Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2-targeted regimens

Abstract

Aims

We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1) to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs. treatment of physician's choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer.

Methods

We compared a historical T-DM1 PopPK model with T-DM1 pharmacokinetics in TH3RESA and performed exposure-response analyses using model-predicted cycle 1 C_max, cycle 1 C_min, and AUC_ss. Kaplan–Meier analyses (OS, PFS) and logistic regression (overall response rate [ORR], safety) were stratified by T-DM1 exposure metrics. Survival hazard ratios (HRs) in the lowest exposure quartile (Q1) of cycle 1 C_min were compared with matched TPC-treated patients.

Results

T-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 C_min and AUC_ss exhibited numerically longer median OS and PFS and higher ORR than patients with lower exposure. Exposure-response relationships were less evident for cycle 1 C_max. No relationship between exposure and safety was identified. HRs for the comparison of T-DM1–treated patients in the Q1 subgroup with matched TPC-treated patients were 0.96 (95% CI 0.63, 1.47) for OS and 0.92 (95% CI 0.64, 1.32) for PFS.

Conclusions

Exposure-response relationships for efficacy were inconsistent across exposure metrics. HRs for survival in patients in the lowest T-DM1 exposure quartile vs. matched TPC-treated patients suggest that, compared with TCP, the approved T-DM1 dose is unlikely to be detrimental to patients with low exposure.

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