A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma
A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma
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DOI：
10.1002/cncr.30571
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发表时间：
2017-06-01
期刊：
影响因子：
6.2
通讯作者：
Zhu, Andrew X.
中科院分区：
文献类型：
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作者：
Goyal, Lipika;Zheng, Hui;Zhu, Andrew X.
背景技术背景：晚期胆管癌预后差，除了一线吉西他滨/铂类化疗外，没有标准治疗。对晚期难治性胆管癌患者进行了卡博替尼（一种对血管内皮生长因子受体2（VEGFR 2）和MET具有强效活性的多激酶抑制剂）的单臂、2期和生物标志物研究。方法：具有不可切除或转移性胆管癌的先前治疗的患者接受卡博替尼（60 mg口服和每日，按连续时间表）。主要终点是无进展生存期（PFS）。评价肿瘤MET表达和血浆生物标志物。结果：该研究纳入了19例胆管癌患者（女性，68%;中位年龄，67岁;肝内vs肝外，84% vs 16%）。中位PFS为1.8个月（95%置信区间，1.6-5.4个月），中位总生存期（OS）为5.2个月（95%置信区间，2.7-10.5个月）。89%的患者发生了3/4级不良事件，包括中性粒细胞减少（5%）、高胆红素血症（5%）、鼻出血（5%）、肠穿孔（5%）、肠外瘘（5%）和高血压（11%）。1例肿瘤中MET表达为3 +的患者持续治疗278天，但MET表达与整个研究人群的结局无关。治疗后，血浆血管内皮生长因子、胎盘生长因子和基质细胞衍生因子1 α升高，可溶性VEGF 2和血管生成素2降低（均P值
BACKGROUND: Advanced cholangiocarcinoma carries a poor prognosis, and no standard treatment exists beyond first-line gemcitabine/platinum-based chemotherapy. A single-arm, phase 2 and biomarker study of cabozantinib, a multikinase inhibitor with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET, was performed for patients with advanced refractory cholangiocarcinoma. METHODS: Previously treated patients with unresectable or metastatic cholangiocarcinoma received cabozantinib (60 mg orally and daily on a continuous schedule). The primary endpoint was progression-free survival (PFS). Tumor MET expression and plasma biomarkers were evaluated. RESULTS: The study enrolled 19 patients with cholangiocarcinoma (female, 68%; median age, 67 years; intrahepatic vs extrahepatic, 84% vs 16%). The median PFS was 1.8 months (95% confidence interval, 1.6-5.4 months), and the median overall survival (OS) was 5.2 months (95% confidence interval, 2.7-10.5 months). Grade 3/4 adverse events occurred in 89% of the patients and included neutropenia (5%), hyperbilirubinemia (5%), epistaxis (5%), bowel perforation (5%), enterocutaneous fistulas (5%), and hypertension (11%). One patient with 3 + MET expression in the tumor stayed on treatment for 278 days, but the MET expression did not correlate with the outcomes in the overall study population. Plasma vascular endothelial growth factor, placental growth factor, and stromal cell-derived factor 1 alpha increased and soluble VEGFR2 and angiopoietin 2 decreased after treatment (all P values