Journal of Neuro-Oncology

, Volume 105, Issue 3, pp 613–620 | Cite as

Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases

  • Nancy U. Lin
  • Wolfgang Eierman
  • Richard Greil
  • Mario Campone
  • Bella Kaufman
  • Klaudia Steplewski
  • Stephen R. Lane
  • Denise Zembryki
  • Stephen D. Rubin
  • Eric P. Winer
Clinical Study – Patient Study


Approximately one-third of patients with advanced, HER2-positive breast cancer develop brain metastases. A significant proportion of women experience central nervous system (CNS) progression after standard radiation therapy. The optimal treatment in the refractory setting is undefined. This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with HER2-positive, progressive brain metastases. Patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and cranial radiotherapy were included. The primary endpoint was CNS objective response, defined as a ≥50% volumetric reduction of CNS lesion(s) in the absence of new or progressive CNS or non-CNS lesions, or increasing steroid requirements. The study was closed early after 22 of a planned 110 patients were enrolled due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. The objective response rate (ORR) in the lapatinib plus capecitabine arm was 38% (exact 95% confidence interval [CI] 13.9–68.4). No responses were observed in the lapatinib plus topotecan arm. Although the study was stopped prior to full enrollment, some promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity.


Lapatinib Capecitabine Topotecan Brain metastases Breast cancer 


  1. 1.
    Bendell JC, Domchek SM, Burstein HJ, Harris L, Younger J, Kuter I, Bunnell C, Rue M, Gelman R, Winer E (2003) Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97:2972–2977PubMedCrossRefGoogle Scholar
  2. 2.
    Stemmler HJ, Kahlert S, Siekiera W, Untch M, Heinrich B, Heinemann V (2006) Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer. Breast (Edinb, Scotl) 15:219–225Google Scholar
  3. 3.
    Lin NU, Winer EP (2007) Brain metastases: the HER2 paradigm. Clin Cancer Res 13:1648–1655PubMedCrossRefGoogle Scholar
  4. 4.
    Gori S, Rimondini S, De Angelis V, Colozza M, Bisagni G, Moretti G, Sidoni A, Basurto C, Aristei C, Anastasi P, Crino L (2007) Central nervous system metastases in HER-2 positive metastatic breast cancer patients treated with trastuzumab: incidence, survival, and risk factors. Oncologist 12:766–773PubMedCrossRefGoogle Scholar
  5. 5.
    Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, Nielsen TO, Gelmon K (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28:3271–3277PubMedCrossRefGoogle Scholar
  6. 6.
    Melisko ME, Moore DH, Sneed PK, De Franco J, Rugo HS (2008) Brain metastases in breast cancer: clinical and pathologic characteristics associated with improvements in survival. J Neurooncol 88:359–365PubMedCrossRefGoogle Scholar
  7. 7.
    Eichler AF, Kuter I, Ryan P, Schapira L, Younger J, Henson JW (2008) Survival in patients with brain metastases from breast cancer: the importance of HER-2 status. Cancer 112:2359–2367PubMedCrossRefGoogle Scholar
  8. 8.
    Gril B, Palmieri D, Bronder JL, Herring JM, Vega-Valle E, Feigenbaum L, Liewehr DJ, Steinberg SM, Merino MJ, Rubin SD, Steeg PS (2008) Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst 100:1092–1103PubMedCrossRefGoogle Scholar
  9. 9.
    Kuhn J, Robins HI, Mehta M, Fine H, Cloughesy T, Wen P, Chang SM, DeAngelis L, Lieberman F, Reardon D, Abrey LE, Lassman AB, Adalpe K, Yung WKA, Grabinski J, Lamborn K, Prados M (2008) Tumor sequestration of lapatinib (NABTC 04-01). Neurooncology 10:abstr ET-05Google Scholar
  10. 10.
    Lin NU, Carey LA, Liu MC, Younger J, Come SE, Ewend M, Harris GJ, Bullitt E, Van den Abbeele AD, Henson JW, Li X, Gelman R, Burstein HJ, Kasparian E, Kirsch DG, Crawford A, Hochberg F, Winer EP (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
  11. 11.
    Lin NU, Dieras V, Paul D, Lossignol D, Christodoulou C, Stemmler HJ, Roche H, Liu MC, Greil R, Ciruelos E, Loibl S, Gori S, Wardley A, Yardley D, Brufsky A, Blum JL, Rubin SD, Dharan B, Steplewski K, Zembryki D, Oliva C, Roychowdhury D, Paoletti P, Winer EP (2009) Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 15:1452–1459PubMedCrossRefGoogle Scholar
