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BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Cholangiocarcinoma | Research article

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

Authors: Markus Moehler, Annett Maderer, Anne Ehrlich, Friedrich Foerster, Arno Schad, Tanja Nickolay, Christian Ruckes, Arndt Weinmann, Visvakanth Sivanathan, Jens U. Marquardt, Peter Robert Galle, Marcus Woerns, Thomas Thomaidis

Published in: BMC Cancer | Issue 1/2019

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Abstract

Background

To 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.

Methods

Afatinib 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.

Results

Overall, 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.

Conclusions

Afatinib 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 registration

NCT01679405 August, 2012.
Appendix
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Metadata
Title
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
Authors
Markus Moehler
Annett Maderer
Anne Ehrlich
Friedrich Foerster
Arno Schad
Tanja Nickolay
Christian Ruckes
Arndt Weinmann
Visvakanth Sivanathan
Jens U. Marquardt
Peter Robert Galle
Marcus Woerns
Thomas Thomaidis
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-5223-7

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