Clinical Study

A phase Ib study of entinostat plus lapatinib with or without trastuzumab in patients with HER2-positive metastatic breast cancer that progressed during trastuzumab treatment

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Human epidermal growth factor 2 (HER2) is an effective therapeutic target in breast cancer; however, resistance to anti-HER2 agents such as trastuzumab and lapatinib develops. In a preclinical model, an HDAC inhibitor epigenetically reversed the resistance of cancer cells to trastuzumab and showed synergistic efficacy with lapatinib in inhibiting growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer.


A phase 1b, dose escalation study was performed to assess maximum tolerated dose, safety/toxicity, clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab.


The combination was safe. The MTD was lapatinib, 1000 mg daily; entinostat, 12 mg every other week; trastuzumab, 8 mg/kg followed by 6 mg/kg every 3 weeks. Adverse events included diarrhoea (89%), neutropenia (31%), and thrombocytopenia (23%). Neutropenia, thrombocytopenia and hypokalaemia were noted. Pharmacodynamic assessment did not yield conclusive results. Among 35 patients with evaluable response, PR was observed in 3 patients and CR in 3 patients, 1 maintained SD for over 6 months.


This study identified the MTD of the entinostat, lapatinib, and trastuzumab combination that provided acceptable tolerability and anti-tumour activity in heavily pre-treated patients with HER2+ metastatic breast cancer, supporting a confirmatory trial.

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We acknowledge other research staff: Angela Marx, Charla Parker at the Morgan Welch Inflammatory Breast Cancer program who are not listed here as authors for their help in managing the study. Tissue and CTC biomarker assays and initial basic statistical analysis were performed by ApoCell. Lapatinib was provided by Novartis, and entinostat was provided by Syndax Pharmaceuticals. Sunita Patterson of the Department of Scientific Publications provided editorial assistance.

Author contributions

First author B.L. and Corresponding author N.T.U. collected, analysed the data along with other members of the team and formulated the whole manuscript. Second author R.K.M. provided her perspective on Her2 therapy in metastatic Her2 cancer in discussion and background session. J.L. helped initial design of clinical trial based on his pre-clinical data, S.A.J., J.S.W. had provided significant clinical trial regulatory efforts. T.I. helped collecting the updated clinical information of the patients. D.W.D. helped with circulating biomarker analysis. J.W. and Y.S. had the primary statistical analysis of the study. D.T., R.A., N.K.I., A.M.B., C.H.B., P.H.B., S.H.G., S.L.M., D.J.B., V.V. enrolled their patients to the study and review the result of the study, validate the data quality of the manuscript. J.A.M. and R.P. provided the guidance of the trial development and conduct from CTEP perspective.

Author information

Correspondence to Naoto T. Ueno.

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Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and was approved by institutional review boards at The University of Texas MD Anderson Cancer Center. All enroled patients provided written informed consent.

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All authors consent the material to publish.

Competing interests

The authors declare no competing interests.

Data availability

All data generated or analysed during this study are included in this published article [and its supplementary information files].


This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).


This study was supported by the National Cancer Institute at the National Institutes of Health through a Cancer Therapy Evaluation Program UM1 grant [NCI #8871] and MD Anderson’s Cancer Center Support Grant [P30CA016672; used the Clinical Trials Support Resource and Biostatistics Resource Group]; MD Anderson’s Center for Genetics and Genomics (used the Molecular Cytogenetics Facility); and the Morgan Welch Inflammatory Breast Cancer Research Program and Clinic.

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