帕博利珠单抗辅助治疗与安慰剂对照用于 III 期黑色素瘤完全切除术后患者的随机、双盲、III 期临床试验
Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma.
机构信息
From the Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif (A.M.M.E., C.R.), Hospices Civils de Lyon Cancer Institute, Cancer Research Center of Lyon, Lyon University, Lyon (S.D.), and Aix-Marseille University, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille (J.-J.G.) - all in France; Netherlands Cancer Institute-Antoni van Leeuwenhoek (C.U.B., A.C.J.A.) and VU University Medical Center (A.J.M.E.), Amsterdam, and Radboud University Medical Center Nijmegen, Nijmegen (R.K.) - all in the Netherlands; Azienda Ospedaliera Papa Giovanni XXIII, Bergamo (M. Mandala), Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples (P.A.A.), and Universita Degli Studi Di Siena-Policlinico le Scotte, Siena (M. Maio) - all in Italy; Melanoma Institute Australia, the University of Sydney, and Mater and Royal North Shore Hospitals (G.V.L.) and Westmead and Blacktown Hospitals, Melanoma Institute Australia and the University of Sydney (M.S.C.), Sydney, Princess Alexandra Hospital, University of Queensland, Brisbane (V.A.), Alfred Hospital (A.H.) and Peter MacCallum Cancer Centre (S. Sandhu), Melbourne, VIC, and Fiona Stanley Hospital-University of Western Australia-Edith Cowan University Perth, Perth (A.K.) - all in Australia; Cancer Research Center, Moscow (M.L.); Royal Marsden Hospital, London (J.L.); Hospital Clinic Universitari de Barcelona, Barcelona (S.P.); Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.); University Hospital Essen, Essen and German Cancer Consortium, Heidelberg (D.S.), and the Skin Cancer Center, Department of Dermatology, Hannover Medical School, Hannover (R.G.) - all in Germany; Washington University School of Medicine, St. Louis (L.H.-A.); Centre Hospitalier de l'Université de Montréal (CHUM), Centre de Recherche du CHUM, Montreal (R.J.); Christie NHS Foundation Trust, Manchester, United Kingdom (P.L.); Merck, Kenilworth, NJ (N.I.); and the European Organization for the Research and Treatment of Cancer Headquarters, Brussels (S.M., S. Suciu).
出版信息
N Engl J Med. 2018 May 10;378(19):1789-1801. doi: 10.1056/NEJMoa1802357. Epub 2018 Apr 15.
BACKGROUND
The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.
METHODS
Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.
RESULTS
At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.
CONCLUSIONS
As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).
背景
程序性死亡 1（PD-1）抑制剂派姆单抗已被发现可延长晚期黑色素瘤患者的无进展生存期和总生存期。我们进行了一项 3 期双盲试验，以评估派姆单抗作为完全切除的高危 III 期黑色素瘤患者的辅助治疗。
方法
完全切除的 III 期黑色素瘤患者按癌症分期和地理区域分层，随机接受 200mg 派姆单抗（514 例）或安慰剂（505 例）静脉输注，每 3 周 1 次，共 18 次（约 1 年），直至疾病复发或出现不可接受的毒性作用。总意向治疗人群和 PD-1 配体（PD-L1）阳性癌症患者亚组的无复发生存是主要终点。还评估了安全性。
结果
中位随访 15 个月时，与安慰剂相比，派姆单抗在总意向治疗人群中显著延长了无复发生存期（1 年无复发生存率，75.4%[95%可信区间，71.3 至 78.9]vs.61.0%[95%可信区间，56.5 至 65.1]；复发或死亡的风险比为 0.57；98.4%可信区间，0.43 至 0.74；P<0.001）和 853 例 PD-L1 阳性肿瘤患者亚组（1 年无复发生存率，派姆单抗组为 77.1%[95%可信区间，72.7 至 80.9]，安慰剂组为 62.6%[95%可信区间，57.7 至 67.0]；风险比，0.54；95%可信区间，0.42 至 0.69；P<0.001）。派姆单抗组 14.7%的患者和安慰剂组 3.4%的患者报告了与试验方案相关的 3 级至 5 级不良事件。派姆单抗组有 1 例治疗相关的肌炎死亡。
结论
作为高危 III 期黑色素瘤的辅助治疗，每 3 周给予 200mg 派姆单抗治疗 1 年可显著延长无复发生存期，未发现新的毒性作用。（由默克公司资助；临床试验.gov 编号，NCT02362594；EudraCT 编号，2014-004944-37）。
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