Department of Medicine, Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
LBI-ACR VIEnna & ACR-ITR VIEnna, Center for Oncology and Haematology, Kaiser Franz Josef-Spital, Vienna, Austria.
Eur J Cancer. 2014 Dec;50(18):3145-52. doi: 10.1016/j.ejca.2014.10.013. Epub 2014 Oct 30.
Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib-a broad-targeted inhibitor of tyrosine kinases, including FGFR3-were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations.
Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3(MUT); n=12), wild-type (FGFR3(WT); n=31), or unknown (n=1) FGFR3 status. Patients received 500 mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR).
Most of the patients were men (75%) and over half of the patients were aged ⩾65 years (61%). All patients had received ⩾1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3(MUT) (0%; 95% confidence interval [CI], 0.0-26.5) and FGFR3(WT) (3.2%; 95% CI, 0.1-16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%).
Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. clinicaltrials.gov NCT00790426.
晚期尿路上皮癌（UC）患者的二线治疗选择有限。成纤维细胞生长因子受体 3（FGFR3）在非突变肿瘤中通过激活突变或蛋白过表达而失调。在这项研究中，评估了多韦替尼（一种广泛靶向的酪氨酸激酶抑制剂，包括 FGFR3）在先前接受过治疗的晚期 UC 患者中的疗效、药效学和安全性，这些患者 FGFR3 突变情况不同。
44 名在接受一种或三种铂类药物为基础的化疗方案和/或联合化疗方案后进展的晚期 UC 成年患者被分为 FGFR3 突变（FGFR3(MUT)；n=12）、野生型（FGFR3(WT)；n=31）或 FGFR3 状态未知（n=1）。患者接受 500mg 多韦替尼，每天一次，5 天用药/2 天停药。本两阶段研究的主要终点是研究者评估的总缓解率（ORR）。
大多数患者为男性（75%），超过一半的患者年龄≥65 岁（61%）。所有患者均接受过≥1 种用于 UC 的抗肿瘤治疗。在研究者评估确定 FGFR3(MUT)（0%；95%置信区间 [CI]，0.0-26.5）和 FGFR3(WT)（3.2%；95% CI，0.1-16.7）组的 ORR 均未达到继续进入第二阶段的标准后，研究在第一阶段结束。最常见的 3/4 级不良事件，疑似与研究药物相关，包括血小板减少症（9%）、疲劳（9%）和乏力（9%）。
尽管多韦替尼总体耐受良好，但在先前治疗的晚期 UC 患者中，无论 FGFR3 突变状态如何，其单药活性都非常有限。clinicaltrials.gov NCT00790426。
