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International Journal of Clinical Oncology

, Volume 18, Issue 4, pp 621–628 | Cite as

A phase II study of lapatinib for brain metastases in patients with HER2-overexpressing breast cancer following trastuzumab based systemic therapy and cranial radiotherapy: subset analysis of Japanese patients

  • Hiroji IwataEmail author
  • Masaru Narabayashi
  • Yoshinori Ito
  • Shigehira Saji
  • Yasuhiro Fujiwara
  • Shigeyuki Usami
  • Koichi Katsura
  • Yasutsuna Sasaki
Original Article

Abstract

Background

It is known that one third of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer (MBC) treated with trastuzumab will develop brain metastases. As the development of brain metastases is fatal, controlling its progression is clinically meaningful. However, effective therapy for MBC patients with brain metastasis after cranial radiation is limited. The international clinical study in which six Japanese patients participated indicated the antitumor activity of lapatinib against brain metastases of HER2-overexpressing breast cancer.

Methods

The efficacy, safety, and pharmacokinetics of lapatinib 750 mg given twice daily to Japanese HER2-overexpressing MBC patients with brain metastases were assessed as part of the international clinical study.

Results

Of six Japanese patients treated in this study, two patients had shown volumetric reduction >20 % in their central nervous system (CNS), one of whom had >50 % reduction. Three patients, including two of these patients, had shown >20 % volumetric reduction in non-CNS lesions. Frequently reported adverse events were diarrhea and rash, all of which were controllable. The AUC0–12 of lapatinib on day 28 was 1.74 times higher than that on day 1.

Conclusion

These results suggest that lapatinib monotherapy 750 mg given twice daily can exert some efficacy and has potential as a clinically meaningful treatment option for Japanese HER2-overexpressing breast cancer patients with brain metastases after cranial radiation.

Keywords

Lapatinib Tyrosine kinase inhibitor HER2 Brain metastases Metastatic breast cancer 

Notes

Acknowledgments

We thank the women who participated in these studies and their families. The authors also acknowledge the dedicated work of all the research nurses and study coordinators at the study centers. This work was sponsored by GlaxoSmithKline K.K.

Conflict of interest

All authors have no conflict of interest.

References

  1. 1.
    Burstein HJ, Lieberman G, Slamon DJ et al (2005) Isolated central nervous system metastases in patients with HER2-overexpressing advance breast cancer treated with first-line trastuzumab-based therapy. Ann Oncol 16:1772–1777PubMedCrossRefGoogle Scholar
  2. 2.
    Pestalozzi BC, Zahrieh D, Price KN et al (2006) Identifying breast cancer patients at risk for central nervous system (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol 17:935–944PubMedCrossRefGoogle Scholar
  3. 3.
    Bendell JC, Domchek SM, Burstein HJ et al (2003) Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer (Phila) 97:2972–2977CrossRefGoogle Scholar
  4. 4.
    Clayton AJ, Danson S, Jolly S et al (2004) Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 91:639–643PubMedGoogle Scholar
  5. 5.
    Lin NU, Winer EP (2007) Brain metastases: the HER2 paradigm. Clin Cancer Res 13:1648–1655PubMedCrossRefGoogle Scholar
  6. 6.
    Stemmler HJ, Kahlert S, Siekiera W et al (2006) Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer. Breast 15:219–225PubMedCrossRefGoogle Scholar
  7. 7.
    Yau T, Swanton C, Chua S et al (2006) Incidence, pattern and timing of brain metastases among patients with advanced breast cancer treated with trastuzumab. Acta Oncol 45:196–201PubMedCrossRefGoogle Scholar
  8. 8.
    Toyama T (2009) 7. Lapatinib and brain metastasis, clinical and experimental aspects of breast cancer. In: Toi M (ed) Iyaku (Medicine and Drug). Journal Co., Tokyo, p 877Google Scholar
  9. 9.
    Bezjak A, Adam J, Barton R et al (2002) Symptom response after palliative radiotherapy for patients with brain metastases. Eur J Cancer 38:487–496PubMedCrossRefGoogle Scholar
  10. 10.
    Arslan C, Dizdar O, Altundag K (2010) Systemic treatment in breast-cancer patients with brain metastasis. Expert Opin Pharmacother 11:1089–1100PubMedCrossRefGoogle Scholar
  11. 11.
    Rusnak DW, Lackey K, Affleck K et al (2001) The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 1:85–94PubMedGoogle Scholar
  12. 12.
    Gril B, Palmieri D, Bronder JL et al (2008) Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst 100:1092–1103PubMedCrossRefGoogle Scholar
  13. 13.
    Lin NU, Carey LA, Liu MC et al (2008) Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 26:1993–1999PubMedCrossRefGoogle Scholar
  14. 14.
    Lin NU, Dieras V, Paul D et al (2009) Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 15:1452–1459PubMedCrossRefGoogle Scholar
  15. 15.
    Nakagawa K, Minami H, Kanezaki M et al (2009) Phase I dose-escalation and pharmacokinetic trial of lapatinib (GW572016), a selective oral dual inhibitor of ErbB-1 and -2 tyrosine kinases, in Japanese patients with solid tumors. Jpn J Clin Oncol 39:116–123PubMedCrossRefGoogle Scholar
  16. 16.
    Toi M, Iwata H, Fujiwara Y et al (2009) Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies. Br J Cancer 101:1676–1682PubMedCrossRefGoogle Scholar
  17. 17.
    Burstein HJ, Storniolo AM, Franco S et al (2008) A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer. Ann Oncol 19:1068–1074PubMedCrossRefGoogle Scholar
  18. 18.
    Blackwell KL, Pegram MD, Tan-Chiu E et al (2009) Single-agent lapatinib for the treatment of HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab containing regimens. Ann Oncol 20:1026–1031PubMedCrossRefGoogle Scholar
  19. 19.
    Burris HA III, Hurwitz HI, Dees EC et al (2005) Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23:5305–5313PubMedCrossRefGoogle Scholar
  20. 20.
    Burris HA III, Taylor CW, Jones SF et al (2009) A phase I and pharmacokinetic study of oral lapatinib administered once or twice daily in patients with solid malignancies. Clin Cancer Res 15:6702–6708PubMedCrossRefGoogle Scholar
  21. 21.
    Stemmler HJ, Schmitt M, Willems A et al (2007) Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood–brain barrier. Anticancer Drugs 18:23–28PubMedCrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2012

Authors and Affiliations

  • Hiroji Iwata
    • 1
    Email author
  • Masaru Narabayashi
    • 2
  • Yoshinori Ito
    • 3
  • Shigehira Saji
    • 4
    • 7
  • Yasuhiro Fujiwara
    • 5
  • Shigeyuki Usami
    • 6
  • Koichi Katsura
    • 6
  • Yasutsuna Sasaki
    • 7
  1. 1.Department of Breast OncologyAichi Cancer Center HospitalNagoyaJapan
  2. 2.Department of Palliative MedicineSaitama Medical University International Medical CenterHidakaJapan
  3. 3.Department of OncologyJapanese Foundation for Cancer ResearchTokyoJapan
  4. 4.Clinical Research DivisionTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalTokyoJapan
  5. 5.Breast and Medical Oncology DivisionNational Cancer Center HospitalTokyoJapan
  6. 6.Development and Medical Affairs DivisionGlaxoSmithKline K.K.TokyoJapan
  7. 7.Department of Medical OncologySaitama Medical University International Medical CenterHidakaJapan

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