Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma
Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma
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DOI：
10.1038/s41416-018-0261-0
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发表时间：
2018-09-11
影响因子：
8.8
通讯作者：
Rosenberg, Jonathan E.
中科院分区：
文献类型：
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作者：
Bellmunt, Joaquim;Lalani, Aly-Khan A.;Rosenberg, Jonathan E.
背景：转移性尿路上皮癌（mUC）是一种基因组多样性疾病，已知mTOR通路和酪氨酸激酶（包括FGFR）发生改变。我们研究了依维莫司和帕唑帕尼（UP）联合治疗mUC基因组谱患者的疗效和安全性。方法：纳入了一项I期剂量递增研究的mUC患者和接受E/P治疗的扩展队列。主要终点为客观缓解率（ORR）；次要终点是安全性、反应持续时间（DOR）、无进展生存期（PFS）和总生存期（OS）。使用下一代测序技术评估患者300个相关癌症相关基因的突变和拷贝数改变，结果与结果相关。时间到事件数据用Kaplan-Meier方法估计。结果：在纳入的23例患者中，19例患有mUC。ORR为21%（1例完全缓解（CR）， 3例部分缓解（PR）， 8例病情稳定（SD））。DOR、PFS、OS分别为6.5、3.6、9.1个月。4例临床获益患者（1例CR， 2例PR， 1例SD）有TSC1/TSC2或mTOR突变，5例PR患者有FGFR3-TACC3融合。结论：联合UP治疗mUC是安全的，选择mTOR或FGFR通路改变的患者可获得显著的临床获益。
BACKGROUND: Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (UP) in genomically profiled patients with mUC.METHODS: mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progressionfree survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods.RESULTS: Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion.CONCLUSIONS: Combination therapy with UP is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.