PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma.
PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma.
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PD-1与晚期Merkel-Cell癌中的Pembrolizumab封锁。
DOI：
10.1056/nejmoa1603702
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发表时间：
2016-06-30
期刊：
影响因子：
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通讯作者：
Cheever MA
中科院分区：
文献类型：
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作者：
Nghiem PT;Bhatia S;Lipson EJ;Kudchadkar RR;Miller NJ;Annamalai L;Berry S;Chartash EK;Daud A;Fling SP;Friedlander PA;Kluger HM;Kohrt HE;Lundgren L;Margolin K;Mitchell A;Olencki T;Pardoll DM;Reddy SA;Shantha EM;Sharfman WH;Sharon E;Shemanski LR;Shinohara MM;Sunshine JC;Taube JM;Thompson JA;Townson SM;Yearley JH;Topalian SL;Cheever MA
Merkel细胞癌是一种侵袭性皮肤癌，与暴露于紫外线和Merkel细胞多瘤病毒（MCPyV）有关。晚期Merkel细胞癌通常对化疗有反应，但反应是短暂的。阻断程序性死亡1（PD-1）免疫抑制途径是令人感兴趣的，因为这些肿瘤通常表达PD-L1，而MCPyV特异性T细胞表达PD-1。在这项多中心、2期、非对照研究中，我们将既往未接受过全身治疗的晚期Merkel细胞癌成人患者分配为每3周一次接受pembrolizumab（抗PD-1）治疗，剂量为2 mg/kg体重。主要终点是根据实体瘤疗效评价标准（第1.1版）的客观缓解率。疗效与肿瘤病毒状态相关，通过血清学和免疫组化检测进行评估。共有26名患者接受了至少一剂帕博利珠单抗。在治疗期间至少进行了一次评估的25例患者中，客观缓解率为56%（95%置信区间[CI]，35 - 76）; 4例患者完全缓解，10例患者部分缓解。中位随访时间为33周（范围7 - 53周），14例有反应的患者中有2例复发（14%）。缓解持续时间范围为至少2.2个月至至少9.7个月。6个月时的无进展生存率为67%（95% CI，49 - 86）。26例患者中共有17例（65%）有病毒阳性肿瘤。MCPyV阳性肿瘤患者的缓解率为62%（16例患者中的10例），病毒阴性肿瘤患者的缓解率为44%（9例患者中的4例）。15%的患者发生了药物相关的3级或4级不良事件。在这项研究中，pembrolizumab一线治疗晚期Merkel细胞癌患者的客观缓解率为56%。在病毒阳性肿瘤患者和病毒阴性肿瘤患者中观察到反应。（由国家癌症研究所和默克公司资助; ClinicalTrials.gov编号，NCT 02267603。
Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti–PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing. A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients. In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.)