背景:Belzutifan,缺氧诱导因子2α抑制剂,在早期研究中显示出透明细胞肾细胞癌的临床活性。
方法:在第三阶段,多中心,开放标签,主动对照试验,我们招募了先前接受过免疫检查点和抗血管生成治疗的晚期透明细胞肾细胞癌参与者,并将他们随机分配,以1:1的比例,每天一次口服120mg的贝祖蒂安或10mg的依维莫司,直到疾病进展或发生不可接受的毒性作用。双重主要终点是无进展生存期和总生存期。关键的次要终点是客观反应(确认的完全或部分反应)的发生。
结果:共有374名参与者被分配到belzutifan,和372依维莫司。在第一次中期分析(中位随访,18.4个月),两组的中位无进展生存期为5.6个月;在18个月时,belzutifan组中24.0%的参与者和依维莫司组中8.3%的参与者存活且无进展(双侧P=0.002,符合预设的显著性标准)。21.9%的参与者出现了确认的客观反应(95%置信区间[CI],belzutifan组的17.8至26.5)和依维莫司组的3.5%(95%CI,1.9至5.9)(P<0.001,符合预设的显著性标准)。在第二次中期分析(中位随访,25.7个月),贝佐蒂安组的中位总生存期为21.4个月,依维莫司组为18.1个月;18个月时,55.2%和50.6%的参与者,分别,还活着(死亡的危险比,0.88;95%CI,0.73~1.07;双侧P=0.20,不符合预设的显著性标准)。任何原因的3级或更高的不良事件发生在belzutifan组的61.8%(3.5%的5级)和依维莫司组的62.5%(5.3%的5级)。不良事件导致5.9%和14.7%的参与者停止治疗,分别。
结论:在先前接受过免疫检查点和抗血管生成治疗的晚期透明细胞肾细胞癌患者的无进展生存期和客观反应方面,Belzutifan显示出比依维莫司显著的益处。Belzutifan没有新的安全信号。(由默克夏普和多姆资助,默克公司的子公司;LITESPARK-005ClinicalTrials.gov编号,NCT04195750。).
BACKGROUND: Belzutifan, a hypoxia-inducible factor 2α inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies.
METHODS: In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response).
RESULTS: A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P = 0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P = 0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively.
CONCLUSIONS: Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies. Belzutifan was associated with no new safety signals. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.).