Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2-targeted regimens

Br J Clin Pharmacol. 2017 Dec;83(12):2767-2777. doi: 10.1111/bcp.13381. Epub 2017 Sep 3.


Aims: We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1), to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA [A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With human epidermal growth factor receptor 2 (HER2)-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy] study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs. treatment of physician's choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer.

Methods: We compared a historical T-DM1 PopPK model with T-DM1 pharmacokinetics in TH3RESA and performed exposure-response analyses using model-predicted cycle 1 maximum concentration (Cmax ), cycle 1 minimum concentration (Cmin ) and area under the concentration-time curve at steady state (AUCss ). Kaplan-Meier analyses [overall survival (OS), progression-free survival (PFS)] and logistic regression [overall response rate (ORR), safety] were stratified by T-DM1 exposure metrics. Survival hazard ratios (HRs) in the lowest exposure quartile (Q1) of cycle 1 Cmin were compared with matched TPC-treated patients.

Results: T-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 Cmin and AUCss exhibited numerically longer median OS and PFS and higher ORR than patients with lower exposure. Exposure-response relationships were less evident for cycle 1 Cmax . No relationship between exposure and safety was identified. HRs for the comparison of T-DM1-treated patients in the Q1 subgroup with matched TPC-treated patients were 0.96 [95% confidence interval (CI) 0.63, 1.47] for OS and 0.92 (95% CI 0.64, 1.32) for PFS.

Conclusions: Exposure-response relationships for efficacy were inconsistent across exposure metrics. HRs for survival in patients in the lowest T-DM1 exposure quartile vs. matched TPC-treated patients suggest that, compared with TCP, the approved T-DM1 dose is unlikely to be detrimental to patients with low exposure.

Keywords: exposure-response (E-R); metastatic breast cancer; population pharmacokinetics (PopPK); trastuzumab emtansine (T-DM1).

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Ado-Trastuzumab Emtansine
  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Agents, Immunological / adverse effects
  • Antineoplastic Agents, Immunological / blood
  • Antineoplastic Agents, Immunological / pharmacokinetics*
  • Area Under Curve
  • Breast Neoplasms / blood
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / mortality
  • Disease-Free Survival
  • Female
  • Humans
  • Infusions, Intravenous
  • Kaplan-Meier Estimate
  • Logistic Models
  • Maytansine / administration & dosage
  • Maytansine / adverse effects
  • Maytansine / analogs & derivatives*
  • Maytansine / blood
  • Maytansine / pharmacokinetics
  • Metabolic Clearance Rate
  • Models, Biological*
  • Nonlinear Dynamics
  • Proportional Hazards Models
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / metabolism
  • Risk Assessment
  • Trastuzumab / administration & dosage
  • Trastuzumab / adverse effects
  • Trastuzumab / blood
  • Trastuzumab / pharmacokinetics*
  • Treatment Outcome
  • Tubulin Modulators / administration & dosage
  • Tubulin Modulators / adverse effects
  • Tubulin Modulators / blood
  • Tubulin Modulators / pharmacokinetics*


  • Antineoplastic Agents, Immunological
  • Tubulin Modulators
  • Maytansine
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab
  • Ado-Trastuzumab Emtansine

Associated data

  • ClinicalTrials.gov/NCT01419197