title: Bosutinib in combination with the aromatase inhibitor exemestane: a phase II trial in postmenopausal women with previously treated locally advanced or metastatic hormone receptor-positive/HER2-negative breast cancer.
abstract: BACKGROUND
  Bosutinib is an oral, selective Src/Abl tyrosine kinase inhibitor with activity in breast cancer (BC). We evaluated bosutinib plus exemestane as second-line therapy in previously treated hormone receptor-positive (HR+) locally advanced or metastatic BC.
  
  
  METHODS
  This was a phase II study with patients enrolled in a single-arm safety lead-in phase. Patients receiving bosutinib at 400 mg or 300 mg/day (based on toxicity) plus exemestane at 25 mg/day were monitored for adverse events (AEs) and dose-limiting toxicities for 28 days, and initial efficacy was assessed. After the lead-in and dose-determination phase, randomized evaluation of combination therapy versus exemestane was planned.
  
  
  RESULTS
  Thirty-nine of 42 patients (93%) experienced treatment-related AEs including diarrhea in 28 (67%) and hepatotoxicity in 11 (26%); overall serious treatment-related AEs were recorded in 4 (10%). No liver toxicity met Hy's law criteria. Dose-limiting toxicities occurred in 5 of 13 patients receiving 400 mg (38%) and 3 of 26 patients receiving 300 mg (12%) of bosutinib; all resolved on treatment discontinuation. One patient (300 mg/day) achieved confirmed partial response; three (400 mg/day, n = 2; 300 mg/day, n = 1) maintained stable disease for >24 weeks; a best response of progressive disease occurred in 15 of 42 patients (36%). Median progression-free survival was 12.3 weeks (80% confidence interval: 11.0-15.6).
  
  
  CONCLUSIONS
  The risk-benefit profile of bosutinib at 300 mg/day plus exemestane resulted in early study termination before the randomized portion. Alternative bosutinib regimens merit investigation in BC.
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, USA;
authors.forename: Beverly
authors.initials: B
authors.lastname: Moy
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lebrun
authors.forename: Meritxell
authors.initials: M
authors.lastname: Bellet
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
authors.forename: Tomasz
authors.initials: T
authors.lastname: Sarosiek
authors.forename: Louis
authors.initials: L
authors.lastname: Chow
authors.forename: Paul
authors.initials: P
authors.lastname: Goss
authors.forename: Charles
authors.initials: C
authors.lastname: Zacharchuk
authors.forename: Eric
authors.initials: E
authors.lastname: Leip
authors.forename: Kathleen
authors.initials: K
authors.lastname: Turnbull
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bardy-Bouxin
authors.forename: Ladan
authors.initials: L
authors.lastname: Duvillié
authors.forename: István
authors.initials: I
authors.lastname: Láng
mesh_terms: D000730:Androstadienes / Q000009:adverse effects / Q000627:therapeutic use*; D000814:Aniline Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D009570:Nitriles / Q000009:adverse effects / Q000627:therapeutic use*; D017698:Postmenopause; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: D000730:Androstadienes; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C471992:bosutinib; C508053:ERBB2 protein, human; C056516:exemestane