In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-free survival (PFS) and overall survival (OS) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer. Using EMILIA data, we evaluated the T-DM1 exposure–response relationship.
Exposure–response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration (C min) and area under the concentration–time curve from time zero to day 21 of T-DM1 at cycle 1] and multiple efficacy (OS, PFS, objective response rate) and safety (grade ≥ 3 adverse events, grade ≥ 3 thrombocytopenia, grade ≥ 3 hepatotoxicity) endpoints.
An apparent exposure–response trend was observed between model-predicted exposure metrics and efficacy; trends for observed exposure metrics were shallower and often not significant. Although median OS and PFS were numerically longer in patients with higher versus lower model-predicted cycle 1 C min, OS and PFS hazard ratios for T-DM1-treated patients in the lowest exposure quartile (Q1) versus control were < 1 after adjusting for baseline risk factors (e.g., ECOG status, tumor burden, measurable disease, and number of disease sites). No meaningful exposure–response relationship was observed for any safety endpoints.
Exposure–response relationships for efficacy were inconsistent across exposure metrics; model-predicted cycle 1 C min showed the strongest exposure–response trend. The Q1 subgroup based on model-predicted cycle 1 C min had numerically similar or better OS and PFS versus control following covariate adjustment. The approved T-DM1 dose (3.6 mg/kg every 3 weeks) has a positive benefit–risk ratio versus control, even for the T-DM1 Q1 subgroup.
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The authors would like to thank Matt Riggs for his help with assessing the feasibility of identifying patients with low T-DM1 exposure. The EMILIA study was funded by Genentech, Inc./F. Hoffmann-La Roche. Support for third-party writing assistance was provided by Tiffany DeSimone, PhD, of CodonMedical, an Ashfield Company, part of UDG Healthcare plc, and was funded by Genentech, Inc.
This work was supported by Genentech, Inc./F. Hoffman-La Roche, Basel, Switzerland.
Conflict of interest
C. Li, B. Wang, S.-C. Chen, D. Lu, X. Wang, S. Vadhavkar, M. Smitt, A. Joshi, M. Samant, A. Quartino, J. Jin, and S. Girish are employees of and own stock in Genentech, Inc., South San Francisco, CA, USA. R. Wada is an employee of Certara and was a paid consultant for Genentech, Inc., in connection with development of this article. D. Polhamus and J. French are employees of Metrum Research Group, LLC, which was contracted to work on behalf of Genentech, Inc. A. Strasak is an employee of and owns stock in F. Hoffmann-La Roche, Basel, Switzerland.
EMILIA was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.
The study protocol was approved by the institutional review board/ethics committee at each participating center, and all participants provided written informed consent.
Chunze Li and Bei Wang authors contributed equally to this work.
Data from this study were previously presented, in part, at the American Society of Clinical Oncology (ASCO) Annual Meeting, May 31–June 4, 2013, Chicago, Illinois, USA, and the San Antonio Breast Cancer Symposium, December 4–8, 2012, San Antonio, Texas, USA.
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Li, C., Wang, B., Chen, SC. et al. Exposure–response analyses of trastuzumab emtansine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Cancer Chemother Pharmacol 80, 1079–1090 (2017). https://doi.org/10.1007/s00280-017-3440-4
- Trastuzumab emtansine (T-DM1)
- Exposure–response relationship
- Antibody–drug conjugate (ADC)
- Metastatic breast cancer
- Human epidermal growth factor receptor 2 (HER2)