title: Bosutinib in combination with the aromatase inhibitor letrozole: a phase II trial in postmenopausal women evaluating first-line endocrine therapy in locally advanced or metastatic hormone receptor-positive/HER2-negative breast cancer.
abstract: BACKGROUND
  Endocrine therapy resistance in hormone receptor-positive (HR+) breast cancer (BC) may involve crosstalk between HRs and growth factor signaling pathways. We evaluated bosutinib, a dual Src/Abl tyrosine kinase inhibitor that has previously demonstrated some antitumor activity in BC, plus letrozole as first-line endocrine therapy in locally advanced or metastatic HR+/HER2- BC. METHODS; Sixteen postmenopausal women were enrolled in a phase II study evaluating the safety/efficacy of bosutinib plus letrozole. In the single-arm safety/dose-confirming lead-in (part 1), patients received oral bosutinib at 400 mg/day plus letrozole at 2.5 mg/day; adverse events (AEs) and dose-limiting toxicities (DLTs) were monitored, and initial efficacy was assessed. A randomized efficacy/safety phase (part 2) was planned to evaluate the combination versus letrozole monotherapy.
  
  
  RESULTS
  Fifteen of 16 subjects experienced treatment-related AEs, most commonly diarrhea (69%). Treatment-related hepatotoxicity AEs (primarily alanine aminotransferase [ALT] or aspartate aminotransferase [AST] elevations) occurred in 6 of 16 patients (38%). Four of 15 evaluable patients (27%) experienced a DLT (grade 3/4 ALT/AST elevations, n = 2; grade 3 rash, n = 1; grade 3 diarrhea or vomiting, n = 1), including 1 Hy's law hepatotoxicity case. All DLTs resolved following treatment discontinuation. One patient achieved confirmed partial response; one had stable disease for >24 weeks. Study termination occurred before part 2.
  
  
  CONCLUSIONS
  The unfavorable risk-benefit ratio did not warrant further investigation of bosutinib plus letrozole.
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: 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; D000077289:Letrozole; 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; D014230:Triazoles / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D000077289:Letrozole; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; C471992:bosutinib; C508053:ERBB2 protein, human