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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

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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.

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Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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

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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.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Hospital Clínico San Carlos, Madrid and Centro Regional de Investigaciones Biomédicas, Universidad de Castilla La Mancha, 02006, Albacete, Spain

    Alberto Ocana

  2. GEICAM, Spanish Breast Cancer Group, Madrid, Spain

    Alberto Ocana, Marta Gil-Martin, Silvia Antolín, Álvaro Montaño, Nuria Ribelles, Ander Urruticoechea, Sonia Pernas, Maria José Escudero, Sara Benito, Rosalía Caballero, Eva Carrasco, Federico Rojo, Atanasio Pandiella & Manuel Ruiz-Borrego

  3. Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, Madrid, Spain

    Alberto Ocana, Juan Carlos Montero, Federico Rojo & Atanasio Pandiella

  4. Department of Medical Oncology, Institut Català d’Oncologia (ICO)-IDIBELL, L’Hospitalet, Barcelona, Spain

    Marta Gil-Martin & Sonia Pernas

  5. Department of Medical Oncology, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain

    Silvia Antolín & Javier Orlando

  6. Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Sevilla, Spain

    María Atienza, Álvaro Montaño, Alejandro Falcón & Manuel Ruiz-Borrego

  7. Department of Medical Oncology, Hospital Universitario Virgen de la Victoria, Institute of Biomedical Reasearch in Malaga, Malaga, Spain

    Nuria Ribelles

  8. Department of Medical Oncology, Fundación Onkologikoa, Donostia, Spain

    Ander Urruticoechea

  9. Instituto de Biología Molecular y Celular del Cáncer, IBSAL, CSIC-Universidad de Salamanca, Salamanca, Spain

    Juan Carlos Montero & Atanasio Pandiella

  10. Fundación Jiménez Díaz, Madrid, Spain

    Federico Rojo

Authors
  1. Alberto Ocana
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  2. Marta Gil-Martin
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  3. Silvia Antolín
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  4. María Atienza
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  5. Álvaro Montaño
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  6. Nuria Ribelles
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  7. Ander Urruticoechea
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  8. Alejandro Falcón
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  9. Sonia Pernas
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  10. Javier Orlando
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  11. Juan Carlos Montero
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  12. Maria José Escudero
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  13. Sara Benito
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  14. Rosalía Caballero
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  15. Eva Carrasco
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  16. Federico Rojo
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  17. Atanasio Pandiella
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  18. Manuel Ruiz-Borrego
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Corresponding author

Correspondence to Alberto Ocana.

Ethics declarations

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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Ocana, A., Gil-Martin, M., Antolín, S. et al. 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. Breast Cancer Res Treat 174, 693–701 (2019). https://doi.org/10.1007/s10549-018-05100-z

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  • DOI: https://doi.org/10.1007/s10549-018-05100-z

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