纳武利尤单抗联合治疗晚期食管鳞癌。
Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.
机构信息
From Osaka University Graduate School of Medicine, Osaka (Y.D., T.M.), National Cancer Center Hospital (K. Kato), Toranomon Hospital (M.U.), and Keio University School of Medicine (Y.K.), Tokyo, Akita University Hospital, Akita (S.M.), Kanagawa Cancer Center, Kanagawa (T.O.), and Kindai University Faculty of Medicine, Osakasayama (H.K.) - all in Japan; University of Texas M.D. Anderson Cancer Center, Houston (J.A.A.); Fifth Medical Center, Chinese PLA General Hospital, Beijing (J.X.), and Zhongshan Hospital, Fudan University, Shanghai (T.L.); Klinika Onkologii i Radioterapii, Narodowy Instytut Onkologii, Warsaw, Poland (L.W.); National Taiwan University Hospital, Taipei (C.-H.H.), and E-Da Hospital and I-Shou University, Kaohsiung (W.-C.Y.) - both in Taiwan; Institut de Recherche en Cancérologie de Montpellier, INSERM, Université Montpellier, Institut du Cancer de Montpellier, Montpellier (A.A.), and Centre Oscar Lambret, Lille (F.E.H.) - both in France; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (M.D.B.); Institute of Cancer of São Paulo, University of São Paulo, São Paulo (M.I.B.); Odense University Hospital, Odense, Denmark (E.H.); Hospital Provincial del Centenario, Rosario, Argentina (S.A.O.); the Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea (H.R.K.); the Christie NHS Foundation Trust, Manchester (W.M.), the UCL Cancer Institute, University College London, London (J.B.), and the Royal Marsden Hospital (Surrey), Sutton (I.C.) - all in the United Kingdom; and Bristol Myers Squibb, Princeton, NJ (I.X., X.L., M.L., K. Kondo, A.P., J.G.).
出版信息
N Engl J Med. 2022 Feb 3;386(5):449-462. doi: 10.1056/NEJMoa2111380.
BACKGROUND
First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma.
METHODS
In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients).
RESULTS
A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone.
CONCLUSIONS
Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).
背景
晚期食管鳞癌的一线化疗结果不佳。单克隆抗体纳武利尤单抗在先前接受治疗的晚期食管鳞癌患者中，与化疗相比显示出总生存获益。
方法
在这项开放标签、3 期试验中，我们以 1:1:1 的比例随机分配未经治疗的、不可切除的晚期、复发性或转移性食管鳞癌的成年患者接受纳武利尤单抗联合化疗、纳武利尤单抗联合单克隆抗体伊匹单抗或化疗。主要终点是由盲法独立中心评估确定的总生存和无进展生存。分层检验首先在肿瘤细胞程序性死亡配体 1（PD-L1）表达为 1%或更高的患者中进行，然后在总体人群（所有随机分配的患者）中进行。
结果
共有 970 名患者接受了随机分组。在 13 个月的最小随访中，与化疗相比，纳武利尤单抗联合化疗在肿瘤细胞 PD-L1 表达为 1%或更高的患者中（中位总生存期，15.4 个月 vs. 9.1 个月；风险比，0.54；99.5%置信区间[CI]，0.37 至 0.80；P<0.001）和总体人群中（中位总生存期，13.2 个月 vs. 10.7 个月；风险比，0.74；99.1%CI，0.58 至 0.96；P=0.002）的总生存期显著延长。与化疗相比，纳武利尤单抗联合伊匹单抗在肿瘤细胞 PD-L1 表达为 1%或更高的患者中（中位总生存期，13.7 个月 vs. 9.1 个月；风险比，0.64；98.6%CI，0.46 至 0.90；P=0.001）和总体人群中（中位总生存期，12.7 个月 vs. 10.7 个月；风险比，0.78；98.2%CI，0.62 至 0.98；P=0.01）的总生存期也显著延长。在肿瘤细胞 PD-L1 表达为 1%或更高的患者中，与化疗相比，纳武利尤单抗联合化疗也显著改善了无进展生存期（疾病进展或死亡的风险比，0.65；98.5%CI，0.46 至 0.92；P=0.002），但纳武利尤单抗联合伊匹单抗与化疗相比无进展生存期无显著改善。3 级或 4 级治疗相关不良事件的发生率为纳武利尤单抗联合化疗组为 47%，纳武利尤单抗联合伊匹单抗组为 32%，化疗组为 36%。
结论
在晚期食管鳞癌患者中，纳武利尤单抗联合化疗的一线治疗和纳武利尤单抗联合伊匹单抗的一线治疗均显著延长了总生存期，与化疗相比，未发现新的安全性信号。（由 Bristol Myers Squibb 和小野制药公司资助；CheckMate 648 临床试验。gov 编号，NCT03143153。）
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