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A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer brain metastases

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Abstract

Brain metastases are common in patients with advanced, Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer. We evaluated the maximum tolerated dose (MTD) and feasibility of lapatinib given concurrently with whole brain radiotherapy (WBRT). Eligible patients had (HER2)-positive breast cancer and ≥1 brain metastasis. Patients received lapatinib 750 mg twice on day one followed by 1000, 1250, or 1500 mg once daily. WBRT (37.5 Gy, 15 fractions) began 1–8 days after starting lapatinib. Lapatinib was continued through WBRT. Following WBRT, patients received trastuzumab 2 mg/kg weekly and lapatinib 1000 mg once daily. The regimen would be considered feasible if <3/27 pts treated at the MTD experienced a dose-limiting toxicity (DLT). Thirty-five patients were enrolled; 17 % had central nervous disease (CNS) only. During dose escalation, no patients receiving 1,000 or 1,250 mg and two of five patients receiving 1,500 mg experienced DLTs (grade 3 mucositis and rash). Overall, 7/27 patients at 1,250 mg (MTD) had DLTs: grade 3 rash (n = 2), diarrhea (n = 2), hypoxia (n = 1), and grade 4 pulmonary embolus (n = 2). Among 28 evaluable patients, the CNS objective response rate (ORR) was 79 % [95% confidence interval (CI) 59–92 %] by pre-specified volumetric criteria; 46 % remained progression-free (CNS or non-CNS) at 6 months. The study did not meet the pre-defined criteria for feasibility because of toxicity, although the relationship between study treatment and some DLTs was uncertain. Given the high ORR, concurrent lapatinib-WBRT could still be considered for future study with careful safety monitoring.

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Acknowledgments

The authors thank all of the patients who participated on this study and who shared their quality of life experiences. In addition, we thank Trinity Urban and the DF/HCC Tumor Imaging Metrics Core (www.tumormetrics.org) for their assistance in central radiology review. We acknowledge the following grant support: American Society of Clinical Oncology Career Development Award, Breast Cancer Research Foundation [NL], the Nancy and Randy Berry Junior Faculty Award [NL], and the Dana-Farber/Harvard Cancer Center Grant CA006516, GlaxoSmithKline.

Ethical Standards

The study was conducted in accordance with the International Conference on Harmonization of Good Clinical Practice guidelines and the Declaration of Helsinki.

Conflict of interest

There are no specific conflicts of interest relevant to this study for any of the authors.

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Authors and Affiliations

  1. Harvard Medical School, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    Nancy U. Lin, Rachel A. Freedman, Rebecca S. Gelman, Emily Eisenberg, Jennifer A. Ligibel, Erica L. Mayer & Eric P. Winer

  2. M.D. Anderson Cancer Center Orlando, Orlando, FL, USA

    Naren Ramakrishna

  3. Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02114, USA

    Jerry Younger, Beverly Moy & April F. Eichler

  4. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA

    Anna Maria Storniolo & Mark A. Henderson

  5. Dana-Farber Cancer Institute and Brigham and Women’s Hospital, 450 Brookline Avenue, Boston, MA, 02215, USA

    Jennifer R. Bellon

  6. Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02115, USA

    Steven E. Come

  7. Massachusetts General Hospital, 25 New Chardon St, Suite 400C, Boston, MA, 02114, USA

    Gordon J. Harris

  8. Massachusetts General Hospital Cancer Center, Yawkey 112, 55 Fruit Street, Boston, MA, 02114, USA

    Shannon M. MacDonald

  9. Department of Radiation Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Finard Basement, Boston, MA, 02215, USA

    Anand Mahadevan

Authors
  1. Nancy U. Lin
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  2. Rachel A. Freedman
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  9. Gordon J. Harris
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  13. Emily Eisenberg
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  14. Jennifer A. Ligibel
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  15. Erica L. Mayer
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  16. Beverly Moy
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  17. April F. Eichler
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  18. Eric P. Winer
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Corresponding author

Correspondence to Rachel A. Freedman.

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Lin, N.U., Freedman, R.A., Ramakrishna, N. et al. A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer brain metastases. Breast Cancer Res Treat 142, 405–414 (2013). https://doi.org/10.1007/s10549-013-2754-0

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  • DOI: https://doi.org/10.1007/s10549-013-2754-0

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