纳武利尤单抗辅助治疗与安慰剂用于肌肉浸润性尿路上皮癌。
Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma.
机构信息
From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.).
出版信息
N Engl J Med. 2021 Jun 3;384(22):2102-2114. doi: 10.1056/NEJMoa2034442.
BACKGROUND
The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear.
METHODS
In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point.
RESULTS
A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group.
CONCLUSIONS
In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).
背景
根治术后高危肌层浸润性尿路上皮癌的辅助治疗作用尚不清楚。
方法
在一项 3 期、多中心、双盲、随机、对照临床试验中，我们将接受根治性手术的肌层浸润性尿路上皮癌患者按 1:1 的比例随机分配，接受纳武利尤单抗（静脉注射 240mg）或安慰剂，每 2 周一次，持续 1 年。试验前允许使用新辅助顺铂为基础的化疗。主要终点是所有患者（意向治疗人群）和肿瘤程序性死亡配体 1（PD-L1）表达水平为 1%或更高的患者的无病生存。无尿路上皮外复发的生存是次要终点。
结果
共有 353 例患者接受纳武利尤单抗治疗，356 例患者接受安慰剂治疗。意向治疗人群的中位无病生存期为纳武利尤单抗组 20.8 个月（95%可信区间，16.5 至 27.6），安慰剂组为 10.8 个月（95%可信区间，8.3 至 13.9）。6 个月时无病生存且存活的患者比例，纳武利尤单抗组为 74.9%，安慰剂组为 60.3%（疾病复发或死亡的风险比，0.70；98.22%可信区间，0.55 至 0.90；P<0.001）。PD-L1 表达水平为 1%或更高的患者比例，分别为 74.5%和 55.7%（风险比，0.55；98.72%可信区间，0.35 至 0.85；P<0.001）。意向治疗人群中无尿路上皮外复发的中位生存时间为纳武利尤单抗组 22.9 个月（95%可信区间，19.2 至 33.4），安慰剂组为 13.7 个月（95%可信区间，8.4 至 20.3）。6 个月时无尿路上皮外复发且存活的患者比例，纳武利尤单抗组为 77.0%，安慰剂组为 62.7%（尿路上皮外复发或死亡的风险比，0.72；95%可信区间，0.59 至 0.89）。PD-L1 表达水平为 1%或更高的患者比例，分别为 75.3%和 56.7%（风险比，0.55；95%可信区间，0.39 至 0.79）。3 级或以上治疗相关不良事件发生率，纳武利尤单抗组为 17.9%，安慰剂组为 7.2%。纳武利尤单抗组有 2 例与治疗相关的肺炎死亡。
结论
在这项涉及接受根治性手术的高危肌层浸润性尿路上皮癌患者的试验中，与安慰剂相比，纳武利尤单抗在意向治疗人群和 PD-L1 表达水平为 1%或更高的患者中改善了无病生存。（由 Bristol Myers Squibb 和小野制药公司资助；CheckMate 274 临床试验.gov 编号，NCT02632409。）
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