University of California Davis Comprehensive Cancer Center, Sacramento.
SWOG Statistical Center, Seattle, Washington.
JAMA Netw Open. 2024 Aug 1;7(8):e2425288. doi: 10.1001/jamanetworkopen.2024.25288.
Clinical trial data on adjuvant therapy in patients with non-clear cell renal cell carcinoma (RCC) are scant.
To evaluate the effect of adjuvant everolimus after nephrectomy on recurrence-free survival (RFS) and overall survival (OS) in patients with localized papillary and chromophobe RCC.
DESIGN, SETTING, AND PARTICIPANTS: This prespecified subgroup analysis of a phase 3 randomized clinical trial, EVEREST, included patients enrolled between April 1, 2011, and September 15, 2016. Eligible patients had fully resected RCC at intermediate-high risk (pT1 grade 3-4, N0 to pT3a grade 1-2, N0) or very-high risk (pT3a grade 3-4 to pT4 any grade or N+) for recurrence who had received radical or partial nephrectomy. Final analyses was completed in March 2022.
The intervention group received 54 weeks of everolimus (10 mg orally daily); the control group received a matching placebo.
The main outcomes were RFS, OS, and rates of adverse events. For testing the hazard ratio (HR) for treatment effect, a Cox regression model was used for both OS and RFS.
Of 1545 adult patients with treatment-naive, nonmetastatic, fully resected RCC in EVEREST, 109 had papillary RCC (median [range] age, 60 [19-81] years; 82 [75%] male; 50 patients [46%] with very high-risk disease) and 99 had chromophobe RCC (median [range] age 51 [18-71] years; 53 [54%] male; 34 patients [34%] with very high-risk disease). Among 57 patients with papillary RCC in the intervention group, 26 (46%) completed 54 weeks of treatment, and among 53 patients with chromophobe RCC in the intervention group, 26 (49%) completed 54 weeks of treatment. With a median (IQR) follow-up of 76 (61-96) months, adjuvant everolimus did not improve RFS compared with placebo in either papillary RCC (5-year RFS: 62% vs 70%; HR, 1.19; 95% CI, 0.61-2.33; P = .61) or chromophobe RCC (5-year RFS: 79% vs 77%; HR, 0.89; 95% CI, 0.37-2.13; P = .79). In the combined non-clear RCC cohort, grade 3 or higher adverse events occurred in 48% of patients who received everolimus and 9% of patients who received placebo.
In this clinical trial assessing the use of adjuvant everolimus, postoperative everolimus did not show evidence of improved RFS among patients with papillary or chromophobe RCC, and results from the study do not support adjuvant everolimus for this cohort. However, since the lower bounds of the 95% CIs were 0.61 and 0.89, respectively, potential treatment benefit in these subgroups cannot be ruled out.
ClinicalTrials.gov Identifier: NCT01120249.
重要性：关于非透明细胞肾细胞癌（RCC）辅助治疗的临床试验数据很少。
目的：评估肾切除术后辅助依维莫司对局限性乳头状和嫌色细胞 RCC 患者无复发生存率（RFS）和总生存率（OS）的影响。
设计、地点和参与者：这是一项 3 期随机临床试验 EVEREST 的预设亚组分析，纳入了 2011 年 4 月 1 日至 2016 年 9 月 15 日期间入组的患者。符合条件的患者为有复发高风险（pT1 分级 3-4、N0 至 pT3a 分级 1-2、N0）或极高风险（pT3a 分级 3-4 至 pT4 任何分级或 N+）的完全切除的 RCC 患者，接受了根治性或部分肾切除术。最终分析于 2022 年 3 月完成。
干预措施：干预组接受了 54 周的依维莫司（10mg 口服，每日一次）；对照组接受了匹配的安慰剂。
主要结果和测量：主要结果是 RFS、OS 和不良事件发生率。为了检验治疗效果的风险比（HR），采用 Cox 回归模型对 OS 和 RFS 进行检验。
结果：在 EVEREST 中，1545 例未经治疗、无转移、完全切除的非转移性 RCC 成年患者中，有 109 例为乳头状 RCC（中位[范围]年龄，60[19-81]岁；82[75%]为男性；50 例[46%]为极高危疾病），99 例为嫌色细胞 RCC（中位[范围]年龄 51[18-71]岁；53[54%]为男性；34 例[34%]为极高危疾病）。干预组 57 例乳头状 RCC 患者中，26 例（46%）完成了 54 周的治疗，干预组 53 例嫌色细胞 RCC 患者中，26 例（49%）完成了 54 周的治疗。中位（IQR）随访 76（61-96）个月，与安慰剂相比，辅助依维莫司并没有改善乳头状 RCC（5 年 RFS：62% vs 70%；HR，1.19；95%CI，0.61-2.33；P=0.61）或嫌色细胞 RCC（5 年 RFS：79% vs 77%；HR，0.89；95%CI，0.37-2.13；P=0.79）患者的 RFS。在非透明细胞 RCC 合并队列中，接受依维莫司治疗的患者中有 48%发生了 3 级或更高级别的不良事件，而接受安慰剂治疗的患者中有 9%发生了不良事件。
结论和相关性：在这项评估辅助依维莫司使用的临床试验中，术后依维莫司并未显示在乳头状或嫌色细胞 RCC 患者中改善 RFS 的证据，因此该研究结果不支持该队列使用依维莫司辅助治疗。然而，由于 95%CI 的下限分别为 0.61 和 0.89，因此不能排除这些亚组中存在潜在的治疗益处。
试验注册：ClinicalTrials.gov 标识符：NCT01120249。
