title: Trastuzumab emtansine for HER2-positive advanced breast cancer.
abstract: BACKGROUND
  Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker.
  
  
  METHODS
  We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted.
  
  
  RESULTS
  Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine.
  
  
  CONCLUSIONS
  T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.).
authors.affiliation: Sunnybrook Odette Cancer Centre, Toronto, ON M4N 3M5, Canada. sunil.verma@sunnybrook.ca
authors.forename: Sunil
authors.initials: S
authors.lastname: Verma
authors.forename: David
authors.initials: D
authors.lastname: Miles
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.forename: Manfred
authors.initials: M
authors.lastname: Welslau
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Mark
authors.initials: M
authors.lastname: Pegram
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.forename: Ellie
authors.initials: E
authors.lastname: Guardino
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lu
authors.forename: Steven
authors.initials: S
authors.lastname: Olsen
authors.forename: Kim
authors.initials: K
authors.lastname: Blackwell
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / 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; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D008453:Maytansine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D015996:Survival Rate; D000068878:Trastuzumab; D055815:Young Adult
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D000077341:Lapatinib; D008453:Maytansine; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab