Exposure–efficacy relationship of trastuzumab emtansine (T-DM1) in EMILIA, a phase III study of T-DM1 versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC).

Abstract

644 Background: T-DM1 is an antibody–drug conjugate composed of trastuzumab (T), a stable thioether linker, and the potent cytotoxic agent DM1. In the phase III study EMILIA, median PFS and OS were significantly prolonged with T-DM1 vs XL in patients (pts) with HER2-positive locally advanced or MBC previously treated with T and a taxane; (PFS hazard ratio [HR]=0.65, p<0.001; OS HR=0.68, p<0.001). We report the effects of T-DM1 exposure on efficacy outcomes in EMILIA. Methods: In EMILIA, pts were randomized 1:1 to receive T-DM1 3.6 mg/kg q3w (n=495) or XL (n=496) in 21-day cycles. Pharmacokinetic (PK) samples were from cycle 1 (n=350, T-DM1 arm only). Exposure variables were T-DM1 AUC, T-DM1 Cmin, total T AUC, and DM1 Cmaxcalculated by noncompartmental analysis. A logistic regression model was used to evaluate the relationship between T-DM1 exposure and objective response rates (ORR) in the T-DM1 arm. Multivariate Cox proportional hazards models were used to calculate HRs of OS and PFS for each T-DM1 exposure quartile vs all randomized pts in the XL arm, adjusting for baseline covariates. Results: For ORR, mean T-DM1 AUC was 536 day*ug/mL for responders and 502 day*ug/mL for non-responders (P=0.09); mean DM1 Cmax was 4.55 ng/mL and 4.64 ng/mL, respectively (P=0.64). OS and PFS HRs (and 95% CIs) of T-DM1 vs XL stratified by T-DM1 exposure quartiles are shown (Table). Conclusions: In EMILIA, no clear trends were observed between T-DM1 exposure and PFS, OS, or ORR, following administration of T-DM1 3.6 mg/kg q3w. However, there was a suggestion of improved OS HR by stratified T-DM1 Cmin quartiles, albeit with mostly overlapping 95% CIs. Ongoing T-DM1 clinical trials will further evaluate this potential relationship. [Table: see text]