Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA.
SWOG Statistics and Data Management Center, Seattle, WA, USA.
Lancet. 2023 Sep 23;402(10407):1043-1051. doi: 10.1016/S0140-6736(23)00913-3. Epub 2023 Jul 28.
Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery.
In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants.
Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo.
Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery.
US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.
接受肾细胞癌切除术的患者存在疾病复发的风险。我们评估了手术后使用雷帕霉素靶蛋白抑制剂依维莫司的效果。
在这项随机、双盲、III 期临床试验中，我们招募了在美国 398 家学术和社区机构中心接受了组织学证实的肾细胞癌切除术且具有中高危或极高复发风险的成年人。在肾切除术之后，患者通过中央基于网络的应用程序（使用动态平衡算法）以 1:1 的比例随机分配，接受每日口服 10 mg 依维莫司或安慰剂，持续 54 周。主要终点是无复发生存。疗效分析包括所有符合条件的、随机分配的患者；安全性分析包括所有接受治疗的患者。这项试验在 ClinicalTrials.gov 注册，NCT01120249，目前已不再招募新的参与者。
在 2011 年 4 月 1 日至 2016 年 9 月 15 日期间，共 1545 名患者被随机分配接受依维莫司（n=775）或安慰剂（n=770）治疗，其中 755 名分配接受依维莫司治疗和 744 名分配接受安慰剂治疗的患者符合纳入疗效分析的标准。中位随访 76 个月（IQR 61-92），依维莫司组的无复发生存率高于安慰剂组（5 年无复发生存率为 67%[95%CI 63-70]vs 63%[60-67]；分层对数秩检验 p=0.050；分层风险比[HR]0.85，95%CI 0.72-1.00；p=0.051），但未达到统计学意义的预设 p 值 0.044。在极高危组中，依维莫司组的无复发生存率高于安慰剂组（HR 0.79，95%CI 0.65-0.97；p=0.022），但在中高危组中无差异（0.99，0.73-1.35；p=0.96）。在接受依维莫司治疗的 740 名患者中，有 343 名（46%）发生了 3 级或以上的不良事件，在接受安慰剂治疗的 723 名患者中，有 79 名（11%）发生了这种情况。
与安慰剂相比，肾细胞癌切除术后的依维莫司并不能改善无复发生存。这些结果不支持依维莫司在手术后用于肾细胞癌的辅助治疗。
美国国立卫生研究院、美国国家癌症研究所、国家临床试验网络、诺华制药公司和希望基金会。
