Ethnic Sensitivity Assessment of the Antibody-Drug Conjugate Trastuzumab Emtansine (T-DM1) in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer

Cancer Chemother Pharmacol. 2016 Sep;78(3):547-58. doi: 10.1007/s00280-016-3099-2. Epub 2016 Jul 16.

Abstract

Purpose: Trastuzumab emtansine (T-DM1) is indicated for previously treated HER2-positive metastatic breast cancer. Ethnic sensitivity assessment of T-DM1 was conducted using data from eight clinical studies to ensure that the clinically recommended dose is appropriate across ethnicities.

Methods: Four approaches were used: (1) non-compartmental analysis (NCA) comparing pharmacokinetic parameters of T-DM1 and relevant analytes across ethnic groups, (2) population pharmacokinetic (popPK) analysis assessing the impact of ethnicity on pharmacokinetics, (3) comparison of T-DM1 pharmacokinetics in Japanese patients versus the global population, and (4) exposure-response analyses assessing the impact of ethnicity on safety and efficacy.

Results: NCA pharmacokinetic parameters (T-DM1, total trastuzumab, DM1) were comparable across ethnic groups; mean cycle 1 T-DM1 AUCinf was 475, 442, and 518 day µg/mL for white (n = 461), Asian (n = 68), and others (n = 57), respectively. PopPK analysis showed that ethnicity (white, Asian, and others) was not a significant covariate for T-DM1 pharmacokinetics (n = 671). Additionally, visual predictive check plots indicated that observed pharmacokinetic profiles in Japanese patients (n = 42) were within the prediction interval generated from the final PopPK model. Exposure-response analyses showed that ethnicity was not a significant covariate impacting efficacy or hepatotoxicity risk, but there was a trend of greater thrombocytopenia risk among Asians versus non-Asians, which could not be explained by similar exposure between the ethnic groups. Most Asians with thrombocytopenia were able to continue T-DM1 using dose-adjustment rules recommended for the global population.

Conclusions: These results suggest that T-DM1 pharmacokinetics are comparable across ethnic groups and that use of the current dosing regimen is appropriate across ethnicities.

Keywords: Antibody–drug conjugate; Ethnic sensitivity; Metastatic breast cancer; Pharmacokinetics; T-DM1; Trastuzumab emtansine.

MeSH terms

  • Ado-Trastuzumab Emtansine
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Area Under Curve
  • Asian Continental Ancestry Group
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / ethnology
  • Breast Neoplasms / pathology
  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase II as Topic
  • Clinical Trials, Phase III as Topic
  • Dose-Response Relationship, Drug
  • Ethnic Groups*
  • Female
  • Humans
  • Maytansine / administration & dosage
  • Maytansine / adverse effects
  • Maytansine / analogs & derivatives*
  • Maytansine / pharmacokinetics
  • Models, Biological
  • Neoplasm Metastasis
  • Receptor, ErbB-2 / metabolism
  • Trastuzumab
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Maytansine
  • Receptor, ErbB-2
  • Trastuzumab
  • Ado-Trastuzumab Emtansine