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Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma Robert J. Motzer, M.D.1, 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., N Engl J Med 2018; 378:1277-1290 DOI: 10.1056/NEJMoa1712126 作者机构：1.纪念斯隆凯特琳癌症中心 Background 背景 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. 在初步研究中，晚期肾细胞癌患者对纳武单抗加易普利姆玛产生了客观缓解。3 期试验对先前未治疗的晚期肾透明细胞癌患者进行了纳武单抗加易普利姆玛与舒尼替尼的对比。 Methods 方法 We randomly a s sig ne d adult s i n a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 week s 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. 我们按1:1 的比例将成人随机分成两组，第一组每3 周 静脉注射一剂纳武单抗（3 mg/kg）加易普利姆玛（1mg/kg），共注射四剂后，每2 周注射一剂纳武单抗（3mg/kg）。第二组每日口服一次舒尼替尼（50 mg），服用4 周（6周为一周期）。复合主要终点是预后风险为中危或高危的患者的总生存率（alpha 值, 0.04）、客观缓解率（alpha值, 0.001）和无进展生存期（alpha 值, 0.009）。 Results 结果 A total of 1096 patients were assigned to receiven ivolumab plus ipilimumab ( 5 5 0 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 4 2% ve r s u s 2 7% ( P < 0 . 0 01), a n d t h e complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8 . 4 month s, respectively ( h a z a rdratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold).Tre atment-related adverse event s occurred in 509 of 547 patients (93%) in the nivolumab-plusipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 2 5 0 patient s (4 6%) a n d 3 3 5 patient s (6 3%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. 共1096 例患者随机分配为纳武单抗加易普利姆玛组（550例）和舒尼替尼组（546 例），两组中分别有425 例和422例为预后风险中危或高危患者。中危和高危患者的中位随访时间为25.2 个月，纳武单抗加易普利姆玛组的18 个月总生存率为75%（95% 置信区间[CI], 70-78），舒尼替尼组为60%（95%CI, 55-65）；纳武单抗加易普利姆玛组未得出中位总生存期，而舒尼替尼组为26.0 个月（死亡风险比, 0.63; P<0.001）。两组的客观缓解率分别为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（疾病进展风险比或死亡风险比, 0.82; P=0.03, 参照既定阈值0.009，无显著意义）。在纳武单抗加易普利姆玛组，547例患者中有509 例（93%）出现治疗相关的不良事件；在舒尼替尼组，535 例患者中有521 例（97%）出现此类不良事件。两组分别有250 例（46%）和335 例（63%）患者出现了三级或四级不良事件，且两组分别有22% 和12%的患者出现了导致治疗中止的治疗相关不良事件。 Conclusions 结论 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.) 在先前未治疗且预后风险为中危和高危的晚期肾细胞癌患者中，纳武单抗加易普利姆玛组的总生存率和客观缓解率明显高于舒尼替尼组。 (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; Check Mate 214 ClinicalTrials.gov number,NCT02231749.) |
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