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

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 [A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With human epidermal growth factor receptor 2 (HER2)‐positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2‐directed Therapy] 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 maximum concentration (C max ), cycle 1 minimum concentration (C min ) and area under the concentration–time curve at steady state (AUC ss ). Kaplan–Meier analyses [overall survival (OS), progression‐free survival (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% confidence interval (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.