贝伐珠单抗联合依维莫司对比舒尼替尼用于晚期肾细胞癌的治疗。

Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma.

机构信息

From Dana-Farber Cancer Institute, Boston (T.K.C.); Barts Cancer Centre, Queen Mary University of London BRC, Royal Free NHS Trust, London (T.P.), and Beatson West of Scotland Cancer Centre and the University of Glasgow, Glasgow (B.V.) - all in the United Kingdom; HUS Helsinki University Hospital, Comprehensive Cancer Center, Helsinki (K.P.); University Hospital 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid (G.V.), and Medical Oncology, Vall d´Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d´Hebron, Vall d´Hebron Barcelona Hospital Campus (C.S.), and Institute Catalan of Oncology-ICO-IDIBELL University of Barcelona (X.G.-M.), Barcelona - all in Spain; Bradford Hill Clinical Research Center, Santiago, Chile (M.B.); Fox Chase Cancer Center, Philadelphia (P.G.); Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome (R.I.), Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (E.V.), the University of Bari "A. Moro" and Azienda Ospedaliera Policlinico di Bari, Bari (C.P.), and Fondazione Salvatore Maugeri clinica del lavoro, Pavia (E.B.) - all in Italy; the University of Colorado Cancer Center, Aurora (E.T.L.); Istanbul Medeniyet University, Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey (M.G.); the University of Chicago Medical Center, Chicago (W.M.S.); BC Cancer-Vancouver Center, Vancouver, BC, Canada (C.K.); the Department of Oncology, Palacký University and University Hospital, Olomouc (B.M.), and the Department of Comprehensive Cancer Care and Faculty of Medicine, Masaryk Memorial Cancer Institute and Masaryk University, Brno (A.P.) - both in the Czech Republic; University Hospital Bordeaux-Hôpital Saint-André, Bordeaux (M.G.-G.), and Département de Médecine Oncologique, Gustave Roussy, Université Paris Saclay, Villejuif (L.A.) - both in France; Charité Universitaetsmedizin Berlin, Department of Urology, Berlin (M.D.S.); the Department of Urology, Medical University of Vienna, Vienna (M.D.S.); BP-A Beneficencia Portuguesa de São Paulo, Sao Paulo (F.A.S.); Samsung Medical Center, Sungkyunkwan University School of Medicine (S.H.P.), and Asan Medical Center, University of Ulsan College of Medicine (J.L.L.) - both in Seoul, South Korea; Central Clinical Hospital with Polyclinic, Moscow (D.A.N.); Sociedad de Oncología y Hematología del Cesar, Valledupar, Colombia (R.M.K.); Keio University Hospital, Tokyo (M.O.); Merck, Rahway, NJ (L.H., A.W., R.F.P., D.V.); and Vanderbilt Ingram Cancer Center, Nashville (B.R.).

出版信息

N Engl J Med. 2024 Aug 22;391(8):710-721. doi: 10.1056/NEJMoa2313906.

DOI:10.1056/NEJMoa2313906

PMID:39167807

Abstract

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.).

摘要

背景

缺氧诱导因子 2α 抑制剂贝伐单抗在早期研究中显示出在透明细胞肾细胞癌中的临床活性。

方法

在一项 3 期、多中心、开放标签、活性对照试验中，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患者，并将其以 1:1 的比例随机分配，接受 120mg 贝伐单抗或 10mg 依维莫司每日口服一次，直至疾病进展或出现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。主要次要终点是客观缓解的发生（确认的完全或部分缓解）。

结果

共有 374 名参与者被分配至贝伐单抗组，372 名参与者被分配至依维莫司组。在第一次中期分析（中位随访时间 18.4 个月）时，两组的无进展生存期中位数均为 5.6 个月；在 18 个月时，贝伐单抗组 24.0%的参与者和依维莫司组 8.3%的参与者存活且无疾病进展（双侧 P=0.002，达到了预设的显著性标准）。贝伐单抗组确认的客观缓解率为 21.9%（95%可信区间 [CI]，17.8 至 26.5），依维莫司组为 3.5%（95%CI，1.9 至 5.9）（P<0.001，达到了预设的显著性标准）。在第二次中期分析（中位随访时间 25.7 个月）时，贝伐单抗组的总生存期中位数为 21.4 个月，依维莫司组为 18.1 个月；在 18 个月时，分别有 55.2%和 50.6%的参与者存活（死亡风险比，0.88；95%CI，0.73 至 1.07；双侧 P=0.20，未达到预设的显著性标准）。任何原因导致的 3 级或更高等级不良事件在贝伐单抗组中发生在 61.8%的参与者中（5 级为 3.5%），在依维莫司组中发生在 62.5%的参与者中（5 级为 5.3%）。不良事件导致 5.9%和 14.7%的参与者分别停止治疗。

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中，贝伐单抗在无进展生存期和客观缓解方面较依维莫司有显著获益。贝伐单抗无新的安全性信号。（由默克密理博公司（Merck Sharp and Dohme，默克公司的子公司）资助；LITESPARK-005 ClinicalTrials.gov 编号，NCT04195750。）