title: Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis.
abstract: OBJECTIVE
  The antibody-drug conjugate trastuzumab emtansine (T-DM1) combines the cytotoxic activity of DM1 with the human epidermal growth factor receptor 2 (HER2) -targeted, antitumor properties of trastuzumab. T-DM1 has shown activity in phase I and II single-arm studies in patients with pretreated HER2-positive metastatic breast cancer (MBC) and has demonstrated superior efficacy and improved tolerability versus standard MBC treatments in randomized phase II and III studies. This analysis, combining available data from all single-agent T-DM1 studies to date, was conducted to better define the T-DM1 safety profile.
  
  
  METHODS
  Six studies in patients with HER2-positive MBC who received T-DM1 3.6 mg/kg every 3 weeks and follow-up data from patients in an extension study were analyzed. Analyses included adverse events (AEs) by grade; AEs leading to death, drug discontinuation, or dose reduction; and select AEs.
  
  
  RESULTS
  Among 884 T-DM1-exposed patients, the most commonly reported all-grade AEs were fatigue (46.4%), nausea (43.0%), thrombocytopenia (32.2%), headache (29.4%), and constipation (26.5%). The most common grade 3 to 4 AEs were the laboratory abnormalities of thrombocytopenia (11.9%) and increased AST serum concentration (4.3%). These were manageable and not generally associated with clinical symptoms. There were 12 AE-related deaths. AEs resulted in dose reductions in 17.2% of patients and drug discontinuations in 7.0%.
  
  
  CONCLUSIONS
  In this analysis of 884 T-DM1-exposed patients, grade 3 or greater AEs were infrequent and typically asymptomatic and manageable. This favorable safety profile makes T-DM1 treatment suitable for exploration in other breast cancer settings.
authors.affiliation: Véronique Diéras, Institut Curie, Paris, France; Nadia Harbeck, University of Munich, Munich, Germany; G. Thomas Budd, Cleveland Clinic, Lerner College of Medicine, Cleveland, OH; Joel K. Greenson, University of Michigan, Ann Arbor, MI; Ellie A. Guardino, Meghna Samant, Nataliya Chernyukhin, and Melanie C. Smitt, Genentech, South San Francisco, CA; and Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA. veronique.dieras@curie.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.affiliation: Véronique Diéras, Institut Curie, Paris, France; Nadia Harbeck, University of Munich, Munich, Germany; G. Thomas Budd, Cleveland Clinic, Lerner College of Medicine, Cleveland, OH; Joel K. Greenson, University of Michigan, Ann Arbor, MI; Ellie A. Guardino, Meghna Samant, Nataliya Chernyukhin, and Melanie C. Smitt, Genentech, South San Francisco, CA; and Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.affiliation: Véronique Diéras, Institut Curie, Paris, France; Nadia Harbeck, University of Munich, Munich, Germany; G. Thomas Budd, Cleveland Clinic, Lerner College of Medicine, Cleveland, OH; Joel K. Greenson, University of Michigan, Ann Arbor, MI; Ellie A. Guardino, Meghna Samant, Nataliya Chernyukhin, and Melanie C. Smitt, Genentech, South San Francisco, CA; and Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: G Thomas
authors.initials: GT
authors.lastname: Budd
authors.affiliation: Véronique Diéras, Institut Curie, Paris, France; Nadia Harbeck, University of Munich, Munich, Germany; G. Thomas Budd, Cleveland Clinic, Lerner College of Medicine, Cleveland, OH; Joel K. Greenson, University of Michigan, Ann Arbor, MI; Ellie A. Guardino, Meghna Samant, Nataliya Chernyukhin, and Melanie C. Smitt, Genentech, South San Francisco, CA; and Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Joel K
authors.initials: JK
authors.lastname: Greenson
authors.affiliation: Véronique Diéras, Institut Curie, Paris, France; Nadia Harbeck, University of Munich, Munich, Germany; G. Thomas Budd, Cleveland Clinic, Lerner College of Medicine, Cleveland, OH; Joel K. Greenson, University of Michigan, Ann Arbor, MI; Ellie A. Guardino, Meghna Samant, Nataliya Chernyukhin, and Melanie C. Smitt, Genentech, South San Francisco, CA; and Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Guardino
authors.affiliation: Véronique Diéras, Institut Curie, Paris, France; Nadia Harbeck, University of Munich, Munich, Germany; G. Thomas Budd, Cleveland Clinic, Lerner College of Medicine, Cleveland, OH; Joel K. Greenson, University of Michigan, Ann Arbor, MI; Ellie A. Guardino, Meghna Samant, Nataliya Chernyukhin, and Melanie C. Smitt, Genentech, South San Francisco, CA; and Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Meghna
authors.initials: M
authors.lastname: Samant
authors.affiliation: Véronique Diéras, Institut Curie, Paris, France; Nadia Harbeck, University of Munich, Munich, Germany; G. Thomas Budd, Cleveland Clinic, Lerner College of Medicine, Cleveland, OH; Joel K. Greenson, University of Michigan, Ann Arbor, MI; Ellie A. Guardino, Meghna Samant, Nataliya Chernyukhin, and Melanie C. Smitt, Genentech, South San Francisco, CA; and Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Chernyukhin
authors.affiliation: Véronique Diéras, Institut Curie, Paris, France; Nadia Harbeck, University of Munich, Munich, Germany; G. Thomas Budd, Cleveland Clinic, Lerner College of Medicine, Cleveland, OH; Joel K. Greenson, University of Michigan, Ann Arbor, MI; Ellie A. Guardino, Meghna Samant, Nataliya Chernyukhin, and Melanie C. Smitt, Genentech, South San Francisco, CA; and Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Melanie C
authors.initials: MC
authors.lastname: Smitt
authors.affiliation: Véronique Diéras, Institut Curie, Paris, France; Nadia Harbeck, University of Munich, Munich, Germany; G. Thomas Budd, Cleveland Clinic, Lerner College of Medicine, Cleveland, OH; Joel K. Greenson, University of Michigan, Ann Arbor, MI; Ellie A. Guardino, Meghna Samant, Nataliya Chernyukhin, and Melanie C. Smitt, Genentech, South San Francisco, CA; and Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
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*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D008453:Maytansine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D016896:Treatment Outcome
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