纳武利尤单抗联合伊匹木单抗治疗晚期黑色素瘤的总生存期
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.
作者信息
Wolchok Jedd D, Chiarion-Sileni Vanna, Gonzalez Rene, Rutkowski Piotr, Grob Jean-Jacques, Cowey C Lance, Lao Christopher D, Wagstaff John, Schadendorf Dirk, Ferrucci Pier F, Smylie Michael, Dummer Reinhard, Hill Andrew, Hogg David, Haanen John, Carlino Matteo S, Bechter Oliver, Maio Michele, Marquez-Rodas Ivan, Guidoboni Massimo, McArthur Grant, Lebbé Celeste, Ascierto Paolo A, Long Georgina V, Cebon Jonathan, Sosman Jeffrey, Postow Michael A, Callahan Margaret K, Walker Dana, Rollin Linda, Bhore Rafia, Hodi F Stephen, Larkin James
机构信息
From the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.D.W., M.A.P., M.K.C.); Oncology Institute of Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua (V.C.-S.), European Institute of Oncology, Milan (P.F.F.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), the Immunotherapy and Somatic Cell Therapy Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (M.G.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy; University of Colorado, Denver (R.G.); Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.); Aix-Marseille University, Hôpital de la Timone, Marseille (J.-J.G.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint-Louis, Université Paris Diderot, Paris (C.L.) - both in France; Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.); University of Michigan, Ann Arbor (C.D.L.); the College of Medicine, Swansea University, Swansea (J.W.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom; the Department of Dermatology, University of Essen, Essen, and the German Cancer Consortium, Heidelberg - both in Germany (D.S.); Cross Cancer Institute, Edmonton, AB (M.S.), and Princess Margaret Cancer Centre, Toronto (D.H.) - both in Canada; Universitäts Spital, Zurich, Switzerland (R.D.); Tasman Oncology Research, Southport Gold Coast, QLD (A.H.), Crown Princess Mary Cancer Centre, Melanoma Institute Australia, University of Sydney (M.S.C.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals (G.V.L.), Sydney, and Peter MacCallum Cancer Centre (G.M.) and the Olivia Newton-John Cancer Research Institute, University of Melbourne (J.C.), Melbourne, VIC - all in Australia; Netherlands Cancer Institute, Amsterdam (J.H.); University Hospitals Leuven, KU Leuven, Leuven, Belgium (O.B.); General University Hospital Gregorio Marañón, Madrid (I.M.-R.); Northwestern University, Chicago (J.S.); Bristol-Myers Squibb, Princeton, NJ (D.W., L.R., R.B.); and the Dana-Farber Cancer Institute, Boston (F.S.H.).
出版信息
N Engl J Med. 2017 Oct 5;377(14):1345-1356. doi: 10.1056/NEJMoa1709684. Epub 2017 Sep 11.
BACKGROUND
Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial.
METHODS
We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group.
RESULTS
At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group.
CONCLUSIONS
Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).
背景
在一项涉及晚期黑色素瘤患者的3期试验中，纳武利尤单抗联合伊匹木单抗较单独使用伊匹木单抗可带来更长的无进展生存期和更高的客观缓解率。我们现在报告该试验的3年总生存结果。
方法
我们将先前未接受过治疗的晚期黑色素瘤患者按1:1:1的比例随机分组，分别接受每千克体重1毫克纳武利尤单抗加每3周一次、每次每千克体重3毫克伊匹木单抗，共四剂，随后每2周一次、每次每千克体重3毫克纳武利尤单抗；每2周一次、每次每千克体重3毫克纳武利尤单抗加安慰剂；或每3周一次、每次每千克体重3毫克伊匹木单抗，共四剂加安慰剂，直至疾病进展、出现不可接受的毒性作用或撤回知情同意。随机分组根据程序性死亡配体1（PD-L1）状态、BRAF突变状态和转移阶段进行分层。两个主要终点是纳武利尤单抗加伊匹木单抗组以及纳武利尤单抗组与伊匹木单抗组相比的无进展生存期和总生存期。
结果
在至少36个月的随访中，纳武利尤单抗加伊匹木单抗组的中位总生存期尚未达到，纳武利尤单抗组为37.6个月，而伊匹木单抗组为19.9个月（纳武利尤单抗加伊匹木单抗与伊匹木单抗相比的死亡风险比，0.55 [P<0.001]；纳武利尤单抗与伊匹木单抗相比的死亡风险比，0.65 [P<0.001]）。3年总生存率在纳武利尤单抗加伊匹木单抗组为58%，纳武利尤单抗组为52%，而伊匹木单抗组为34%。安全性与最初报告相比没有变化。3/4级治疗相关不良事件在纳武利尤单抗加伊匹木单抗组的患者中发生率为59%，纳武利尤单抗组为21%，伊匹木单抗组为28%。
结论
在晚期黑色素瘤患者中，纳武利尤单抗加伊匹木单抗联合治疗或单独使用纳武利尤单抗的总生存期显著长于单独使用伊匹木单抗。（由百时美施贵宝等公司资助；CheckMate 067临床试验注册号，NCT01844505。）
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