Abstract P4-15-09: Phase 1 study of trastuzumab emtansine in HER2-positive metastatic breast cancer patients with normal or reduced hepatic function
Authors: Li Chunze , Agarwal Priya , Dent Susan , Goncalves Anthony , Yi Joo-Hee , Strasak Alexander , Green Marjorie , Girish Sandhya , LoRusso Pat 
Published: May 2015

Abstract
Introduction
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab, a stable linker, and the microtubule inhibitor DM1. In phase 3 studies of HER2-positive metastatic breast cancer (MBC), T-DM1 significantly increased progression-free survival (EMILIA and TH3RESA) and overall survival (EMILIA) vs. control regimens. Few patients (2–4%) treated with T-DM1 experience grade ≥3 increases in transaminases. Currently, there are no data on the pharmacokinetics (PK) of T-DM1 in patients with hepatic impairment. This international, multicenter, open-label, parallel group, phase 1 PK study (BO25499/NCT01513083) is designed to assess the PK of T-DM1 and relevant analytes in MBC patients with normal hepatic function and mild or moderate hepatic impairment; safety and efficacy will also be evaluated.
Methods
To obtain 8 evaluable patients, up to 10 patients each with HER2-positive MBC and ECOG performance status of 0–2 were enrolled in 1 of 3 independent cohorts based on hepatic function per Child-Pugh criteria: normal hepatic function, mild hepatic impairment (Child-Pugh A), and moderate hepatic impairment (Child-Pugh B). Patients with severe hepatic impairment (Child Pugh C) were ineligible. Patients received 3 cycles of T-DM1 3.6 mg/kg every 3 weeks. After 3 cycles, patients could continue to receive T-DM1 until disease progression, unmanageable toxicity, or study termination in the present study, or enroll in an extension study (BO25430/TDM4529g). PK samples were collected during cycle 1 (days 1 [predose, 30 m and 4 h postinfusion], 2, 3, 4, 8, 11, 15, and 18); cycle 2 (day 1 [predose, 30 m postinfusion]); and cycle 3 (days 1 [predose, 30 m postinfusion], 8, 15, and 22). T-DM1, total trastuzumab, DM1, MCC-DM1, and Lys-MCC-DM1 were measured using validated assays. Adverse events were graded per NCI CTCAE, v4.03. All analyses are descriptive. The clinical cutoff date for this interim analysis was January 30, 2014.
Results
PK data were fully evaluable for 10 out of 10 patients each in the normal and mild cohorts and for 6 out of 7 patients in the moderate cohort. Compared with the normal cohort, T-DM1 clearance at cycle 1 was ∼1.9- and 3.3-fold faster in the mild and moderate cohorts, respectively. The trend of faster clearance was less apparent for cycle 3 after repeated dosing, with similar T-DM1 exposures across the 3 cohorts. Plasma concentrations of DM1 and DM1-containing catabolites were largely comparable across the 3 cohorts. No new safety signals were seen relative to the known safety profile of T-DM1. Updated safety data will be presented.
Conclusions
There is a trend for faster clearance of T-DM1 at cycle 1 in patients with mild and moderate hepatic impairment vs. those with normal hepatic function, which can be partly explained by demographic and pathophysiological covariates such as tumor burden, albumin, and body weight. The study’s small sample size could also partly explain the variability. Work to better understand the mechanisms for the observed differences in clearance is ongoing. No increase in the systemic concentration of DM1 was observed in patients with mild or moderate hepatic impairment vs. those with normal hepatic function. No additional safety concerns were observed.
Citation Format: Chunze Li, Priya Agarwal, Susan Dent, Anthony Goncalves, Joo-Hee Yi, Alexander Strasak, Marjorie Green, Sandhya Girish, Pat LoRusso. Phase 1 study of trastuzumab emtansine in HER2-positive metastatic breast cancer patients with normal or reduced hepatic function [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-09.