Pharmacokinetics of trastuzumab emtansine (T-DM1) as a single agent or in combination with pertuzumab in HER2-positive breast cancer patients with recurrent or locally advanced metastatic breast cancer.

Abstract

PURPOSE:

The phase III MARIANNE study investigated single-agent trastuzumab emtansine (T-DM1) and combination T-DM1 plus pertuzumab as the first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Pharmacokinetic properties of T-DM1 and pertuzumab in these patients and the potential for drug-drug interactions (DDIs) were assessed.

METHODS:

Pharmacokinetic samples of T-DM1-related analytes (T-DM1 conjugate, total trastuzumab, DM1) and pertuzumab were analyzed. Observed pharmacokinetic data were summarized for all analytes. Historical population pharmacokinetic models for T-DM1 conjugate and pertuzumab in HER2-positive MBC were used to derive empirical Bayes estimates of pharmacokinetic parameters.

RESULTS:

In MARIANNE (N = 375), mean ± standard deviation population pharmacokinetic model-predicted Cycle 1 Cmax for T-DM1 conjugate was 74.4 ± 10.1 µg/mL, Cycle 1 Ctrough was 1.34 ± 0.802 µg/mL, and area under the concentration-time curve from time zero to infinity after first dose (AUCinf) was 338 ± 69.5 µg*day/mL. These values were similar to other T-DM1 studies. Pharmacokinetics of T-DM1 conjugate and other analytes (total trastuzumab, DM1) were similar with or without pertuzumab. In the pertuzumab plus T-DM1 arm, mean model-predicted Cycle 1 pertuzumab Cmax, Ctrough, and AUCinf were 276 ± 50.0 µg/mL, 64.8 ± 17.9 μg/mL, and 4470 ± 1360 µg*day/mL, respectively. These values were similar to other pertuzumab studies.

CONCLUSIONS:

Based on the population pharmacokinetic analysis of T-DM1 conjugate and pertuzumab, pharmacokinetics are similar across different lines of treatment and stages of disease including previously untreated MBC patients, and no DDIs were identified for combined use of T-DM1 and pertuzumab.

• Authors: Dan Lu, Chunze Li, Matthew Riggs, Daniel Polhamus, Jonathan French, Priya Agarwal, Shang-Chiung Chen, Shweta Vadhavkar, Monika Patre, Alexander Strasak, Angelica Quartino, Jin Yan Jin, Sandhya Girish
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 84 Issue 1 Pg. 175-185 (07 2019) ISSN: 1432-0843 [Electronic] Germany
• PMID: 31102024 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Immunological
• ERBB2 protein, human
• Receptor, ErbB-2
• pertuzumab
• Ado-Trastuzumab Emtansine

Topics

• Ado-Trastuzumab Emtansine (administration & dosage, pharmacokinetics)
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antineoplastic Agents, Immunological (administration & dosage, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacokinetics)
• Area Under Curve
• Breast Neoplasms (drug therapy, pathology)
• Drug Interactions
• Female
• Humans
• Models, Biological
• Neoplasm Recurrence, Local
• Neoplasm Staging
• Receptor, ErbB-2 (metabolism)