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

Sandhya Girish, Manish Gupta, Bei Wang, Dan Lu, Ian E. Krop, Charles L. Vogel, Howard A. Burris, Patricia M. LoRusso, Joo Hee Yi, Ola Saad, Barbara Tong, Yu Waye Chu, Scott Holden, Amita Joshi

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167 Scopus citations

Abstract

Purpose 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. Methods 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. Results 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. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)1229-1240
Number of pages12
JournalCancer Chemotherapy And Pharmacology
Volume69
Issue number5
DOIs
StatePublished - May 1 2012

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Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Girish, S., Gupta, M., Wang, B., Lu, D., Krop, I. E., Vogel, C. L., Burris, H. A., LoRusso, P. M., Yi, J. H., Saad, O., Tong, B., Chu, Y. W., Holden, S., & Joshi, A. (2012). Clinical pharmacology of trastuzumab emtansine (T-DM1): An antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemotherapy And Pharmacology, 69(5), 1229-1240. https://doi.org/10.1007/s00280-011-1817-3