{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["83(12)"],"submitter":["Chen SC"],"pubmed_abstract":["<h4>Aims</h4>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.<h4>Methods</h4>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<sub>max</sub> ), cycle 1 minimum concentration (C<sub>min</sub> ) and area under the concentration-time curve at steady state (AUC<sub>ss</sub> ). 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<sub>min</sub> were compared with matched TPC-treated patients.<h4>Results</h4>T-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 C<sub>min</sub> and AUC<sub>ss</sub> 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<sub>max</sub> . 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.<h4>Conclusions</h4>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."],"journal":["British journal of clinical pharmacology"],"pagination":["2767-2777"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC5698565"],"repository":["biostudies-literature"],"pubmed_title":["Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ?2 HER2-targeted regimens."],"pmcid":["PMC5698565"],"pubmed_authors":["Jin JY","Li C","Quartino A","Girish S","Strasak A","Polhamus D","French J","Vadhavkar S","Riggs M","Hoersch S","Chen SC","Wang X","Smitt M"],"additional_accession":[]},"is_claimable":false,"name":"Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ?2 HER2-targeted regimens.","description":"<h4>Aims</h4>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.<h4>Methods</h4>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<sub>max</sub> ), cycle 1 minimum concentration (C<sub>min</sub> ) and area under the concentration-time curve at steady state (AUC<sub>ss</sub> ). 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<sub>min</sub> were compared with matched TPC-treated patients.<h4>Results</h4>T-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 C<sub>min</sub> and AUC<sub>ss</sub> 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<sub>max</sub> . 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.<h4>Conclusions</h4>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.","dates":{"release":"2017-01-01T00:00:00Z","publication":"2017 Dec","modification":"2021-02-21T12:05:41Z","creation":"2019-03-27T00:09:13Z"},"accession":"S-EPMC5698565","cross_references":{"pubmed":["28733983"],"doi":["10.1111/bcp.13381"]}}