  12. 12.
    Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743PubMedCrossRefGoogle Scholar
  13. 13.
    Geyer CE, Martin A, Newstat B, Casey MA, Berger MS, Oliva CR, Rubin SD, Stein S, Cameron D (2007) Lapatinib (L) plus capecitabine (C) in HER2+ advanced breast cancer (ABC): updated efficacy and biomarker analysis. J Clin Oncol 25:40s (abstr 1035)Google Scholar
  14. 14.
    Sung C, Blaney SM, Cole DE, Balis FM, Dedrick RL (1994) A pharmacokinetic model of topotecan clearance from plasma and cerebrospinal fluid. Cancer Res 54:5118–5122PubMedGoogle Scholar
  15. 15.
    Baker SD, Heideman RL, Crom WR, Kuttesch JF, Gajjar A, Stewart CF (1996) Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 37:195–202PubMedCrossRefGoogle Scholar
  16. 16.
    Oberhoff C, Kieback DG, Wurstlein R, Deertz H, Sehouli J, van Soest C, Hilfrich J, Mesrogli M, von Minckwitz G, Staab HJ, Schindler AE (2001) Topotecan chemotherapy in patients with breast cancer and brain metastases: results of a pilot study. Onkologie 24:256–260PubMedCrossRefGoogle Scholar
  17. 17.
    Erlichman C, Boerner SA, Hallgren CG, Spieker R, Wang XY, James CD, Scheffer GL, Maliepaard M, Ross DD, Bible KC, Kaufmann SH (2001) The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. Cancer Res 61:739–748PubMedGoogle Scholar
  18. 18.
    Erlichman C, Adjei AA, Joy ME, Rubin SD, Friedman RA, Ames MM, Reid JM, Mandrekar S, Felten S, Molina JR (2005) A phase I study of lapatinib (GW572016) and topotecan in patients with solid tumors. Clin Cancer Res 11:8994s (abstr A8122)Google Scholar
  19. 19.
    Molina JR, Kaufmann SH, Reid JM, Rubin SD, Galvez-Peralta M, Friedman R, Flatten KS, Koch KM, Gilmer TM, Mullin RJ, Jewell RC, Felten SJ, Mandrekar S, Adjei AA, Erlichman C (2008) Evaluation of lapatinib and topotecan combination therapy: tissue culture, murine xenograft, and phase I clinical trial data. Clin Cancer Res 14:7900–7908PubMedCrossRefGoogle Scholar
  20. 20.
    Boccardo F, Kaufman B, Baselga J, Dieras V, Link J, Casey MA, Fittipaldo A, Oliva C, Zembryki D, Rubin SD (2008) Evaluation of lapatinib (Lap) plus capecitabine (Cap) in patients with brain metastses (BM) from HER2+ breast cancer (BC) enrolled in the Lapatinib Expanded Access Program (LEAP) and French Authorisation Temporaire d’Utilisation (ATU). J Clin Oncol 26:abstract 1094Google Scholar
  21. 21.
    Sutherland S, Ashley S, Miles D, Chan S, Wardley A, Davidson N, Bhatti R, Shehata M, Nouras H, Camburn T, Johnston SR (2010) Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases—the UK experience. Br J Cancer 102:995–1002Google Scholar
  22. 22.
    Metro G, Foglietta J, Russillo M, Stocchi L, Vidiri A, Giannarelli D, Crino L, Papaldo P, Mottolese M, Cognetti F, Fabi A, Gori S (2010) Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine. Ann Oncol 22:625–630PubMedCrossRefGoogle Scholar
  23. 23.
    Ekenel M, Hormigo AM, Peak S, Deangelis LM, Abrey LE (2007) Capecitabine therapy of central nervous system metastases from breast cancer. J Neurooncol 85:223–227PubMedCrossRefGoogle Scholar
  24. 24.
    Rivera E, Meyers C, Groves M, Valero V, Francis D, Arun B, Broglio K, Yin G, Hortobagyi GN, Buchholz T (2006) Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Cancer 107:1348–1354PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Nancy U. Lin
    • 1
  • Wolfgang Eierman
    • 2
  • Richard Greil
    • 3
  • Mario Campone
    • 4
  • Bella Kaufman
    • 5
  • Klaudia Steplewski
    • 6
  • Stephen R. Lane
    • 6
  • Denise Zembryki
    • 6
  • Stephen D. Rubin
    • 6
  • Eric P. Winer
    • 1
  1. 1.Division of Women’s Cancers, Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  2. 2.Frauen Klinik Vom Roten KreuzMunichGermany
  3. 3.IIIrd Medical Department with Hematology and Medical OncologyPrivate Medical University HospitalSalzburgAustria
  4. 4.Centre Rene GauducheauSaint-HerblainFrance
  5. 5.Sheba Medical CenterTel HasomerIsrael
  6. 6.GlaxoSmithKlineCollegevilleUSA

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