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A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: the Trastyvere study

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Abstract

Purpose

To evaluate the efficacy and safety of lapatinib (L) and trastuzumab (T) combination in HER2-positive metastatic breast cancer (MBC) patients previously treated with T and/or L.

Materials and methods

We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L–T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed.

Results

One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1–43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and ≥ 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naïve patients (31.5% versus 40.5% for L-pretreated versus L-naïve). Grade 3/4 adverse events were reported in 19 patients (16.5%).

Conclusion

The combination of L–T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L–T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.

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References

  1. Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. JCO 2010;28:92–8. https://ascopubs.org/doi/full/10.1200/JCO.2008.19.9844.

    Article  CAS  Google Scholar 

  2. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted anti–HER-2 therapy and personalized medicine. Oncol 2009;14:320–68. https://theoncologist.alphamedpress.org/content/14/4/320.

    Article  CAS  Google Scholar 

  3. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol. 2005;23:2445–599.

    Article  CAS  Google Scholar 

  4. Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs. 2000;59:753–67.

    Article  CAS  Google Scholar 

  5. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92.

    Article  CAS  Google Scholar 

  6. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365:1273–83. https://doi.org/10.1056/NEJMoa0910383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, et al. CEREBEL (EGF111438): a Phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015;33:1564–73.

    Article  CAS  Google Scholar 

  8. Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66:1630–9.

    Article  CAS  Google Scholar 

  9. Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15:924–34.

    Article  CAS  Google Scholar 

  10. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783–91. https://doi.org/10.1056/NEJMoa1209124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Krop IE, Kim S-B, González-Martín A, LoRusso PM, Ferrero J-M, Smitt M, et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:689–99.

    Article  CAS  Google Scholar 

  12. Storniolo AM, Pegram MD, Overmoyer B, Silverman P, Peacock NW, Jones SF, et al. Phase I dose escalation and pharmacokinetic study of lapatinib in combination with trastuzumab in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2008;26:3317–23.

    Article  CAS  Google Scholar 

  13. Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28:803–14.

    Article  CAS  Google Scholar 

  14. Xia W, Gerard CM, Liu L, Baudson NM, Ory TL, Spector NL. Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene. 2005;24:6213–21.

    Article  CAS  Google Scholar 

  15. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124–30.

    Article  CAS  Google Scholar 

  16. Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30:2585–92.

    Article  CAS  Google Scholar 

  17. A’Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med. 2001;20:859–66.

    Article  Google Scholar 

  18. Montemurro F, Donadio M, Clavarezza M, Redana S, Jacomuzzi ME, Valabrega G, et al. Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy. Oncol. 2006;11:318–24. https://theoncologist.alphamedpress.org/content/11/4/318.

    Article  CAS  Google Scholar 

  19. Tripathy D, Slamon DJ, Cobleigh M, Arnold A, Saleh M, Mortimer JE, et al. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol. 2004;22:1063–70.

    Article  CAS  Google Scholar 

  20. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German breast group 26/breast international group 03–05 study. J Clin Oncol. 2009;27:1999–2006.

    Article  Google Scholar 

  21. Cortés J, Fumoleau P, Bianchi GV, Petrella TM, Gelmon K, Pivot X, et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012;30:1594–600.

    Article  Google Scholar 

  22. Finn RS, Press MF, Dering J, Arbushites M, Koehler M, Oliva C, et al. Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer. J Clin Oncol. 2009;27:3908–15.

    Article  CAS  Google Scholar 

  23. Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008;29:217–33.

    Article  CAS  Google Scholar 

  24. Olson EM, Abdel-Rasoul M, Maly J, Wu CS, Lin NU, Shapiro CL. Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab. Ann Oncol. 2013;24:1526–33.

    Article  CAS  Google Scholar 

  25. Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, et al. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC CTG MA.31. J Clin Oncol. 2015;33:1574–83.

    Article  CAS  Google Scholar 

  26. Bachelot T, Romieu G, Campone M, Diéras V, Cropet C, Dalenc F, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14:64–71.

    Article  CAS  Google Scholar 

  27. Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA, et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol. 2013;31:1726–31.

    Article  CAS  Google Scholar 

  28. Perez EA, Koehler M, Byrne J, Preston AJ, Rappold E, Ewer MS. Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc. 2008;83:679–86.

