Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study
Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study
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DOI：
10.1111/iju.13776
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发表时间：
2018-11-01
影响因子：
2.6
通讯作者：
Takahashi, Shunji
中科院分区：
文献类型：
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作者：
Matsubara, Nobuaki;Naito, Yoichi;Takahashi, Shunji
目的评价日本晚期或转移性肾癌患者经血管内皮生长因子靶向治疗后，口服多受体酪氨酸激酶抑制剂lenvatinib与哺乳动物靶向雷帕霉素抑制剂伊维洛莫司联合应用的耐受性、安全性、药代动力学和抗肿瘤活性。方法列瓦替尼18 mg和维罗莫司5 mg，每日1次，连续给药28天，直至病情进展或出现不可接受的毒性反应。根据4.03版不良事件通用术语标准评估不良事件，并根据实体瘤1.1版中的反应评估标准评估肿瘤反应。在第一周期中进行药代动力学采样。结果7例肾透明细胞癌患者接受了该联合治疗。未观察到剂量限制性毒性。最常见的不良事件是血小板减少和食欲下降(100%)，其次是高甘油三酯血症和掌底红觉障碍综合征(86%)。最常见的3级不良事件是淋巴细胞减少(43%)。未发生4级或5级不良事件。药物浓度-时间曲线下的稳态平均面积分别为3220和401 ng中心点h/mL。5例(71%)患者部分缓解，1例(14%)病情稳定。结论列瓦替尼18 mg和维罗莫司5 mg每日1次给药耐受性和可控性良好，联合用药对两药的药代动力学无明显影响。总体而言，这种联合疗法在日本肾癌患者中显示出令人鼓舞的抗肿瘤活性。
Objectives To assess the tolerability, safety, pharmacokinetics and antitumor activities of lenvatinib, an oral inhibitor of multiple receptor tyrosine kinases, in combination with everolimus, an inhibitor of mammalian target of rapamycin, in Japanese patients with advanced or metastatic renal cell carcinoma after disease progression with vascular endothelial growth factor-targeted therapy. Methods Lenvatinib 18 mg and everolimus 5 mg once daily were administered on 28-day continuous cycles until disease progression or unacceptable toxicity. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 4.03, and tumor response was assessed according to the Response Evaluation Criteria in Solid Tumor version 1.1. Pharmacokinetics sampling was carried out during the first cycle. Results Seven patients with clear cell renal cell carcinoma received this combination treatment. Dose-limiting toxicity was not observed. The most commonly observed adverse events were thrombocytopenia and decreased appetite (100%), followed by hypertriglyceridaemia and palmar-plantar erythrodysesthesia syndrome (86%). The most common grade 3 adverse event was lymphopenia (43%). No grade 4 or 5 adverse events occurred. The steady-state mean areas under the concentration-time curves of lenvatinib and everolimus were 3220 and 401 ng center dot h/mL, respectively. Five patients (71%) had partial response, and one (14%) had stable disease. Conclusions Lenvatinib 18 mg and everolimus 5 mg once daily are well tolerated and manageable, and their combined administration has no significant effect on either drug's pharmacokinetics. Overall, this combination therapy shows encouraging antitumor activity in Japanese patients with renal cell carcinoma.