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

Abstract

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.30 mg afatinib could be safely administered as add-on to 80% of standard dose gemcitabine/cisplatin. The mOS and mPFS were 7.7 and 6.0 months, 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.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5223-7) contains supplementary material, which is available to authorized users.

Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience

“…Additionally, a trial has been designed that combines a PD-1 antibody, a tyrosine kinase inhibitor (TKI, lenvatinib) and GEMOX for the treatment of ICCs (NCT0395197). All studies accessing the therapeutic efficacies of TKIs (including the multitarget TKIs cabozantinib [31], vandetanib [32], sorafenib [33]; the panErbB family receptor TKI afatinib [34]; the VEGF family receptor TKI cediranib [35]; and the combination of pazopanib and trametinib [36]) failed to show survival improvements. The use of checkpoint inhibitor and TKIs in combination may bring hope to patients with ICC.…”

Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells

“…ErbB activates the RAS/RAF/mitogen-activated protein kinase (MAPK)/extracellular signalregulated kinase (ERK) and AKT downstream effector pathways, culminating in cell proliferation and survival. Inhibitors of the ErbB receptors are currently being explored in clinical trials for CCA, including afatinib (NCT01679405) [8], lapatinib (NCT00107536) [9], gefitinib (NCT02836847), and erlotinib (NCT00033462) [8] [9] However, there is still a poor current understanding of the differential expression of ErbB receptor family either in tissues from CCA patients or in CCA cell lines [10]. The optimal response of chemotherapeutic drugs and specific target ErbB inhibitors is also not known, and particularly, the optimal combinations of chemotherapeutics and specific target ErbB inhibitors, or their synergistic effects and potential use in CCA cells.…”

Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience

“…Additionally, a trial has been designed that combines a PD-1 antibody, a tyrosine kinase inhibitor (TKI, lenvatinib) and GEMOX for the treatment of ICCs (NCT0395197). All studies accessing the therapeutic e cacies of TKIs (including the multitarget TKIs cabozantinib 30 , vandetanib 31 , sorafenib 32 ; the panErbB family receptor TKI afatinib 33 ; the VEGF family receptor TKI cediranib 34 ; and the combination of pazopanib and trametinib 35 ) failed to show survival improvements. The use of checkpoint inhibitor and TKIs in combination may bring hope to patients with ICC.…”