Everolimus in the management of metastatic renal cell carcinoma: an evidence-based review of its place in therapy.
Everolimus in the management of metastatic renal cell carcinoma: an evidence-based review of its place in therapy.
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DOI：
10.2147/ce.s98687
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Bersanelli M
中科院分区：
文献类型：
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作者：
Buti S;Leonetti A;Dallatomasina A;Bersanelli M
肾细胞癌（Renal cell carcinoma，RCC）是成人中最常见的肾癌类型，其发病机制与细胞对缺氧的反应改变密切相关，其中mTOR信号通路参与其中。依维莫司是一种mTOR丝氨酸/苏氨酸激酶抑制剂，代表了治疗晚期RCC的治疗选择。本文的目的是审查依维莫司治疗转移性肾细胞癌的证据。根据一项III期关键性试验的结果，依维莫司被批准用于晚期RCC患者的二线和三线治疗，该试验证明，在既往治疗失败后，与安慰剂相比，依维莫司的中位无进展生存期约为2个月，其中至少一种是抗VEGFR酪氨酸激酶抑制剂（TKI）。该药物在一线环境中的作用已在II期试验中进行了研究，即使与贝伐单抗联合使用，也没有显着的临床获益。依维莫司在非透明细胞肾细胞癌中的活性得到了两项随机II期试验的支持，这两项试验证实了依维莫司在二线治疗中的获益，但在一线治疗中没有获益。最近，两项随机III期试验（METEOR和CheckMate 025）证明了依维莫司在二线治疗中分别劣于TKI卡博替尼和免疫检查点抑制剂纳武单抗。此外，最近的一项II期研究表明，与依维莫司单药相比，依维莫司+乐伐替尼（一种新型TKI）二线联合治疗在无进展生存期和总生存期方面具有显著获益。基于临床前数据，mTOR级联的主要下游效应物S6 RP及其磷酸化形式可能是对依维莫司应答的良好预测生物标志物。该药物的安全性是有利的，与二线索拉非尼或阿西替尼相比具有良好的成本效益，并且对治疗患者的生活质量没有显著影响。关于两种新分子卡博替尼和纳武单抗的证据，在最近发表的III期试验中成功地与依维莫司进行了头对头测试，这将决定依维莫司向三线设置和后续治疗线的转变。
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, and its pathogenesis is strictly related to altered cellular response to hypoxia, in which mTOR signaling pathway is implicated. Everolimus, an mTOR serine/threonine kinase inhibitor, represents a therapeutic option for the treatment of advanced RCC. The objective of this article is to review the evidence for the treatment of metastatic RCC with everolimus. Everolimus was approved for second- and third-line therapy in patients with advanced RCC according to the results of a Phase III pivotal trial that demonstrated a benefit in median progression-free survival of ~2 months compared to placebo after failure of previous lines of therapy, of which at least one was an anti-VEGFR tyrosine kinase inhibitor (TKI). The role of this drug in first-line setting has been investigated in Phase II trials, with no significant clinical benefit, even in combination with bevacizumab. Everolimus activity in non-clear cell RCC is supported by two randomized Phase II trials that confirmed the benefit in second-line setting but not in first line. Recently, two randomized Phase III trials (METEOR and CheckMate 025) demonstrated the inferiority of everolimus in second-line setting compared to the TKI cabozantinib and to the immune checkpoint inhibitor nivolumab, respectively. Moreover, a recent Phase II study demonstrated a significant benefit for the second-line combination treatment with everolimus plus lenvatinib (a novel TKI) in terms of progression-free survival and overall survival compared to the single-agent everolimus. Basing on preclinical data, the main downstream effectors of mTOR cascade, S6RP and its phosphorylated form, could be good predictive biomarkers of response to everolimus. The safety profile of the drug is favorable, with a good cost-effectiveness compared to second-line sorafenib or axitinib, and no significant impact on the quality of life of treated patients has been found. Everolimus still represents a current standard of treatment for RCC progressive to previous treatment lines with VEGFR-TKI. The evidence about two new molecules, cabozantinib and nivolumab, successfully tested head-to-head with everolimus in recently published Phase III trials, will determine the shift of everolimus to the third-line setting and subsequent lines of treatment.