Abstract P4-21-26: Population pharmacokinetics (PK) and exposure-response (E-R) analysis of trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer (MBC) who have received at least two prior regimens of HER2-directed therapy
Authors: Chen S-C , Polhamus D , Riggs M , French J , Wang X , Smitt M , Hoersch S , Strasak A , Chernyukhin N , Quartino A , Jin J , Girish S , Li C 
Published: May 2019

Abstract
Background:
TH3RESA was a Phase III randomized study to evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) compared to treatment of physician's choice (TPC) in patients with HER2+ MBC who have progression after at least two regimens of HER2-directed therapy. Population pharmacokinetic (PK) and exposure-response (E-R) analyses were performed to characterize T-DM1 PK as well as E-R relationship for key efficacy and safety endpoints in the population.
Methods:
Post-hoc analysis based on historical T-DM1 population PK models was performed to assess whether PK is consistent with historical data. E-R analyses with OS and PFS were conducted using Cox proportional hazard (CPH) models with exposure metrics (model-predicted Cycle 1 Cmin and AUCss) included in the model. Logistic regression models were used for binary endpoints of overall response rate (ORR) and key safety endpoints with exposure metrics included as continuous variable only. To supplement the E-R analysis for OS and PFS, case matching analyses were conducted to compare OS and PFS in the lowest exposure quartile (Q1) vs. higher exposure quartiles (Q2-4) to their corresponding matched control.
Results:
Historical T-DM1 population PK model well described T-DM1 PK in TH3RESA study. In CPH analyses with OS and PFS, hazard ratios (HR) of both efficacy endpoints consistently decreased with increasing T-DM1 exposure. The E-R relationship is supported by case matching analyses, where T-DM1 treated patients were stratified by model-predicted Cycle 1 Cmin. HRs of OS and PFS for patients at Q2−4 versus their matched TPC patients (HR (95%CI): 0.58 (0.44, 0.78) for OS; 0.47 (0.36, 0.62) for PFS) were numerically smaller than that of T-DM1 treated patients at Q1 versus their corresponding matched TPC patients (HR (95%CI): 0.96 (0.63, 1.47) for OS; 0.92 (0.64, 1.32) for PFS). For ORR, an E-R trend was also noted. On the other hand, no E-R relationship was identified with key safety endpoints.
HR for Quartile of Cmin Before and After Adjusting for Risk Factors QuartileUnadjusted HR (95% CI)Adjusted HR (95% CI)OSQ11.14 (0.832, 1.55)0.886 (0.64, 1.23) Q20.828 (0.6, 1.14)0.685 (0.493, 0.952) Q30.532 (0.374, 0.757)0.559 (0.391, 0.798) Q40.352 (0.238, 0.521)0.405 (0.272, 0.603)PFSQ10.852 (0.63, 1.15)0.831 (0.614, 1.12) Q20.635 (0.463, 0.872)0.619 (0.451, 0.85) Q30.428 (0.3, 0.609)0.442 (0.31, 0.632) Q40.237 (0.158, 0.357)0.258 (0.171, 0.389)
HR for Quartile of AUCss Before and After Adjusting for Risk Factors QuartileUnadjusted HR (95% CI)Adjusted HR (95% CI)OSQ11.07 (0.782, 1.47)0.774 (0.555, 1.08) Q20.651 (0.464, 0.912)0.567 (0.402, 0.801) Q30.662 (0.472, 0.929)0.736 (0.523, 1.04) Q40.406 (0.280, 0.588)0.458 (0.315, 0.667)PFSQ10.69 (0.505, 0.941)0.657 (0.481, 0.897) Q20.66 (0.479, 0.908)0.681 (0.494, 0.940) Q30.524 (0.377, 0.730)0.545 (0.390, 0.760) Q40.235 (0.155, 0.355)0.253 (0.167, 0.383)
Conclusion:
T-DM1 PK in TH3RESA patient population is similar to historical data. Although an E-R relationship was observed for efficacy, the results need to be interpreted with caution given the potential confounding association between risk factor and PK. No E-R relationship was observed for the safety endpoints examined.
Citation Format: Chen S-C, Polhamus D, Riggs M, French J, Wang X, Smitt M, Hoersch S, Strasak A, Chernyukhin N, Quartino A, Jin J, Girish S, Li C. Population pharmacokinetics (PK) and exposure-response (E-R) analysis of trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer (MBC) who have received at least two prior regimens of HER2-directed therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-26.