Exposure-response relationship of T-DM1: insight into dose optimization for patients with HER2-positive metastatic breast cancer

J Wang; P Song; S Schrieber; Q Liu; Q Xu; G Blumenthal; L Amiri Kordestani; P Cortazar; A Ibrahim; R Justice; Y Wang; S Tang; B Booth; N Mehrotra; A Rahman

doi:10.1038/clpt.2014.24

Exposure-response relationship of T-DM1: insight into dose optimization for patients with HER2-positive metastatic breast cancer

Clin Pharmacol Ther. 2014 May;95(5):558-64. doi: 10.1038/clpt.2014.24. Epub 2014 Jan 31.

Authors

J Wang¹, P Song¹, S Schrieber¹, Q Liu¹, Q Xu², G Blumenthal³, L Amiri Kordestani³, P Cortazar³, A Ibrahim³, R Justice³, Y Wang¹, S Tang², B Booth¹, N Mehrotra¹, A Rahman¹

Affiliations

¹ Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
² Office of Biostatistics, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
³ Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

PMID: 24488143
DOI: 10.1038/clpt.2014.24

Abstract

Exposure-response (E-R) analyses for ado-trastuzumab emtansine (T-DM1, Kadcyla) were performed using data from a randomized, active control (lapatinib plus capecitabine) trial in patients with human epidermal growth factor 2-positive metastatic breast cancer. Kaplan-Meier survival analyses stratified by T-DM1 trough concentration on day 21 of cycle 1 (Cmin,C1D21) were performed for overall survival (OS) and progression-free survival (PFS). E-R analyses indicated that after adjusting for baseline risk factors, higher T-DM1 exposure is associated with improved efficacy. T-DM1-treated patients with Cmin,C1D21 lower than the median value had values of OS and PFS comparable to those of the active control arm. The percentage of patients who received T-DM1 dose adjustments was similar across the exposure range and was lower than that of the active control arm. Our findings suggest that there may be an opportunity to optimize Kadcyla dose in the patient subgroup with low T-DM1 exposure for improved efficacy with acceptable tolerability.

Publication types

Clinical Trial, Phase III
Comparative Study
Randomized Controlled Trial

MeSH terms

Ado-Trastuzumab Emtansine
Adult
Aged
Antibodies, Monoclonal, Humanized / administration & dosage
Antibodies, Monoclonal, Humanized / pharmacokinetics
Antibodies, Monoclonal, Humanized / therapeutic use*
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Breast Neoplasms / drug therapy*
Breast Neoplasms / pathology
Capecitabine
Deoxycytidine / administration & dosage
Deoxycytidine / analogs & derivatives
Disease-Free Survival
Dose-Response Relationship, Drug
Female
Fluorouracil / administration & dosage
Fluorouracil / analogs & derivatives
Humans
Kaplan-Meier Estimate
Lapatinib
Maytansine / administration & dosage
Maytansine / analogs & derivatives*
Maytansine / pharmacokinetics
Maytansine / therapeutic use
Middle Aged
Neoplasm Metastasis
Quinazolines / administration & dosage
Receptor, ErbB-2 / metabolism*
Survival Rate
Trastuzumab
Treatment Outcome

Substances

Antibodies, Monoclonal, Humanized
Antineoplastic Agents
Quinazolines
Lapatinib
Deoxycytidine
Maytansine
Capecitabine
Receptor, ErbB-2
Trastuzumab
Ado-Trastuzumab Emtansine
Fluorouracil