Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program
Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program
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DOI：
10.1186/s12885-018-5223-7
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发表时间：
2019-01-11
期刊：
影响因子：
3.8
通讯作者：
Thomaidis, Thomas
中科院分区：
文献类型：
--
作者：
Moehler, Markus;Maderer, Annett;Thomaidis, Thomas
背景迄今为止，晚期或转移性胆管癌（CCA）患者治疗的基础是基于吉西他滨和铂类衍生物联合的全身化疗。其他治疗方法，包括靶向药物和酪氨酸激酶抑制剂（TKI）已显示出令人失望的结果，突出了CCA的复杂性。最近，针对抑制HER-受体的药物已显示出在晚期疾病患者中的首次治疗益处。本I期研究的目的是测试阿法替尼（一种高度特异性的panErbB家族受体TKI）在未接受化疗的晚期CCA患者中的剂量水平毒性（DLT）、安全性和有效性，并结合广泛的生物标志物程序。作为接受吉西他滨/顺铂常规化疗的晚期CCA患者的辅助治疗。采用了一项经典的3+3 I期研究，而口服阿法替尼的最大耐受剂量（MTD）是在2步剂量递增中确定的。评价所有患者的安全性、总生存期（OS）和无进展生存期（PFS）。最后，EGFR和VEGF信号cascades.ResultsOverall，9例患者入组的翻译生物标志物分析进行。由于缺乏试验药物在其他适应症中的疗效结果，停止了进一步招募。30 mg阿法替尼可以安全地作为80%标准剂量吉西他滨/顺铂的添加给药。mOS和mPFS分别为7.7和6.0个月。腹泻和血液系统疾病是最常见的AE。几乎所有患者的肿瘤组织都过表达EGFR，而没有一个患者在外显子18、19和21中表达突变。无应答者显示VEGF-C，-D，瘦素和sEGFR在他们的serum.ConclusionsAfatinib未能显示与吉西他滨/顺铂联合治疗晚期CCA患者的生存益处更高的变化。EGFR和与VEGF-C、-D和瘦素相关的通路的突变分析可能在未来的研究中显示出有希望的结果。
BackgroundTo date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease.The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with advanced CCA in conjunction with an extensive biomarker program.MethodsAfatinib was administered continuously p. o. as add-on in patients with advanced CCA who received conventional chemotherapy with gemcitabine/cisplatin. A classical 3+3 phase I study was employed, while the maximum tolerated dose (MTD) of oral afatinib was determined in a 2 step dose escalation. Safety, overall survival (OS) and progression free survival (PFS) were evaluated for all patients. Finally, a translational biomarker analysis was conducted for the EGFR and VEGF signalling cascades.ResultsOverall, 9 patients were enrolled. Further recruitment was discontinued due to lack of efficacy results of the tested drug in other indications.30mg afatinib could be safely administered as add-on to 80% of standard dose gemcitabine/cisplatin. The mOS and mPFS were 7.7 and 6.0months, respectively. Diarrhoea and haematological disorders were the most common observed AEs. Almost all patients overexpressed EGFR on their tumour tissues, whereas none of them expressed mutations in Exons 18, 19 and 21. Non-responders showed a higher variation of VEGF-C, -D, leptin and sEGFR in their sera.ConclusionsAfatinib failed to show survival benefits in combination with gemcitabine/cisplatin in patients with advanced CCA. Mutational analysis of EGFR and pathways associated with VEGF-C, -D and leptin might show promising results in future studies.Clinical trials registrationNCT01679405 August, 2012.