title: Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy.
abstract: OBJECTIVE
  The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2)-overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population.
  
  
  METHODS
  This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy.
  
  
  RESULTS
  With a follow-up of ≥ 12 months among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 months), and median progression-free survival time was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients with confirmed HER2-positive tumors (immunohistochemistry 3+ or fluorescent in situ hybridization positive) by retrospective central testing (n = 74). Higher response rates were also observed in patients whose tumors expressed ≥ median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade ≥ 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%).
  
  
  CONCLUSIONS
  T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose.
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN 37203-1632, USA. howard.burris@scresearch.net
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.forename: Svetislava J
authors.initials: SJ
authors.lastname: Vukelja
authors.forename: Charles L
authors.initials: CL
authors.lastname: Vogel
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Borson
authors.forename: Steven
authors.initials: S
authors.lastname: Limentani
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tan-Chiu
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.forename: Richard A
authors.initials: RA
authors.lastname: Michaelson
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
authors.forename: Lukas
authors.initials: L
authors.lastname: Amler
authors.forename: Maoxia
authors.initials: M
authors.lastname: Zheng
authors.forename: Yu-Waye
authors.initials: YW
authors.lastname: Chu
authors.forename: Barbara
authors.initials: B
authors.lastname: Klencke
authors.forename: Joyce A
authors.initials: JA
authors.lastname: O'Shaughnessy
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008453:Maytansine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D000068878:Trastuzumab; D016896:Treatment Outcome; D014481:United States
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000922:Immunotoxins; D008453:Maytansine; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human