纳武利尤单抗联合伊匹单抗与舒尼替尼治疗晚期肾细胞癌的比较研究 - NEJM医学前沿
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纳武利尤单抗联合伊匹单抗与舒尼替尼治疗晚期肾细胞癌的比较研究
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma


Robert J. Motzer ... 肿瘤 • 2018.04.05
相关阅读
• 晚期肾细胞癌的纳武利尤单抗联合伊匹单抗疗法 • ASCO 2017报告——泌尿生殖系统癌症 • 转移性肾细胞癌的全身性治疗 • 抗PD-1抗体在癌症治疗中的安全性、有效性和免疫的相关性

转移性肾癌的首选药物:免疫治疗还是抗血管生成

 

刘天舒

复旦大学附属中山医院肿瘤内科

 

在很长的一段历史时期,细胞因子曾作为晚期转移性肾癌唯一的选择。因为肾癌被认为是一种免疫源性肿瘤,在癌细胞的周围浸润着大量的炎症细胞,包括T细胞、NK细胞、树突状细胞和巨噬细胞等。而细胞因子是一类由细胞分泌的具有生物活性的小分子蛋白质,通过作用于上述炎症细胞,增强杀伤作用和免疫监视来发挥抗肿瘤效应。目前用于治疗转移性肾癌的细胞因子主要为IL-2和IFN-α。然而,大剂量IL-2治疗转移性肾透明细胞癌的客观反应率仅为15%,而IFN-α单药治疗转移性肾癌的有效率仅为5%~15%,且未见很好的生存优势。因此,新型药物,尤其是新型免疫治疗药物的开发一直是转移性肾癌治疗中亟待解决的问题。

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摘要


背景

在一项先导性研究中,纳武利尤单抗联合伊匹单抗治疗晚期肾细胞癌患者可获得客观缓解。在本项3期临床试验中,以未经治疗的晚期肾透明细胞癌患者为研究对象,对纳武利尤单抗联合伊匹单抗治疗和舒尼替尼治疗进行了比较。

 

方法

我们将成人患者按照1∶1的比例随机分组,接受以下两种方案的治疗:纳武利尤单抗(3 mg/kg体重)联合伊匹单抗(1 mg/kg)静脉输入治疗,每3周1次,共4次,继之以纳武利尤单抗(3 mg/kg),每2周1次;或舒尼替尼(50 mg)口服,每日1次,每个周期用药4周(每6周1个周期)。联合主要终点包括预后中危或高危患者的总生存期(α水平为0.04)、客观缓解率(α水平为0.001)和无进展生存期(α水平为0.009)。

 

结果

共有1,096例患者接受分组,分别接受纳武利尤单抗联合伊匹单抗治疗(550例)或舒尼替尼治疗(546例);两组分别有425例和422例中危或高危患者。在中位随访时间为25.2个月时,对于中危或高危的患者,纳武利尤单抗联合伊匹单抗治疗组的18个月总生存率为75%(95%置信区间[CI],70~78),舒尼替尼治疗组则为60%(95% CI,55~65);纳武利尤单抗联合伊匹单抗治疗组的中位总生存期尚未达到,而舒尼替尼组则为26.0个月(死亡风险比,0.63;P<0.001)。客观缓解率分别为42%与27%(P<0.001),完全缓解率分别为9%与1%。两组的中位无进展生存期分别为11.6个月和8.4个月(疾病进展或死亡风险比,0.82;P=0.03,预先设定的阈值为0.009,差异无显著性)。在纳武利尤单抗联合伊匹单抗治疗组547例患者中,509例患者(93%)出现治疗相关不良事件;而舒尼替尼组535例患者中,521例(97%)发生治疗相关不良事件;两组分别有250例(46%)与335例(63%)患者出现3级或4级不良事件。两组分别有22%与12%的患者因治疗相关不良事件而终止治疗。

 

