Feasibility Study of EndoTAG-1, a Tumor Endothelial Targeting Agent, in Combination with Paclitaxel followed by FEC as Induction Therapy in HER2-Negative Breast Cancer

Michail Ignatiadis, Dimitrios Zardavas, Marc Lemort, Celine Wilke, Marie-Catherine Vanderbeeken, Veronique D'Hondt, Evandro De Azambuja, Andrea Gombos, Fabienne Lebrun, Lissandra Dal Lago, Fanny Bustin, Marion Maetens, Lieveke Ameye, Isabelle Veys, Stefan Michiels, Marianne Paesmans, Denis Larsimont, Christos Sotiriou, Jean-Marie Nogaret, Martine Piccart, Ahmad Awada, Michail Ignatiadis, Dimitrios Zardavas, Marc Lemort, Celine Wilke, Marie-Catherine Vanderbeeken, Veronique D'Hondt, Evandro De Azambuja, Andrea Gombos, Fabienne Lebrun, Lissandra Dal Lago, Fanny Bustin, Marion Maetens, Lieveke Ameye, Isabelle Veys, Stefan Michiels, Marianne Paesmans, Denis Larsimont, Christos Sotiriou, Jean-Marie Nogaret, Martine Piccart, Ahmad Awada

Abstract

Background: EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel.

Methods: HER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated.

Results: Fifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001) for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04).

Conclusions: The EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2- patients. Further studies are warranted with need of premedication optimization.

Trial registration: ClinicalTrials.gov NCT01537536.

Conflict of interest statement

Competing Interests: Medigene AG provided the EndoTAG-1 and an educational grant for this study. Celine Wilke is employed by Medigene AG. There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. CONSORT Diagram.
Fig 1. CONSORT Diagram.

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