    Article  Google Scholar 

  29. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633–40.

    Article  CAS  Google Scholar 

  30. Gianni L, Pienkowski T, Im Y-H, Roman L, Tseng L-M, Liu M-C, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25–322.

    Article  CAS  Google Scholar 

  31. Valachis A, Nearchou A, Polyzos NP, Lind P. Cardiac toxicity in breast cancer patients treated with dual HER2 blockade. Int J Cancer. 2013;133:2245–52.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank the patients, their families, the nurses, and the investigators who participated in this study. The authors acknowledge Miguel Sampayo for his advice on the statistical analysis.

Author information

Authors and Affiliations

  1. Medical Oncology Department, Instituto Valenciano de Oncología, Valencia, Spain

    J. Gavilá & A. L. Guerrero-Zotano

  2. Medical Oncology Department, Hospital Reina Sofía, Córdoba, Spain

    J. De La Haba

  3. Medical Oncology Department, Hospital Clínico Valencia, Valencia, Spain

    B. Bermejo & M. Huerta

  4. Medical Oncology Department, Hospital General Elche, Elche, Spain

    Á. Rodríguez-Lescure & A. Cotes-Sanchís

  5. Medical Oncology Department, Hospital Miguel Servet, Zaragoza, Spain

    A. Antón & J. Lao Romera

  6. Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain

    E. Ciruelos

  7. Medical Oncology Department, Institut Català D’Oncologia, Girona, Spain

    J. Brunet

  8. Medical Oncology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    E. Muñoz-Couselo

  9. Medical Oncology Department, Clínica Universidad de Navarra, Pamplona, Spain

    M. Santisteban

  10. Medical Oncology Department, Hospital Universitario de Salamanca - IBSAL, Salamanca, Spain

    C. A. Rodríguez Sánchez

  11. Medical Oncology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain

    A. Santaballa

  12. Medical Oncology Department, Complejo Hospitalario de Jaén, Jaén, Spain

    P. Sánchez Rovira

  13. Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain

    J. Á. García Sáenz

  14. Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain

    M. Ruiz-Borrego

  15. Medical Oncology Department, Hospital de Día QuirónSalud, Zaragoza, Spain

    E. Aguirre

  16. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

    J. Cortés

  17. IOB, Institute of Oncology, QuirónSalud Group, Madrid and Barcelona, Spain

    J. Cortés

  18. Medica Scientia Innovation Research (MedSIR), Barcelona, Spain

    J. Cortés & A. Llombart-Cussac

  19. Medical Oncology Department, Hospital Arnau de Vilanova - FISABIO, Valencia, Spain

    A. Llombart-Cussac

Authors
  1. J. Gavilá
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Corresponding author

Correspondence to A. Llombart-Cussac.

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Conflict of interest

This work was supported by GlaxoSmithKline plc (GSK) through a contract with Medica Scientia Innovation Research (MedSIR), an academic research organization focused on independent clinical research development. Joaquín Gavilá: Roche, Novartis, Celgene (H, SAB); César Augusto Rodríguez Sánchez: Roche, Novartis, Celgene, Eisai, AstraZeneca (H, SAB); Javier Cortés: Roche, Celgene (C/A, H), Eisai, Novartis (H); Antonio Llombart-Cussac: Roche, GlaxoSmithKline, Novartis, Celgene, Eisai, AstraZeneca (H, SAB), GlaxoSmithKline, Sanofi, Puma Biotechnology (RF); all remaining authors have declared no financial relationships. (C/A) Consulting/advisory relationship; (RF) research funding; (E) employment; (ET) expert testimony; (H) honoraria received; (OI) ownership interests; (IP) intellectual property rights/inventor/patent holder; (SAB) scientific advisory board.

Ethical approval

The protocol of this trial and informed consent were approved by the ethics committee of each participating hospital and the study has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This study was classified by the Spanish Agency of Medicines and Health Products.

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Written informed consent was obtained from all individual participants included in the study.

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Gavilá, J., De La Haba, J., Bermejo, B. et al. A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: the Trastyvere study. Clin Transl Oncol 22, 420–428 (2020). https://doi.org/10.1007/s12094-019-02145-4

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