title: Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA.
abstract: BACKGROUND
  We characterized the incidence of central nervous system (CNS) metastases after treatment with trastuzumab emtansine (T-DM1) versus capecitabine-lapatinib (XL), and treatment efficacy among patients with pre-existing CNS metastases in the phase III EMILIA study.
  
  
  METHODS
  In EMILIA, patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer previously treated with trastuzumab and a taxane were randomized to T-DM1 or XL until disease progression. Patients with treated, asymptomatic CNS metastases at baseline and patients developing postbaseline CNS metastases were identified retrospectively by independent review; exploratory analyses were carried out.
  
  
  RESULTS
  Among 991 randomized patients (T-DM1 = 495; XL = 496), 95 (T-DM1 = 45; XL = 50) had CNS metastases at baseline. CNS progression occurred in 9 of 450 (2.0%) and 3 of 446 (0.7%) patients without CNS metastases at baseline in the T-DM1 and XL arms, respectively, and in 10 of 45 (22.2%) and 8 of 50 (16.0%) patients with CNS metastases at baseline. Among patients with CNS metastases at baseline, a significant improvement in overall survival (OS) was observed in the T-DM1 arm compared with the XL arm [hazard ratio (HR) = 0.38; P = 0.008; median, 26.8 versus 12.9 months]. Progression-free survival by independent review was similar in the two treatment arms (HR = 1.00; P = 1.000; median, 5.9 versus 5.7 months). Multivariate analyses demonstrated similar results. Grade ≥3 adverse events were reported in 48.8% and 63.3% of patients with CNS metastases at baseline administered T-DM1 and XL, respectively; no new safety signals were observed.
  
  
  CONCLUSIONS
  In this retrospective, exploratory analysis, the rate of CNS progression in patients with HER2-positive advanced breast cancer was similar for T-DM1 and for XL, and higher overall in patients with CNS metastases at baseline compared with those without CNS metastases at baseline. In patients with treated, asymptomatic CNS metastases at baseline, T-DM1 was associated with significantly improved OS compared with XL.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston. Electronic address: ikrop@partners.org.
authors.forename: I E
authors.initials: IE
authors.lastname: Krop
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston.
authors.forename: N U
authors.initials: NU
authors.lastname: Lin
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham.
authors.forename: K
authors.initials: K
authors.lastname: Blackwell
authors.affiliation: Product Development, Oncology, Genentech, Inc., South San Francisco, USA.
authors.forename: E
authors.initials: E
authors.lastname: Guardino
authors.affiliation: Department of Medical Oncology and Breast Centre, Cantonal Hospital, St Gallen, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Huober
authors.affiliation: Product Development, Oncology, Genentech, Inc., South San Francisco, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK.
authors.forename: D
authors.initials: D
authors.lastname: Miles
authors.affiliation: Biostatistics, Genentech, Inc., South San Francisco, USA.
authors.forename: M
authors.initials: M
authors.lastname: Samant
authors.affiliation: Hematology, Medical Office, Aschaffenburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Welslau
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Diéras
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000069287:Capecitabine; D016543:Central Nervous System Neoplasms / Q000401:mortality / Q000556:secondary*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D000077341:Lapatinib; D008453:Maytansine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008875:Middle Aged; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012189:Retrospective Studies; D000068878:Trastuzumab; D055815:Young Adult
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D000077341:Lapatinib; D008453:Maytansine; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: T-DM1; ado-trastuzumab emtansine; central nervous system metastasis; metastatic breast cancer