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.

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Acknowledgements

The authors acknowledge the investigators, patients, and their families who participated in these clinical trials. The authors are grateful for the assistance of Jia Kang, PhD, from Metrum Research Group, for her assistance in reviewing the data presented in this manuscript.

Funding

This study was funded by Genentech, Inc. Support for third-party writing assistance for this manuscript was provided by Genentech, Inc.

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Correspondence to Dan Lu.

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Conflict of interest

DL, CL, PA, S-CC, AQ, JYJ, and SG are employees of Genentech and own stock in F. Hoffmann-La Roche; MP and AS are employees of and own stock in F. Hoffmann-La Roche; MR, DP, and JF are salaried employees of Metrum Research Group, which was contracted by Genentech, Inc.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Lu, D., Li, C., Riggs, M. et al. 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. Cancer Chemother Pharmacol 84, 175–185 (2019). https://doi.org/10.1007/s00280-019-03852-z

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Keywords

  • Trastuzumab emtansine (T-DM1)
  • HER2
  • Pharmacokinetics
  • Previously untreated metastatic breast cancer
  • MARIANNE