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Cancer Chemother Pharmacol. 2017 Dec;80(6):1079-1090. doi: 10.1007/s00280-017-3440-4. Epub 2017 Oct 11.

Exposure-response analyses of trastuzumab emtansine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane.

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Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
Certara Strategic Consulting, Certara, Menlo Park, CA, USA.
Stastical Modeling and Simulation, Metrum Research Group, Tariffville, CT, USA.
Biostatistics, F. Hoffmann-La Roche, Basel, Switzerland.
Clinical Sciences, Genentech, Inc., South San Francisco, CA, USA.
Biostatistics, Genentech, Inc., South San Francisco, CA, USA.



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.


Antibody–drug conjugate (ADC); Exposure–response relationship; Human epidermal growth factor receptor 2 (HER2); Metastatic breast cancer; Pharmacokinetics; Trastuzumab emtansine (T-DM1)

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