卡博替尼联合纳武利尤单抗和伊匹单抗治疗肾细胞癌。

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma.

机构信息

From the Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School - both in Boston (T.K.C.); the Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust, London (T.P.); the Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France (L.A.); Bradford Hill Clinical Research Center, Santiago (M.B.), and James Lind Centro de Investigación del Cáncer, Temuco (E.Y.R.) - both in Chile; the Postgraduate Medical Center, Department of Oncology, European Health Center, Otwock, Warsaw (C. Szczylik), and the Department of Outpatient Chemotherapy, Professor Franciszek Łukaszczyk Oncology Center, Bydgoszcz (B.Z.) - both in Poland; Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IRCCS, Padua, Italy (M.M.); Consultorio de Medicina Especializada, Benito Juárez, Mexico City (A.S.Z.); Instituto de Oncología de Rosario, Rosario, Argentina (L.E.F.); Latin American Cooperative Oncology Group, Porto Alegre, and Beneficência Portuguesa de São Paulo, São Paulo - both in Brazil (F.A.S.); the Department of Medical Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada (D.Y.C.H.); Exelixis, Alameda, CA (F.W., F.M., Y.-L.C.); Bristol Myers Squibb, Boudry, Switzerland (M.K.L.); the Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Barcelona (C. Suarez); and the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.J.M.).

出版信息

N Engl J Med. 2023 May 11;388(19):1767-1778. doi: 10.1056/NEJMoa2212851.

DOI:10.1056/NEJMoa2212851

PMID:37163623

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10257898/

Abstract

BACKGROUND

The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown.

METHODS

In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization.

RESULTS

Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P = 0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing.

CONCLUSIONS

Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.).

摘要

背景

卡博替尼联合纳武利尤单抗和伊匹单抗治疗未经治疗的晚期肾细胞癌患者的疗效和安全性尚不清楚。

方法

在这项 3 期、双盲试验中，我们招募了未接受过治疗且根据国际转移性肾细胞癌数据库联盟分类具有中危或高危预后的晚期透明细胞肾细胞癌患者。患者被随机分配接受每日 40mg 卡博替尼联合纳武利尤单抗和伊匹单抗（实验组）或纳武利尤单抗和伊匹单抗联合匹配安慰剂（对照组）治疗。纳武利尤单抗（3mg/千克体重）和伊匹单抗（1mg/千克体重）每 3 周给药 1 次，共 4 个周期。然后，患者接受纳武利尤单抗维持治疗（480mg/每 4 周），最长 2 年。主要终点是根据实体瘤反应评价标准 1.1 进行盲法独立评估的无进展生存期，在接受随机分组的前 550 例患者中进行评估。次要终点是所有接受随机分组的患者的总生存期。

结果

共有 855 例患者接受了随机分组：428 例分配至实验组，427 例分配至对照组。在接受随机分组的前 550 例患者中（实验组 276 例，对照组 274 例），实验组 12 个月无进展生存率为 0.57，对照组为 0.49（疾病进展或死亡风险比，0.73；95%置信区间，0.57 至 0.94；P=0.01）；实验组 43%的患者有反应，对照组为 36%。实验组 79%的患者和对照组 56%的患者发生 3 级或 4 级不良事件。总生存随访仍在进行中。

结论

在具有中危或高危预后的未经治疗的晚期肾细胞癌患者中，卡博替尼联合纳武利尤单抗和伊匹单抗治疗与纳武利尤单抗和伊匹单抗单药治疗相比，无进展生存期显著延长。实验组比对照组更常见 3 级或 4 级不良事件。（由 Exelixis 资助；COSMIC-313 临床试验.gov 编号，NCT03937219）。