Abstract P5-18-11: Pharmacokinetics and exposure-efficacy relationship of trastuzumab emtansine in EMILIA, a phase 3 study of trastuzumab emtansine vs capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer

Abstract

Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab (T), the cytotoxic agent DM1, and a stable thioether linker; it is being evaluated for the treatment (tx) of HER2-positive cancer. EMILIA is a randomized, multicenter, open-label phase 3 study assessing the efficacy and safety of T-DM1 vs capecitabine (X) and lapatinib (L) in pts with HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with T and a taxane. We report the pharmacokinetics (PK) of T-DM1 in EMILIA and compare these data with historical data of single-agent T-DM1. The effects of T-DM1 exposure on efficacy outcomes in EMILIA are also reported. Methods: In EMILIA, pts were randomized 1:1 to receive T-DM1 3.6 mg/kg q3w (n = 495) or X + L (n = 496) in 21-day cycles. At least 1 PK sample was collected from 350 pts in the T-DM1 arm; 307 of these had adequate PK profiles for the estimation of ≥1 PK parameter in cycle 1. PK parameters were estimated by noncompartmental analysis for serum T-DM1, serum total T (conjugated and unconjugated T), and plasma DM1. A logistic regression model was used to evaluate the relationship between T-DM1 exposure (ie, T-DM1 AUC and DM1 Cmax) and objective response rates (ORR). Analyses of progression-free survival (PFS) and overall survival (OS), stratified by T-DM1 exposure, were conducted. Cox regression was used to evaluate the effect of T-DM1 exposure and other potential covariates on PFS and OS. Results: The PK parameters for T-DM1, total T, and DM1 in EMILIA and other studies of single-agent T-DM1 are summarized in Table 1. The PK parameters appear similar regardless of prior tx for MBC. No significant differences in mean serum T-DM1 AUC (P = 0.091) or plasma DM1 Cmax (P = 0.812) were observed between responders and non-responders following T-DM1 tx. Furthermore, variability in T-DM1 AUC and DM1 Cmax does not appear to affect the probability of response to therapy (P = 0.23 for T-DM1 AUC and P = 0.74 for DM1 Cmax). Based on Cox proportional hazards analysis, no significant exposure-efficacy relationship was observed between T-DM1 AUC (P = 0.23 for PFS and p = 0.53 for OS) or DM1 Cmax (P = 0.96 for PFS and P = 0.34 for OS) and PFS or OS, respectively. Conclusions: T-DM1 PK data in EMILIA pts were similar to those observed in previous phase 2 studies, which include pts who have and have not received prior therapy for MBC. Variation in T-DM1 exposure among pts who received T-DM1 3.6 mg/kg q3w had no significant impact on ORR, PFS, or OS. Detailed analyses will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-11.

Targeted therapy for HER2 positive breast cancer

“…Wang concluded that T-DM1 pharmacokinetics data were similar in previous phase II studies with historical data of single agent T-DM1 [40]. Furthermore, there was no significant exposure-efficacy relationship observed between T-DM1 AUC ( P  = 0.23 for PFS and P = 0.53 for OS) or DM1 Coax ( P  = 0.96 for PFS and P  = 0.34 for OS) and PFS or OS, respectively [40]. …”

Antibody–Drug Conjugates: Design and Development of Trastuzumab Emtansine (T‐DM1)

“…T-DM1 was also examined for exposure-response relationships using data from Phase II and III clinical trials (including T-DM1 area under the curve [AUC], peak plasma concentration [C max ], minimum plasma concentration [C min ], trastuzumab AUC, and DM1 C max ) [28,32]. Analysis of the Phase III EMILIA study showed no clear trends between T-DM1 exposure (C max and AUC) and efficacy (progression-free survival [PFS]; overall survival [OS]; or response rate) [32].…”

“…Analysis of the Phase III EMILIA study showed no clear trends between T-DM1 exposure (C max and AUC) and efficacy (progression-free survival [PFS]; overall survival [OS]; or response rate) [32]. A slight trend was observed for improved OS by stratified T-DM1 C min quartiles, although with overlapping 95% confidence intervals.…”