Wolchok Jedd D, Chiarion-Sileni Vanna, Rutkowski Piotr, Cowey C Lance, Schadendorf Dirk, Wagstaff John, Queirolo Paola, Dummer Reinhard, Butler Marcus O, Hill Andrew G, Postow Michael A, Gaudy-Marqueste Caroline, Medina Theresa, Lao Christopher D, Walker John, Márquez-Rodas Iván, Haanen John B A G, Guidoboni Massimo, Maio Michele, Schöffski Patrick, Carlino Matteo S, Sandhu Shahneen, Lebbé Céleste, Ascierto Paolo A, Long Georgina V, Ritchings Corey, Nassar Ayman, Askelson Margarita, Benito Melanie Pe, Wang Wenjia, Hodi F Stephen, Larkin James
From the Sandra and Edward Meyer Cancer Center (J.D.W.) and the Department of Medicine (J.D.W., M.A.P.), Weill Cornell Medicine, and Memorial Sloan Kettering Cancer Center (M.A.P.) - both in New York; Istituto Oncologico Veneto, IRCCS, Padua (V.C.-S.), European Institute of Oncology, IRCCS, Milan (P.Q.), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola (M.G.), University of Siena and the Center for Immuno-Oncology, University Hospital of Siena, Siena (M.M.), and Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples (P.A.A.) - all in Italy; Maria Sklodowska-Curie National Institute of Oncology, Warsaw, Poland (P.R.); Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas (C.L.C.); University Hospital Essen, the German Cancer Consortium, the National Center for Tumor Diseases-West, the Research Alliance Ruhr, Research Center One Health, and University Duisburg-Essen - all in Essen, Germany (D.S.); the College of Medicine, Swansea University, Swansea (J.W.), Bristol Myers Squibb, Uxbridge (A.N.), and the Royal Marsden Hospital, London (J.L.) - all in the United Kingdom; the Department of Dermatology, University of Zurich, Zurich, Switzerland (R.D.); University Health Network Princess Margaret Cancer Centre, Toronto (M.O.B.), and Cross Cancer Institute, University of Alberta, Edmonton (J.W.) - both in Canada; Tasman Oncology Research, Southport, QLD (A.G.H.), Westmead Hospital, Westmead, NSW (M.S.C.), Blacktown Hospital, Blacktown, NSW (M.S.C.), the Melanoma Institute Australia, University of Sydney (M.S.C., G.V.L.), Royal North Shore Hospital (G.V.L.), and Mater Hospital (G.V.L.), Sydney, and Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC (S.S.) - all in Australia; Aix-Marseille Université, Assistance Publique-Hôpitaux de Marseille, Marseille (C.G.-M.), and Université Paris Cité, Assistance Publique-Hôpitaux de Paris (AP-HP) Dermato-oncology, Clinical Investigation Center, the Cancer Institute, AP-HP Nord Paris Cité, INSERM Unité 976, and St. Louis Hospital, Paris (C.L.) - all in France; the University of Colorado Cancer Center, Aurora (T.M.); Rogel Cancer Center, University of Michigan, Ann Arbor (C.D.L.); Hospital General Universitario Gregorio Marañon, Madrid (I.M-R.); the Netherlands Cancer Institute, Amsterdam (J.B.A.G.H.); University Hospital Leuven and Leuven Cancer Institute, KU Leuven, Leuven, Belgium (P.S.); Bristol Myers Squibb, Princeton, NJ (C.R., M.A., M.P.B., W.W.); and Dana-Farber Cancer Institute, Boston (F.S.H.).
N Engl J Med. 2025 Jan 2;392(1):11-22. doi: 10.1056/NEJMoa2407417. Epub 2024 Sep 15.
Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions.
We randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo. Treatment was continued until the occurrence of disease progression, unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to mutation status, metastasis stage, and programmed death ligand 1 expression. Here, we report the final, 10-year results of this trial, including results for overall survival and melanoma-specific survival, as well as durability of response.
With a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI], 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52 to 0.76) for nivolumab as compared with ipilimumab. Median melanoma-specific survival was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the trial), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab.
The final trial results showed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. (Funded by Bristol Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
该试验之前的结果显示，在晚期黑色素瘤患者中，与单纯使用伊匹木单抗治疗相比，使用纳武利尤单抗联合伊匹木单抗或纳武利尤单抗单药治疗后的总生存期更长。鉴于晚期黑色素瘤患者的生存期超过7.5年，因此需要更长期的数据来解决新出现的临床相关问题。
我们将先前未接受过治疗的晚期黑色素瘤患者按1:1:1的比例随机分配至以下治疗方案之一：纳武利尤单抗（每千克体重1毫克）联合伊匹木单抗（每千克体重3毫克），每3周一次，共4剂，随后每2周给予纳武利尤单抗（每千克体重3毫克）；每2周给予纳武利尤单抗（每千克体重3毫克）联合安慰剂；或每3周给予伊匹木单抗（每千克体重3毫克），共4剂联合安慰剂。治疗持续至疾病进展、出现不可接受的毒性作用或患者撤回知情同意。随机分组根据突变状态、转移阶段和程序性死亡配体1表达进行分层。在此，我们报告该试验的最终10年结果，包括总生存期和黑色素瘤特异性生存期结果以及缓解持续时间。
在至少随访10年的情况下，纳武利尤单抗联合伊匹木单抗治疗组的中位总生存期为71.9个月，纳武利尤单抗单药治疗组为36.9个月，伊匹木单抗单药治疗组为19.9个月。与伊匹木单抗相比，纳武利尤单抗联合伊匹木单抗治疗组的死亡风险比为0.53（95%置信区间[CI]，0.44至0.65），纳武利尤单抗单药治疗组为0.63（95%CI，0.52至0.76）。纳武利尤单抗联合伊匹木单抗治疗组的中位黑色素瘤特异性生存期超过120个月（未达到，37%的患者在试验结束时仍存活），纳武利尤单抗单药治疗组为49.4个月，伊匹木单抗单药治疗组为21.9个月。在3年时存活且无疾病进展的患者中，纳武利尤单抗联合伊匹木单抗治疗组的10年黑色素瘤特异性生存率为96%，纳武利尤单抗单药治疗组为97%，伊匹木单抗单药治疗组为88%。
最终试验结果显示，与伊匹木单抗单药治疗相比，在晚期黑色素瘤患者中，纳武利尤单抗联合伊匹木单抗及纳武利尤单抗单药治疗持续具有生存获益。（由百时美施贵宝公司等资助；CheckMate 067临床试验注册号，NCT01844505。）
