Original Article

Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 5, pp 1229-1240

Open Access This content is freely available online to anyone, anywhere at any time.

Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer

  • Sandhya GirishAffiliated withGenentech, Inc Email author 
  • , Manish GuptaAffiliated withGenentech, IncBristol-Myers Squibb
  • , Bei WangAffiliated withGenentech, Inc
  • , Dan LuAffiliated withGenentech, Inc
  • , Ian E. KropAffiliated withDana-Farber Cancer Institute
  • , Charles L. VogelAffiliated withSylvester Comprehensive Cancer Center
  • , Howard A. Burris IIIAffiliated withSarah Cannon Research Institute
  • , Patricia M. LoRussoAffiliated withKarmanos Cancer Center
  • , Joo-Hee YiAffiliated withGenentech, Inc
    • , Ola SaadAffiliated withGenentech, Inc
    • , Barbara TongAffiliated withGenentech, Inc
    • , Yu-Waye ChuAffiliated withGenentech, Inc
    • , Scott HoldenAffiliated withGenentech, Inc
    • , Amita JoshiAffiliated withGenentech, Inc



Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate.


Multiple analytes—T-DM1, total trastuzumab (TT), DM1, and key metabolites—were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays.


PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w.


The PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.


Trastuzumab emtansine T-DM1 Breast cancer HER2 Antibody–drug conjugate