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
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.
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.
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.
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.
KeywordsPhase II HER2-positive breast cancer Dasatinib SRC kinase inhibitor Trastuzumab resistance Metastatic breast cancer
Antibody drug conjugate
Cell signalling technology
Central nervous system
Clinical benefit rate
Common terminology criteria for adverse events
- ECOG PS
Eastern Cooperative Oncology Group performance status
Fluorescence in situ hybridization
- ICH GCP
International conference on harmonization good clinical practice guidelines
Left ventricular ejection fraction
Metastatic breast cancer
National Cancer Institute
Objective response rate
Peripheral blood mononuclear cells
Red blood cells
Response evaluation criteria in solid tumours
Time to progression
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.
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.
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.
Written informed consent was obtained from all individual participants included in the study.
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