From the Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, 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 National Health Service Trust, London (T.P.); the Bradford Hill Clinical Research Center, Santiago, Chile (M.B.); the Department of Medical Oncology, Gustave Roussy, Villejuif, France (B.E.); the Department of Hemato-Oncology, Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (M.T.B.), the Department of Medical Oncology, Centro Universitario contra el Cáncer, Hospital Universitario "Dr. José Eleuterio González," Universidad Autónoma de Nuevo León, Nuevo León (V.M.O.J.), and the Department of Medical Oncology, Hospital H+ Querétaro, Querétaro (J.P.F.) - all in Mexico; the Department of Outpatient Chemotherapy, Professor Franciszek Lukaszczyk Oncology Center, Bydgoszcz (B.Z.), and the Department of Clinical Oncology and Hematology, Regional Specialist Hospital, Biała Podlaska (J. Żołnierek) - both in Poland; the Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis (J.J.H.); Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IRCCS, Padua (U.B.), the Department of Medical Oncology, Ospedale San Donato, Istituto Toscano i, Arezzo (A.H.), the Department of Internal Medicine, University of Pavia, Pavia (C.P.), and the University of Bari "A. Moro," Bari (C.P.) - all in Italy; the Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston (A.Y.S.); the Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona (C.S.); the Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, QLD (J.C.G.), and Cabrini Monash University Department of Medical Oncology, Cabrini Health, Malvern, VIC (D.P.) - both in Australia; the Oncology Research Center, Hospital São Lucas, Porto Alegre, Brazil (C.B.); Fundacion Richardet Longo, Instituto Oncologico de Cordoba, Cordoba (M.R.), and Instituto Multidisciplinario de Oncología, Clínica Viedma, Viedma (R.K.) - both in Argentina; the Division of Medical Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora (E.R.K.); the Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata (Y.T.), and the Department of Urology, Keio University School of Medicine, Tokyo (R.M.) - both in Japan; the Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany (J.B.); the Departments of Clinical Research (J. Zhang.), Clinical Oncology (M.A.M.), Biostatistics (B.S.), and Health Economics and Outcomes Research (F.E.), Bristol Myers Squibb, Princeton, NJ; the Department of Clinical Oncology, Exelixis, Alameda, CA (G.M.S.); the Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.B.A.); and the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.J.M.).
N Engl J Med. 2021 Mar 4;384(9):829-841. doi: 10.1056/NEJMoa2026982.
BACKGROUND: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known. METHODS: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point. RESULTS: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib. CONCLUSIONS: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).
背景：纳武利尤单抗联合卡博替尼与舒尼替尼在治疗未经治疗的晚期肾细胞癌方面的疗效和安全性尚未可知。
方法：在这项 3 期、随机、开放标签试验中，我们将未经治疗的透明细胞、晚期肾细胞癌的成人患者随机分配，接受纳武利尤单抗（每 2 周 240mg）加卡博替尼（每日 40mg）或舒尼替尼（每 6 周周期的 4 周内每日 50mg）治疗。主要终点是盲法独立中心评估的无进展生存期。次要终点包括总生存期、独立评估的客观缓解率和安全性。健康相关生活质量是一个探索性终点。
结果：共有 651 例患者被分配接受纳武利尤单抗加卡博替尼（323 例）或舒尼替尼（328 例）治疗。在总生存期的中位随访 18.1 个月时，纳武利尤单抗加卡博替尼组的中位无进展生存期为 16.6 个月（95%CI，12.5 至 24.9），舒尼替尼组为 8.3 个月（95%CI，7.0 至 9.7）（疾病进展或死亡风险比，0.51；95%CI，0.41 至 0.64；P<0.001）。纳武利尤单抗加卡博替尼组 12 个月总生存率为 85.7%（95%CI，81.3 至 89.1），舒尼替尼组为 75.6%（95%CI，70.5 至 80.0）（死亡风险比，0.60；98.89%CI，0.40 至 0.89；P = 0.001）。接受纳武利尤单抗加卡博替尼治疗的患者中有 55.7%发生客观缓解，而接受舒尼替尼治疗的患者中有 27.1%发生客观缓解（P<0.001）。纳武利尤单抗加卡博替尼的疗效获益在各亚组中是一致的。接受纳武利尤单抗加卡博替尼治疗的 320 例患者中，有 75.3%发生任何级别 3 级及以上的不良事件，接受舒尼替尼治疗的 320 例患者中，有 70.6%发生任何级别 3 级及以上的不良事件。总体而言，联合治疗组中有 19.7%的患者因不良事件至少停止了一种试验药物的治疗，5.6%的患者停止了两种药物的治疗。与舒尼替尼相比，接受纳武利尤单抗加卡博替尼治疗的患者报告了更好的健康相关生活质量。
结论：与舒尼替尼相比，纳武利尤单抗联合卡博替尼在未经治疗的晚期肾细胞癌患者的无进展生存期、总生存期和缓解率方面具有显著优势。（由 Bristol Myers Squibb 等资助；CheckMate 9ER ClinicalTrials.gov 编号，NCT03141177。）
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