title: Expected benefits of topotecan combined with lapatinib in recurrent ovarian cancer according to biological profile: a phase 2 trial.
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/m 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.
authors.affiliation: Medical Oncology Department, Clinical Research Department, Centre François-Baclesse, 3 avenue Général Harris, 14076 Caen Cedex 5, France. s.lheureux@baclesse.fr
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lheureux
authors.forename: Sophie
authors.initials: S
authors.lastname: Krieger
authors.forename: Béatrice
authors.initials: B
authors.lastname: Weber
authors.forename: Patricia
authors.initials: P
authors.lastname: Pautier
authors.forename: Michel
authors.initials: M
authors.lastname: Fabbro
authors.forename: Frédéric
authors.initials: F
authors.lastname: Selle
authors.forename: Hugues
authors.initials: H
authors.lastname: Bourgeois
authors.forename: Thierry
authors.initials: T
authors.lastname: Petit
authors.forename: Alain
authors.initials: A
authors.lastname: Lortholary
authors.forename: Anne
authors.initials: A
authors.lastname: Plantade
authors.forename: Mélanie
authors.initials: M
authors.lastname: Briand
authors.forename: Alexandra
authors.initials: A
authors.lastname: Leconte
authors.forename: Nicolas
authors.initials: N
authors.lastname: Richard
authors.forename: Paul
authors.initials: P
authors.lastname: Vilquin
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Clarisse
authors.forename: Cécile
authors.initials: C
authors.lastname: Blanc-Fournier
authors.forename: Florence
authors.initials: F
authors.lastname: Joly
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077216:Carcinoma, Ovarian Epithelial; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077341:Lapatinib; D055442:Metabolome / Q000502:physiology; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D018570:Risk Assessment; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D011799:Quinazolines; D000077341:Lapatinib; D019772:Topotecan