Background We did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort.Methods This was an open-label, phase 2 study of patients from the Yale Cancer Center (CT, USA). Eligible patients were at least 18 years of age with stage IV NSCLC with at least one brain metastasis 5-20 mm in size, not previously treated or progressing after previous radiotherapy, no neurological symptoms or corticosteroid requirement, and Eastern Cooperative Oncology Group performance status less than two. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was used to evaluate CNS disease; systemic disease was not required for participation. Patients were treated with pembrolizumab 10 mg/kg intravenously every 2 weeks. Patients were in two cohorts: cohort 1 was for those with PD-L1 expression of at least 1% and cohort 2 was patients with PD-L1 less than 1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response (partial response or complete response, according to mRECIST). All treated patients were analysed for response and safety endpoints. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT02085070.Findings Between March 31,2014, and May 21,2018,42 patients were treated. Median follow-up was 8.3 months (IQR 4.5-26.2). 11 (29.7% [95% CI 15.9-47.0]) of 37 patients in cohort 1 had a brain metastasis response. There were no responses in cohort 2. Grade 3-4 adverse events related to treatment included two patients with pneumonitis, and one each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycaemia, and hypokalaemia. Treatment-related serious adverse events occurred in six (14%) of 42 patients and were pneumonitis (n=2), acute kidney injury, colitis, hypokalaemia, and adrenal insufficiency (n=1 each). There were no treatment-related deaths.Interpretation Pembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression at least 1% and is safe in selected patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted. Copyright (C) 2020 Elsevier Ltd. All rights reserved.