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Breast Cancer Research and Treatment

, Volume 112, Issue 3, pp 533–543 | Cite as

A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses

  • David Cameron
  • Michelle Casey
  • Michael Press
  • Deborah Lindquist
  • Tadeusz Pienkowski
  • C. Gilles Romieu
  • Stephen Chan
  • Agnieszka Jagiello-Gruszfeld
  • Bella Kaufman
  • John Crown
  • Arlene Chan
  • Mario Campone
  • Patrice Viens
  • Neville Davidson
  • Vera Gorbounova
  • Johannes Isaac Raats
  • Dimosthenis Skarlos
  • Beth Newstat
  • Debasish Roychowdhury
  • Paolo Paoletti
  • Cristina Oliva
  • Stephen Rubin
  • Steven Stein
  • Charles E. Geyer
Clinical Trial

Abstract

Purpose Lapatinib is a small molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor type 2 (HER2). Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab. Updated efficacy and initial biomarker results from this trial are reported. Methods Women with HER2-positive, locally advanced or metastatic breast cancer previously treated with anthracycline-, taxane-, and trastuzumab-containing regimens were randomized to lapatinib 1,250 mg/day continuously plus capecitabine 2,000 mg/m2 days 1–14 of a 21-day cycle or capecitabine 2,500 mg/m2 on the same schedule. The primary endpoint was time to progression (TTP) as determined by an independent review panel. Relationship between progression-free survival (PFS) and tumor HER2 expression and serum levels of HER2 extracellular domain (ECD) were assessed. Results 399 women were randomized. The addition of lapatinib prolonged TTP with a hazard ratio (HR) of 0.57 (95% CI, 0.43–0.77; P < 0.001) and provided a trend toward improved overall survival (HR: 0.78, 95% CI: 0.55–1.12, P = 0.177), and fewer cases with CNS involvement at first progression (4 vs. 13, P = 0.045). Baseline serum HER2 ECD did not predict for benefit from lapatinib. Conclusion The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive, advanced breast cancer progressing after treatment with anthracycline-, taxane-, and trastuzumab-based therapy. Biomarker studies could not identify a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine.

Keywords

Metastatic breast cancer Advanced breast cancer Lapatinib Capecitabine Dual tyrosine kinase inhibitor Phase III Biomarker HER2-positive 

Notes

Acknowledgments

We thank the patients who participated in this study and their families; the medical, nursing and research staff at the study centres; the independent data and safety monitoring committee; the monitors, clinical operations staff, data managers, statisticians, and programmers at GlaxoSmithKline. This study was sponsored and funded by GlaxoSmithKline.

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Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • David Cameron
    • 1
    • 2
  • Michelle Casey
    • 3
  • Michael Press
    • 4
  • Deborah Lindquist
    • 5
  • Tadeusz Pienkowski
    • 6
  • C. Gilles Romieu
    • 7
  • Stephen Chan
    • 8
  • Agnieszka Jagiello-Gruszfeld
    • 9
  • Bella Kaufman
    • 10
  • John Crown
    • 11
  • Arlene Chan
    • 12
  • Mario Campone
    • 13
  • Patrice Viens
    • 14
  • Neville Davidson
    • 15
  • Vera Gorbounova
    • 16
  • Johannes Isaac Raats
    • 17
  • Dimosthenis Skarlos
    • 18
  • Beth Newstat
    • 3
  • Debasish Roychowdhury
    • 3
  • Paolo Paoletti
    • 3
  • Cristina Oliva
    • 3
  • Stephen Rubin
    • 3
  • Steven Stein
    • 3
  • Charles E. Geyer
    • 19
  1. 1.University of LeedsLeedsEngland
  2. 2.NCRN Co-ordinating centerLeedsUK
  3. 3.GlaxoSmithKlineCollegevilleUSA
  4. 4.Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos AngelesUSA
  5. 5.US OncologyHoustonUSA
  6. 6.Breast Cancer and Reconstruction Surgery DepartmentCentrum Onkologii Klinika Nowotworów Piersi i ChirurgiiWarsawPoland
  7. 7.Département OncologieCRLCC Val d’AurelleMontpellierFrance
  8. 8.Department of Clinical OncologyNottingham University HospitalsNottinghamEngland
  9. 9.Chemotherapy DepartmentZOZ MSWiAOlsztynPoland
  10. 10.Oncology DivisionChaim Sheba Medical CenterTel-HashomerIsrael
  11. 11.Irish Clinical Oncology Research GroupDublinIreland
  12. 12.Mount Medical CentreMount HospitalPerthAustralia
  13. 13.Oncology DepartmentCentre René GauducheauGauducheau, Saint HerblainFrance
  14. 14.Institut Paoli CalmetteUniversité de la MediterranéeMarseilleFrance
  15. 15.Broomfield HospitalChelmsfordUK
  16. 16.Russian National Cancer Research Center MoscowRussia
  17. 17.Panorama Medical CenterCape TownSouth Africa
  18. 18.2nd Medical Oncology Department of Errikos Dunan HospitalErrikos Dynan Hospital-BAthensGreece
  19. 19.Department of Human OncologyAllegheny General HospitalPittsburghUSA

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