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

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, 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

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.

Keywords: Afatinib; BIBW 2992; Biomarkers; Cholangiocarcinoma; EGFR; panHER inhibition.

Conflict of interest statement

Ethics approval and consent to participate

The study was performed in accordance with the provisions of the Declaration of Helsinki, International Conference on Harmonisation, and Good Clinical Practice guidelines (NCT01679405). All patients provided written informed consent before enrolment. The study was approved by the ethic committee of the “Landesärztekammer Rheinland-Pfalz” Reference number: 837.541.11 (8083).

Consent for publication

Not applicable

Competing interests

M.M is an associate Editor of BMC Cancer. The authors have otherwise no competing interests to declare.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Overall survival analysis in all patients under the combination of BIBW 2992 + gem/cis
Fig. 2
Fig. 2
Progression free survival analysis in all patients under the combination of BIBW 2992 + gem/cis
Fig. 3
Fig. 3
Immunohistochemical staining, a) negative control, positive staining of b) EGFR (3+), c) HER2neu (1+), d) HER3 (2+) and e) HER4 (only sporadic)
Fig. 4
Fig. 4
sEGFR, VEGF-C, VEGF-D and leptin serum analysis of non-responders (n = 4) OS <=7.5 months and responders (n = 5) OS > 7.5 months. Circulated sEGFR, VEGF-C, VEGF-D and leptin levels at baseline (a-d). Median changes from the first to the second cycle of treatment of the described markers (e-h). Mann-Whitney-U test p < 0.05 is determined as significant. n.s. not significant

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