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Expected Benefits of Topotecan Combined With Lapatinib in Recurrent Ovarian Cancer According to Biological Profile: A Phase 2 Trial
  1. Stéphanie Lheureux, MD*,,,
  2. Sophie Krieger, PharmD, PhD§,
  3. Béatrice Weber, MD,
  4. Patricia Pautier, MD,
  5. Michel Fabbro, MD#,
  6. Frédéric Selle, MD**,
  7. Hugues Bourgeois, MD††,
  8. Thierry Petit, MD‡‡,
  9. Alain Lortholary, MD§§,
  10. Anne Plantade, MD∥∥,
  11. Mélanie Briand, MSc,
  12. Alexandra Leconte, MSc,
  13. Nicolas Richard, MD¶¶,
  14. Paul Vilquin, PhD§,
  15. Bénédicte Clarisse, PharmD, PhD,
  16. Cécile Blanc-Fournier, MD* and
  17. Florence Joly, MD, PhD*,,¶¶
  1. *Medical Oncology Department, and
  2. Clinical Research Department, Centre François Baclesse, Caen;
  3. Unit of Biology and Innovative Therapies of Locally Aggressive Cancers, Groupe Régional d’Etudes sur le Cancer (GRECAN), Université de Caen;
  4. §Clinical Biology and Oncology Laboratory, Centre François Baclesse, Caen;
  5. Medical Oncology Department, Centre Alexis Vautrin, Nancy;
  6. Medical Oncology Department, Institut Gustave Roussy, Villejuif;
  7. #Medical Oncology Department, Centre Val d’Aurelle Paul Lamarque, Montpellier;
  8. **Medical Oncology Department, Centre Hospitalo-Universitaire Tenon, Paris;
  9. ††Medical Oncology Department, Clinique Victor Hugo, Le Mans;
  10. ‡‡Medical Oncology Department, Centre Paul Strauss, Strasbourg;
  11. §§Medical Oncology Department, Clinique Catherine de Sienne, Nantes;
  12. ∥∥Medical Oncology Department, Hôpital des Diaconesses, Paris; and
  13. ¶¶Medical Oncology Department, Centre Hospitalier Universitaire, Caen, France.
  1. Address correspondence and reprint requests to Stéphanie Lheureux, MD, Clinical Research Department, Centre François-Baclesse, 3 avenue Général Harris, 14076 Caen Cedex 5, France. E-mail: s.lheureux@baclesse.fr.

Abstract

Objective Lapatinib, a tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), also inhibits breast cancer resistance protein (BCRP) involved in resistance to topotecan. The aim of this multicenter study was to assess the efficacy of the combination topotecan-lapatinib in epithelial ovarian cancer relapsing after a first line of chemotherapy.

Methods Patients having relapsed within 6 months (n = 20) or between 6 and 12 months (n = 19) received weekly topotecan (3.2 mg/m2 given intravenously on days 1, 8, and 15) and daily oral lapatinib (1250 mg). Translational studies were performed on tumor and serum.

Results An objective (partial) response was observed for 5 patients (14%), all with late relapse. The rates of overall benefits, including responses and stabilizations, were 37% and 62% in patients having relapsed within or after 6 months, respectively. Corresponding median time to progression were 58 and 94 days. The most frequent toxicity was hematological, including grade 4 neutropenia (18%) and thrombocytopenia (3%). None of the tumors overexpressed HER2 or EGFR, and no mutation was found. Two Kras mutations were identified. Positive expressions of BCRP and cyclin A (median, 70% and 40%) were not correlated to the response to treatment.

Conclusions This study failed to demonstrate a clinical benefit of lapatinib-topotecan compared to previously described activity with topotecan alone in a context of low levels of EGFR and HER2 expressions, and no biomarkers could be identified. The absence of correlation between BCRP expression and clinical outcomes suggests that other mechanisms of resistance to topotecan could predominate.

  • Topotecan
  • Lapatinib
  • Relapsing ovarian carcinoma
  • HER2
  • BCRP

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Footnotes

  • This work was supported by GlaxoSmithKline.

  • Stéphanie Lheureux and Sophie Krieger contributed equally to this work.

  • Florence Joly participated in advisory board sessions for GlaxoSmithKline and Roche.

  • The authors declare no conflicts of interest.

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