结论

对于未经治疗、中危或高危的晚期肾细胞癌患者,纳武利尤单抗联合伊匹单抗的总生存率与客观缓解率均显著高于舒尼替尼(由百时美施贵宝公司和小野制药株式会社[Ono Pharmaceutical]资助;CheckMate 214在ClinicalTrials.gov注册号为NCT02231749)。





作者信息

Robert J. Motzer, M.D., Nizar M. Tannir, M.D., David F. McDermott, M.D., Osvaldo Arén Frontera, M.D., Bohuslav Melichar, M.D., Ph.D., Toni K. Choueiri, M.D., Elizabeth R. Plimack, M.D., Philippe Barthélémy, M.D., Ph.D., Camillo Porta, M.D., Saby George, M.D., Thomas Powles, M.D., Frede Donskov, M.D., Ph.D., Victoria Neiman, M.D., Christian K. Kollmannsberger, M.D., Pamela Salman, M.D., Howard Gurney, M.D., Robert Hawkins, M.D., Alain Ravaud, M.D., Ph.D., Marc-Oliver Grimm, M.D., Sergio Bracarda, M.D., Carlos H. Barrios, M.D., Yoshihiko Tomita, M.D., Ph.D., Daniel Castellano, M.D., Brian I. Rini, M.D., Allen C. Chen, M.D., Sabeen Mekan, M.D., M. Brent McHenry, Ph.D., Megan Wind-Rotolo, Ph.D., Justin Doan, M.Sc., M.P.H., Padmanee Sharma, M.D., Ph.D., Hans J. Hammers, M.D., Ph.D., and Bernard Escudier, M.D. for the CheckMate 214 Investigators*
From Memorial Sloan Kettering Cancer Center, New York (R.J.M.), and Roswell Park Cancer Institute, Buffalo (S.G.) — both in New York; University of Texas M.D. Anderson Cancer Center, Houston (N.M.T., P. Sharma); Beth Israel Deaconess Medical Center, Dana–Farber/Harvard Cancer Center (D.F.M.), and Dana–Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School (T.K.C.), Boston; Centro Internacional de Estudios Clínicos (O.A.F.) and Fundación Arturo López Pérez (P. Salman), Santiago, Chile; Palacký University and University Hospital Olomouc, Olomouc, Czech Republic (B.M.); Fox Chase Cancer Center, Philadelphia (E.R.P.); Hôpitaux Universitaires de Strasbourg, Strasbourg (P.B.), Bordeaux University Hospital, Hôpital Saint-André, Bordeaux (A.R.), and Institut Gustave Roussy, Villejuif (B.E.) — all in France; Istituto di Ricovero e Cura a Carattere Scientifico San Matteo University Hospital Foundation, Pavia (C.P.), and Ospedale San Donato, Azienda Unità Sanitaria Locale Toscana Sud-Est, Istituto Toscano Tumori, Arezzo (S.B.) — both in Italy; Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust (T.P.), and Cancer Research UK (R.H.), London; Aarhus University Hospital, Aarhus, Denmark (F.D.); Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, and Tel Aviv University, Tel Aviv — both in Israel (V.N.); British Columbia Cancer Agency, Vancouver, Canada (C.K.K.); Westmead Hospital and Macquarie University, Sydney (H.G.); Jena University Hospital, Jena, Germany (M.-O.G.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Porto Alegre, Brazil (C.H.B.); Niigata University, Niigata, Japan (Y.T.); Hospital Universitario 12 de Octubre, Madrid (D.C.); Cleveland Clinic Taussig Cancer Institute, Cleveland (B.I.R.); Bristol-Myers Squibb, Princeton, NJ (A.C.C., S.M., M.B.M., M.W.-R., J.D.); and Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore (H.J.H.). Address reprint requests to Dr. Motzer at Memorial Sloan Kettering Cancer Center, Memorial Hospital, 1275 York Ave., New York, NY 10065, or at motzerr@mskcc.org; or to Dr. Sharma at M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, or at padsharma@mdanderson.org. *A complete list of investigators in the CheckMate 214 trial is provided in the Supplementary Appendix, available at NEJM.org.

 

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