Nghiem Paul T, Bhatia Shailender, Lipson Evan J, Kudchadkar Ragini R, Miller Natalie J, Annamalai Lakshmanan, Berry Sneha, Chartash Elliot K, Daud Adil, Fling Steven P, Friedlander Philip A, Kluger Harriet M, Kohrt Holbrook E, Lundgren Lisa, Margolin Kim, Mitchell Alan, Olencki Thomas, Pardoll Drew M, Reddy Sunil A, Shantha Erica M, Sharfman William H, Sharon Elad, Shemanski Lynn R, Shinohara Michi M, Sunshine Joel C, Taube Janis M, Thompson John A, Townson Steven M, Yearley Jennifer H, Topalian Suzanne L, Cheever Martin A
From the University of Washington Medical Center (P.T.N., S. Bhatia, N.J.M., E.M.S., M.M.S., J.A.T., M.A.C.), Fred Hutchinson Cancer Research Center (P.T.N., S. Bhatia, S.P.F., L.L., J.A.T., M.A.C.), Cancer Immunotherapy Trials Network (S.P.F., L.L., M.A.C.), and Cancer Research and Biostatistics (A.M., L.R.S.) - all in Seattle; Johns Hopkins University School of Medicine and Kimmel Cancer Center, Baltimore (E.J.L., S. Berry, D.M.P., W.H.S., J.C.S., J.M.T., S.L.T.), and Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda. (E.S.) - both in Maryland; Winship Cancer Institute of Emory University, Atlanta (R.R.K.); Merck Research Laboratories, Kenilworth, NJ (L.A., E.K.C., S.M.T., J.H.Y.); University of California, San Francisco, San Francisco (A.D.), and Stanford University, Stanford (H.E.K., K.M., S.A.R.) - both in California; Mt. Sinai Medical Center, New York (P.A.F.); Yale University, New Haven, CT (H.M.K.); and Ohio State University, Columbus (T.O.).
N Engl J Med. 2016 Jun 30;374(26):2542-52. doi: 10.1056/NEJMoa1603702. Epub 2016 Apr 19.
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.).
默克尔细胞癌是一种侵袭性皮肤癌，与紫外线暴露和默克尔细胞多瘤病毒（MCPyV）有关。晚期默克尔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）免疫抑制途径受到关注，因为这些肿瘤通常表达PD-L1，且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，我们将未接受过全身治疗的晚期默克尔细胞癌成人患者分配为每3周接受一次剂量为2毫克/千克体重的帕博利珠单抗（抗PD-1）治疗。主要终点是根据实体瘤疗效评价标准1.1版确定的客观缓解率。疗效与通过血清学和免疫组织化学检测评估的肿瘤病毒状态相关。
共有26例患者接受了至少一剂帕博利珠单抗。在25例治疗期间至少接受一次评估的患者中，客观缓解率为56%（95%置信区间[CI]，35%至76%）；4例患者完全缓解，10例患者部分缓解。中位随访33周（范围7至53周），14例有反应的患者中有2例复发（14%）。缓解持续时间从至少2.2个月至至少9.7个月不等。6个月时无进展生存率为67%（95%CI，49%至86%）。26例患者中有17例（65%）肿瘤病毒阳性。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%的患者发生了与药物相关的3级或4级不良事件。
在本研究中，晚期默克尔细胞癌患者一线使用帕博利珠单抗治疗的客观缓解率为56%。病毒阳性肿瘤患者和病毒阴性肿瘤患者均观察到缓解。（由美国国立癌症研究所和默克公司资助；ClinicalTrials.gov编号，NCT02267603。）
