Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Cancer. 2012 Apr 1;118(7):1868-76. doi: 10.1002/cncr.26429. Epub 2011 Sep 6.
Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC.
Sequential cohorts of 3 to 6 patients with advanced RCC received dose-escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5-5 mg daily or 20-30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained.
Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1 to 28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed.
The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC.
同时抑制血管内皮生长因子（VEGF）和哺乳动物雷帕霉素靶蛋白（mTOR）通路可能会改善晚期肾细胞癌（RCC）的治疗反应。依维莫司是一种口服 mTOR 抑制剂，舒尼替尼是一种针对 VEGF 的口服酪氨酸激酶抑制剂，是转移性 RCC 治疗的标准药物。
先后有 3 至 6 例晚期 RCC 患者入组，接受舒尼替尼（每日 37.5 或 50mg，4 周给药/2 周停药）与依维莫司（每日 2.5-5mg 或每周 20-30mg）剂量递增联合治疗。在首个 6 周周期中评估剂量限制性毒性（DLT），以确定最大耐受剂量（MTD）。测定药代动力学特征。
5 个队列共入组 20 例患者（13 例透明细胞和 7 例非透明细胞 RCC）。当与舒尼替尼联合使用时，每日依维莫司无法耐受；第 2 个队列的前 2 例患者发生 DLT。每周使用依维莫司时，MTD 为 30mg 依维莫司在第 7、14、21 和 28 天，加上 37.5mg 舒尼替尼在第 1 至 28 天的 42 天周期；然而，慢性治疗与 3 级和 4 级毒性相关。每周 20mg 依维莫司/37.5mg 舒尼替尼的方案可耐受慢性治疗。5 例患者（25%）有确认的部分缓解，3 例为非透明细胞 RCC。未观察到依维莫司、舒尼替尼或 N-去乙基舒尼替尼的意外蓄积。
依维莫司和舒尼替尼的联合应用与明显的急性和慢性毒性相关，仅在减毒剂量下才可耐受。该联合方案在非透明细胞和透明细胞 RCC 中均观察到疗效。
