纳武利尤单抗联合伊匹木单抗与舒尼替尼治疗晚期肾细胞癌的比较
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.
作者信息
Motzer Robert J, Tannir Nizar M, McDermott David F, Arén Frontera Osvaldo, Melichar Bohuslav, Choueiri Toni K, Plimack Elizabeth R, Barthélémy Philippe, Porta Camillo, George Saby, Powles Thomas, Donskov Frede, Neiman Victoria, Kollmannsberger Christian K, Salman Pamela, Gurney Howard, Hawkins Robert, Ravaud Alain, Grimm Marc-Oliver, Bracarda Sergio, Barrios Carlos H, Tomita Yoshihiko, Castellano Daniel, Rini Brian I, Chen Allen C, Mekan Sabeen, McHenry M Brent, Wind-Rotolo Megan, Doan Justin, Sharma Padmanee, Hammers Hans J, Escudier Bernard
机构信息
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.).
出版信息
N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21.
BACKGROUND
Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma.
METHODS
We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk.
RESULTS
A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups.
CONCLUSIONS
Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749 .).
背景
在一项初步研究中，纳武利尤单抗联合伊匹木单抗在晚期肾细胞癌患者中产生了客观缓解。这项3期试验比较了纳武利尤单抗联合伊匹木单抗与舒尼替尼用于既往未接受治疗的透明细胞晚期肾细胞癌的疗效。
方法
我们将成年人按1:1的比例随机分配，一组接受纳武利尤单抗（每千克体重3毫克）联合伊匹木单抗（每千克1毫克），每3周静脉注射一次，共4剂，随后每2周接受纳武利尤单抗（每千克体重3毫克）治疗；另一组接受舒尼替尼（50毫克）口服，每日一次，共4周（6周为一个周期）。共同主要终点是预后风险为中度或较差的患者的总生存期（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1096例患者被分配接受纳武利尤单抗联合伊匹木单抗（550例患者）或舒尼替尼（546例患者）治疗；分别有425例和422例患者预后风险为中度或较差。在中度和低风险患者中，中位随访25.2个月时，纳武利尤单抗联合伊匹木单抗组的18个月总生存率为75%（95%置信区间[CI]，70至78），舒尼替尼组为60%（95%CI，55至65）；纳武利尤单抗联合伊匹木单抗组未达到中位总生存期，而舒尼替尼组为26.0个月（死亡风险比，0.63；P<0.001）。客观缓解率分别为42%和27%（P<0.001），完全缓解率分别为9%和1%。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，根据预先设定的0.009阈值无统计学意义）。纳武利尤单抗联合伊匹木单抗组547例患者中有509例（93%）发生了与治疗相关的不良事件，舒尼替尼组535例患者中有521例（97%）发生了与治疗相关的不良事件；3级或4级事件分别发生在250例患者（46%）和335例患者（63%）中。导致停药的与治疗相关的不良事件分别发生在各组22%和12%的患者中。
结论
在既往未接受治疗的晚期肾细胞癌的中度和低风险患者中，纳武利尤单抗联合伊匹木单抗的总生存期和客观缓解率显著高于舒尼替尼。（由百时美施贵宝公司和小野制药公司资助；CheckMate 214临床试验注册号，NCT02231749。）
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