title: Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial.
abstract: BACKGROUND
  Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options. We aimed to compare trastuzumab emtansine, an antibody-drug conjugate comprising the cytotoxic agent DM1 linked to trastuzumab, with treatment of physician's choice in this population of patients.
  
  
  METHODS
  This randomised, open-label, phase 3 trial took place in medical centres in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients (≥18 years, left ventricular ejection fraction ≥50%, Eastern Cooperative Oncology Group performance status 0-2) with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting, were randomly assigned (in a 2:1 ratio) to trastuzumab emtansine (3·6 mg/kg intravenously every 21 days) or physician's choice using a permuted block randomisation scheme by an interactive voice and web response system. Patients were stratified according to world region (USA vs western Europe vs other), number of previous regimens (excluding single-agent hormonal therapy) for the treatment of advanced disease (two to three vs more than three), and presence of visceral disease (any vs none). Coprimary endpoints were investigator-assessed progression-free survival (PFS) and overall survival in the intention-to-treat population. We report the final PFS analysis and the first interim overall survival analysis. This study is registered with ClinicalTrials.gov, number NCT01419197.
  
  
  RESULTS
  From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned (404 to trastuzumab emtansine and 198 to physician's choice). At data cutoff (Feb 11, 2013), 44 patients assigned to physician's choice had crossed over to trastuzumab emtansine. After a median follow-up of 7·2 months (IQR 5·0-10·1 months) in the trastuzumab emtansine group and 6·5 months (IQR 4·1-9·7) in the physician's choice group, 219 (54%) patients in the trastuzumab emtansine group and 129 (65%) of patients in the physician's choice group had PFS events. PFS was significantly improved with trastuzumab emtansine compared with physician's choice (median 6·2 months [95% CI 5·59-6·87] vs 3·3 months [2·89-4·14]; stratified hazard ratio [HR] 0·528 [0·422-0·661]; p<0·0001). Interim overall survival analysis showed a trend favouring trastuzumab emtansine (stratified HR 0·552 [95% CI 0·369-0·826]; p=0·0034), but the stopping boundary was not crossed. A lower incidence of grade 3 or worse adverse events was reported with trastuzumab emtansine than with physician's choice (130 events [32%] in 403 patients vs 80 events [43%] in 184 patients). Neutropenia (ten [2%] vs 29 [16%]), diarrhoea (three [<1%] vs eight [4%]), and febrile neutropenia (one [<1%] vs seven [4%]) were grade 3 or worse adverse events that were more common in the physician's choice group than in the trastuzumab emtansine group. Thrombocytopenia (19 [5%] vs three [2%]) was the grade 3 or worse adverse event that was more common in the trastuzumab emtansine group. 74 (18%) patients in the trastuzumab emtansine group and 38 (21%) in the physician's choice group reported a serious adverse event.
  
  
  CONCLUSIONS
  Trastuzumab emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received trastuzumab and lapatinib.
  
  
  BACKGROUND
  Genentech.
authors.affiliation: Dana-Farber Cancer Institute, Harvard University School of Medicine, Boston, MA, USA. Electronic address: ikrop@partners.org.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.affiliation: Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, South Korea.
authors.forename: Sung-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: MD Anderson Cancer Center, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: González-Martín
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferrero
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Smitt
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Yu
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Abraham C F
authors.initials: AC
authors.lastname: Leung
authors.affiliation: Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Wildiers
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008453:Maytansine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D000068878:Trastuzumab
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human