Goyal Lipika, Zheng Hui, Yurgelun Matthew B, Abrams Thomas A, Allen Jill N, Cleary James M, Knowles Michelle, Regan Eileen, Reardon Amanda, Khachatryan Anna, Jain Rakesh K, Nardi Valentina, Borger Darrell R, Duda Dan G, Zhu Andrew X
Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
Cancer. 2017 Jun 1;123(11):1979-1988. doi: 10.1002/cncr.30571. Epub 2017 Feb 13.
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.
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.
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 1α increased and soluble VEGFR2 and angiopoietin 2 decreased after treatment (all P values < .01). Plasma tissue inhibitor of matrix metalloproteinase 1 was inversely correlated with PFS, and soluble MET (sMET) and interleukin 6 were inversely correlated with OS.
In unselected patients with cholangiocarcinoma, cabozantinib demonstrated limited activity and significant toxicity. In the first clinical trial to assess the role of MET inhibition in cholangiocarcinoma, 1 patient with a MET-high tumor had a prolonged benefit from treatment. Baseline plasma soluble MET was associated with OS. Any further development of this drug in cholangiocarcinoma should include a dose reduction and a biomarker-driven approach. Cancer 2017;123:1979-1988. © 2017 American Cancer Society.
晚期胆管癌预后较差，除一线吉西他滨/铂类化疗外，尚无标准治疗方案。开展了一项针对晚期难治性胆管癌患者的单臂2期生物标志物研究，研究对象为卡博替尼，这是一种对血管内皮生长因子受体2（VEGFR2）和MET具有强效活性的多激酶抑制剂。
既往接受过治疗的不可切除或转移性胆管癌患者接受卡博替尼治疗（口服60mg，每日一次，持续给药）。主要终点为无进展生存期（PFS）。评估肿瘤MET表达和血浆生物标志物。
该研究纳入了19例胆管癌患者（女性占68%；中位年龄67岁；肝内胆管癌与肝外胆管癌的比例为84%对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%）、肠皮肤瘘（5%）和高血压（11%）。1例肿瘤MET表达为3 + 的患者持续治疗278天，但MET表达与总体研究人群的预后无关。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1α升高，可溶性VEGFR2和血管生成素2降低（所有P值<0.01）。血浆基质金属蛋白酶1组织抑制剂与PFS呈负相关，可溶性MET（sMET）和白细胞介素6与OS呈负相关。
在未经过筛选的胆管癌患者中，卡博替尼显示出有限的活性和显著的毒性。在评估MET抑制在胆管癌中作用的首个临床试验中，1例MET高表达肿瘤患者从治疗中获得了延长的获益。基线血浆可溶性MET与OS相关。该药物在胆管癌中的任何进一步研发都应包括剂量降低和生物标志物驱动的方法。《癌症》2017年；123:1979 - 1988。©2017美国癌症协会
