Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma A Preplanned Interim Analysis of a Clinical Trial
Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma A Preplanned Interim Analysis of a Clinical Trial
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DOI：
10.1001/jamaoncol.2018.0077
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发表时间：
2018-09-01
期刊：
影响因子：
28.4
通讯作者：
Kaufman, Howard L.
中科院分区：
文献类型：
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作者：
D'Angelo, Sandra P.;Russell, Jeffery;Kaufman, Howard L.
重要性默克尔细胞癌(MCC)是一种侵袭性皮肤癌，与远处转移性疾病患者的预后不良有关。标枪MERKEL 200试验A部分(Avelumab用于默克尔细胞癌患者)的结果显示，Avelumab是一种抗程序化细胞死亡配体1(PD-L1)抗体，对转移性MCC(MMCC)患者二线或以后治疗有效。目的评价Avelumab作为一线治疗远处MMCC患者的有效性和安全性。设计、设置和参与者标枪200 B部分是一线Avelumab治疗的国际多中心、单臂、开放标签临床试验。符合条件的患者是患有MMCC的成年人，他们之前没有接受过转移性疾病的系统治疗。患者没有选择PD-L1表达或Merkel细胞多瘤病毒状态。数据从2016年4月15日到2017年3月24日收集，登记正在进行。干预患者每两周静脉滴注阿维卢单抗1小时，10 mg/kg，直到确认疾病进展、不可接受的毒性反应或停药。主要结果和测量肿瘤状态每6周评估一次，并由独立审查委员会根据实体瘤1.1版的反应评估标准进行评估。主要终点是持久反应，定义为持续至少6个月的客观反应。次要终点包括最佳总体反应、反应持续时间、无进展生存期、安全性和耐受性。结果截至2017年3月24日，纳入39例患者(男性30例，女性9例；中位年龄75岁，范围47-88岁)，中位随访时间5.1个月(范围0.3-11.3个月)。在预先计划的分析中，对29名至少有3个月随访的患者进行了疗效评估；确认的客观应答率为62.1%(95%可信区间为42.3%-79.3%)，18例应答中有14例(77.8%)在分析时仍在进行。在有反应的患者中，估计有效时间至少3个月的比例为93%(95%可信区间为61%~99%)；有效持续时间至少为6个月的比例为83%(95%可信区间为46%~96%)。一线Avelumab治疗总体耐受性良好，没有发生与治疗相关的死亡或4级不良事件。结论和相关性：在二线或更晚治疗后，远端MMCC患者对一线Avelumab治疗的高应答率建立在先前报道的抗肿瘤活性的基础上，成熟的无进展生存数据表明，这种反应是持久的。这些数据进一步支持了Avelumab在美国和欧盟的批准，并将其用作MMCC的标准治疗。
IMPORTANCE Merkel cell carcinoma (MCC) is an aggressive skin cancer that is associated with poor survival outcomes in patients with distant metastatic disease. Results of part A of the JAVELIN Merkel 200 trial (avelumab in patients with Merkel cell carcinoma) showed that avelumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, demonstrated efficacy in second-line or later treatment of patients with metastatic MCC (mMCC).OBJECTIVE To evaluate the efficacy and safety of avelumab as first-line treatment for patients with distant mMCC.DESIGN, SETTING, AND PARTICIPANTS JAVELIN Merkel 200 part B is an international, multicenter, single-arm, open-label clinical trial of first-line avelumab monotherapy. Eligible patients were adults with mMCC who had not received prior systemic treatment for metastatic disease. Patients were not selected for PD-L1 expression or Merkel cell polyomavirus status. Data were collected from April 15, 2016, to March 24, 2017, and enrollment is ongoing.INTERVENTIONS Patients received avelumab, 10mg/kg, by 1-hour intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxic effects, or withdrawal occurred.MAIN OUTCOMES AND MEASURES Tumor statuswas assessed every 6weeks and evaluated by independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1. The primary end point was durable response, defined as an objective response with a duration of at least 6 months. Secondary end points include best overall response, duration of response, progression-free survival, safety, and tolerability.RESULTS As of March 24, 2017, 39 patients were enrolled (30 men and 9 women; median age, 75 years [range, 47-88 years]), with a median follow-up of 5.1 months (range, 0.3-11.3 months). In a preplanned analysis, efficacy was assessed in 29 patients with at least 3 months of follow-up; the confirmed objective response rate was 62.1% (95% CI, 42.3%-79.3%), with 14 of 18 responses (77.8%) ongoing at the time of analysis. In responding patients, the estimated proportion with duration of response of at least 3 months was 93%(95% CI, 61%-99%); duration of response of at least 6 months, 83%(95% CI, 46%-96%). First-line avelumab treatment was generally well tolerated, and no treatment-related deaths or grade 4 adverse events occurred.CONCLUSIONS AND RELEVANCE High rates of response to first-line avelumab therapy in patients with distant mMCC build on previously reported antitumor activity after second-line or later treatment, and maturing progression-free survival data suggest that responses are durable. These data further support avelumab's approval in the United States and European Union and use as a standard-of-care treatment for mMCC.