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Efficacy and safety of dasatinib with trastuzumab and paclitaxel in first line HER2-positive metastatic breast cancer: results from the phase II GEICAM/2010-04 study

  • Alberto OcanaEmail author
  • Marta Gil-Martin
  • Silvia Antolín
  • María Atienza
  • Álvaro Montaño
  • Nuria Ribelles
  • Ander Urruticoechea
  • Alejandro Falcón
  • Sonia Pernas
  • Javier Orlando
  • Juan Carlos Montero
  • Maria José Escudero
  • Sara Benito
  • Rosalía Caballero
  • Eva Carrasco
  • Federico Rojo
  • Atanasio Pandiella
  • Manuel Ruiz-Borrego
Clinical trial

Abstract

Background

An important proportion of HER2-positive metastatic breast cancer patients do not respond to trastuzumab. The combination of dasatinib and trastuzumab has shown to be synergistic in preclinical models.

Methods

We conducted a phase II trial combining dasatinib 100 mg once daily with trastuzumab 2 mg/kg and paclitaxel 80 mg/m2 weekly. Primary objective was objective response rate (ORR) and secondary included safety, other efficacy parameters and pharmacodynamics in tumour tissue, blood samples and skin biopsies.

Results

From June 2013 to December 2015, 29 patients were included. Median number of cycles was 12 (1–49). Only 6 patients discontinued due to adverse events. ORR was 79.3% (95% CI 60.3–92), clinical benefit rate 82.8% (95% CI 64.2–94.2). Median time to progression 23.9 months (95% CI 14.9–not reached [NR]), median progression-free survival 23.9 months (95% CI 10.3–NR). No grade 4 toxicity was seen. Grade 3 toxicities included: ejection fraction decrease, neutropenia, hyponatremia, fatigue and sensory neuropathy and one left ventricular systolic dysfunction. Phosphorylated (p)-SRC was reduced in peripheral blood mononuclear cells. Phosphorylated SRC, ERK and AKT were also reduced in epidermal keratinocytes.

Conclusions

Dasatinib can be safely combined with trastuzumab and paclitaxel. The combination is active with an ORR of almost 80%. Trial registration: NCT01306942, EudraCT 2010-023304-27.

Keywords

Phase II HER2-positive breast cancer Dasatinib SRC kinase inhibitor Trastuzumab resistance Metastatic breast cancer 

Abbreviations

AE

Adverse events

ADC

Antibody drug conjugate

BCA

Bicinchoninic acid

CST

Cell signalling technology

CNS

Central nervous system

CBR

Clinical benefit rate

CTCAE

Common terminology criteria for adverse events

ECOG PS

Eastern Cooperative Oncology Group performance status

ECG

Electrocardiogram

FISH

Fluorescence in situ hybridization

FFPE

Formalin-fixed paraffin-embedded

IHC

Immunohistochemistry

ICH GCP

International conference on harmonization good clinical practice guidelines

LVEF

Left ventricular ejection fraction

MBC

Metastatic breast cancer

NCI

National Cancer Institute

ORR

Objective response rate

PBMCs

Peripheral blood mononuclear cells

PBS

Phosphate-buffered saline

PFS

Progression-free survival

RBC

Red blood cells

RD

Response duration

RECIST

Response evaluation criteria in solid tumours

TTP

Time to progression

T-DM1

Trastuzumab entamsine

Notes

Acknowledgements

We acknowledge the investigators (see list below), pathology departments and other site staff of the participant sites, the patients, and GEICAM staff involved in this trial.

Funding

The study was financially supported by Bristol-Myers Squibb which also supplied the dasatinib.

Compliance with ethical standards

Conflict of interest

Dr. A. Ocaña has received honorarium for consultant/advisory from Daiichi Sankyo, Entrechem and Servier. Dr. A. Urruticoechea has received honorarium for consultant/advisory from Roche. Dr. A. Falcón has received honorarium as speaker from Roche and Astra-Zeneca. Dr. S. Pernas has received honorarium as speaker and travel grants from Roche, she also participated as advisor for Polyphor. Dr. E. Carrasco owns Ely Lilly stock options and has received travel grants from Roche. Her husband received honoraria from Celgene, BMS, Janssen Cilag and Takeda. Dr F Rojo has received speaker honorarium from Roche, BMS, Merck and Pfizer. Dr M Ruíz-Borrego received honorarium as speaker and advisory from Roche and Astra-Zeneca. The rest of authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study are in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the institutions’ ethical review boards of the participating sites and health authorities in Spain.

Informed consent

Written informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Alberto Ocana
    • 1
    • 2
    • 3
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  • Marta Gil-Martin
    • 2
    • 4
  • Silvia Antolín
    • 2
    • 5
  • María Atienza
    • 6
  • Álvaro Montaño
    • 2
    • 6
  • Nuria Ribelles
    • 2
    • 7
  • Ander Urruticoechea
    • 2
    • 8
  • Alejandro Falcón
    • 6
  • Sonia Pernas
    • 2
    • 4
  • Javier Orlando
    • 5
  • Juan Carlos Montero
    • 3
    • 9
  • Maria José Escudero
    • 2
  • Sara Benito
    • 2
  • Rosalía Caballero
    • 2
  • Eva Carrasco
    • 2
  • Federico Rojo
    • 2
    • 3
    • 10
  • Atanasio Pandiella
    • 2
    • 3
    • 9
  • Manuel Ruiz-Borrego
    • 2
    • 6
  1. 1.Department of Medical Oncology, Hospital Clínico San Carlos, Madrid and Centro Regional de Investigaciones BiomédicasUniversidad de Castilla La ManchaAlbaceteSpain
  2. 2.GEICAMSpanish Breast Cancer GroupMadridSpain
  3. 3.Centro de Investigación Biomédica en Red de OncologíaCIBERONC-ISCIIIMadridSpain
  4. 4.Department of Medical Oncology, Institut Català d’Oncologia (ICO)-IDIBELLL’HospitaletBarcelonaSpain
  5. 5.Department of Medical OncologyComplejo Hospitalario Universitario A CoruñaA CoruñaSpain
  6. 6.Department of Medical OncologyHospital Universitario Virgen del RocíoSevillaSpain
  7. 7.Department of Medical Oncology, Hospital Universitario Virgen de la VictoriaInstitute of Biomedical Reasearch in MalagaMalagaSpain
  8. 8.Department of Medical OncologyFundación OnkologikoaDonostiaSpain
  9. 9.Instituto de Biología Molecular y Celular del Cáncer, IBSALCSIC-Universidad de SalamancaSalamancaSpain
  10. 10.Fundación Jiménez DíazMadridSpain

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