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Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial.

辅助nivolumab联合ipilimumab或nivolumab单药治疗与安慰剂治疗无疾病证据的切除IV期黑色素瘤患者 (免疫): 一项随机、双盲、安慰剂对照、 2 期试验。

  • 影响因子:10.28
  • DOI:10.1016/S0140-6736(20)30417-7
  • 作者列表:"Zimmer L","Livingstone E","Hassel JC","Fluck M","Eigentler T","Loquai C","Haferkamp S","Gutzmer R","Meier F","Mohr P","Hauschild A","Schilling B","Menzer C","Kieker F","Dippel E","Rösch A","Simon JC","Conrad B","Körner S","Windemuth-Kieselbach C","Schwarz L","Garbe C","Becker JC","Schadendorf D","Dermatologic Cooperative Oncology Group.
  • 发表时间:2020-05-16
Abstract

BACKGROUND:Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced-ie, unresectable or metastatic-melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population. METHODS:We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1-12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing. FINDINGS:Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n=56), nivolumab (n=59), or placebo (n=52). As of July 2, 2019, at a median follow-up of 28·4 months (IQR 17·7-36·8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12·4 months (95% CI 5·3-33·3) in the nivolumab group and 6·4 months (3·3-9·6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0·23 (97·5% CI 0·12-0·45; p<0·0001), and for the nivolumab group versus placebo group was 0·56 (0·33-0·94; p=0·011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61·0-84·9) and at 2 years was 70% (55·1-81·0); in the nivolumab group, 1-year recurrence-free survival was 52% (38·1-63·9) and at 2 years was 42% (28·6-54·5); and in the placebo group, this rate was 32% (19·8-45·3) at 1 year and 14% (5·9-25·7) at 2 years. Treatment-related grade 3-4 adverse events were reported in 71% (95% CI 57-82) of patients in the nivolumab plus ipilimumab group and in 27% (16-40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment. INTERPRETATION:Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3-4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease. FUNDING:Bristol-Myers Squibb.

摘要

背景: Nivolumab和ipilimumab,单独或联合使用,是广泛用于晚期ie、不可切除或转移性黑色素瘤患者的免疫治疗选择。然而,该标准排除了没有疾病证据的IV期黑色素瘤患者。因此,我们旨在评价辅助nivolumab联合ipilimumab或nivolumab单药治疗与安慰剂在该患者人群中的安全性和有效性。 方法: 我们在 20 个德国学术医疗中心进行了一项随机、双盲、安慰剂对照的 2 期试验。符合条件的患者年龄 18-80 岁,患有IV期黑色素瘤,手术或放疗后无疾病证据。关键排除标准包括葡萄膜或粘膜黑色素瘤、既往使用检查点抑制剂的治疗以及研究药物给药前 30 天内的任何既往免疫抑制治疗。符合条件的患者被随机分配 (1:1:1),使用中央,互动,在线系统,向nivolumab加ipilimumab组 (每 3 周静脉注射 1 mg/kg nivolumab,每 3 周静脉注射 3 mg/kg ipilimumab,共 4 个剂量,随后每 2 周注射 3 mg/kg nivolumab),nivolumab单药治疗组(每 2 周静脉注射nivolumab 3 mg/kg,在 1-12 周内加用ipilimumab匹配安慰剂),或双匹配安慰剂组。主要终点是意向治疗人群的无复发生存率。本报告中显示的结果反映了在报告 90 例事件后对无复发生存期的预先设定的中期分析。本研究在ClinicalTrials.gov,NCT02523313 注册,正在进行中。 结果: 在Sept 2015 和 2018 年 11 月 20 日之间,167 例患者被随机分配接受nivolumab联合ipilimumab (n = 56),nivolumab (n = 59),或安慰剂 (n = 52)。截至 2019 年 7 月 2 日,中位随访时间 28 · 4 个月 (IQR 17 · 7-36 · 8),nivolumab联合ipilimumab组未达到中位无复发生存期,而中位无复发生存期为 12 · 4 个月 (95% CI 5 · 3-33 · 3) nivolumab组和安慰剂组 6 · 4 个月 (3 · 3-9 · 6)。Nivolumab联合ipilimumab组与安慰剂组的复发风险比为 0 · 23 (97 · 5% CI 0 · 12-0 · 45; p<0 · 0001),nivolumab组与安慰剂组比较为 0 · 56 (0 · 33-0 · 94; p = 0 · 011)。在nivolumab联合ipilimumab组,1 年无复发生存率为 75% (95% CI 61 · 0-84 · 9) 2 年时为 70% (55 · 1-81 · 0); 在nivolumab组,1 年无复发生存率为 52% (38 · 1-63 · 9) 2 年时为 42% (28 · 6-54 · 5); 在安慰剂组中,1 年时这一比率为 32% (19 · 8-45 · 3),2 年时为 14% (5 · 9-25 · 7)。Nivolumab联合ipilimumab组 71% (95% CI 57-82) 的患者报告了治疗相关的 3-4 级不良事件,27% (16-40) 在nivolumab组中。任何级别的治疗相关不良事件导致nivolumab加ipilimumab组 55 例患者中 34 例 (62%) 停止治疗,nivolumab组 56 例患者中 7 例 (13%) 停止治疗。报告了 3 例不良事件死亡,但被认为与研究治疗无关。 解读: 在没有疾病证据的IV期黑色素瘤患者中,与安慰剂相比,nivolumab单独或联合ipilimumab的辅助治疗显著增加了无复发生存率。两个积极治疗组的 3-4 级治疗相关不良事件发生率均高于既往在具有可测量疾病的晚期黑色素瘤中进行的关键试验中报告的发生率。 资助: 百时美施贵宝。

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皮肤肿瘤方向

皮肤肿瘤是发生在皮肤的细胞增生性疾病,是一种常见病。发生于皮内或皮下组织的新生物,种类很多,临床上分良性肿瘤和恶性肿瘤。恶性肿瘤可以不断增殖,引起转移,威胁生命,称为皮肤癌。

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