Abstract PS18-23: Population pharmacokinetics (Pop PK) of MYL-1401O (a trastuzumab biosimilar) and reference trastuzumab (Herceptin®) in patients with HER2-positive metastatic breast cancer (mBC)
Authors: Owen Joel , Rackley Russell , Liu Mark , Fuentes-Alburo Adolfo , Idris Tazeen , Loganathan Subramanian , Barve Abhijit , Waller Cornelius F. , Rugo Hope S. 
Published: February 2021

Background: Mylan trastuzumab (MYL-1401O) is a biosimilar to trastuzumab (Herceptin®). A multicenter, double blind, randomized, phase III study (HERITAGE) compared the efficacy, safety, Pop PK and immunogenicity of MYL-1401O and trastuzumab in patients with HER2-positive mBC. Patients were randomized 1:1 to receive either MYL-1401O or Herceptin®, in combination with taxane Q3W for 24 weeks followed by monotherapy until unacceptable toxicity, disease progression or early discontinuation.Objectives: The objectives of the Pop PK analysis were to compare the Pop PK derived AUC, Cmax, clearance, Vd, and T1/2 profiles of MYL1401O and Herceptin® and to perform an exploratory assessment of the impact of shed extracellular domain (ECD) fragments of the HER2 receptor (HER2/ ECD) on PK parameters.Methods: One end of infusion PK sample was collected at Cycle 1 and Cycle 6, and 1 trough sample per cycle from all patients; additional samples were taken in a Pop PK subset (MYL-1401O: 45; Herceptin®: 37) in the first dosing interval and at subsequent times. Pop PK modeling was performed using NONMEM. Individual patient empiric Bayesian parameter estimates were used to estimate PK measures. The impact of HER2/ECD presence on PK levels was evaluated in the primary covariate analysis. Results: Two hundred forty-five (245) patients in the PK population received MYL-1401O, while 240 received Herceptin® of which 482 were included in the base model Pop PK analysis. 3170 concentration records with sufficient information were included in the Pop PK analysis. There were no notable demographic differences between the treatment groups. Bayesian parameter based exposure estimates at or near steady-state dosing were comparable between treatments, confirming similar PK (Table 1). Treatment was not a significant covariate of clearance (p=0.177) or volume of the central compartment (p=0.584) using the likelihood ratio Chi-square test.The test-to reference mean ratios of Cmin for Cycle 1 and Cycle 6 (end of cycle) were 103.11(90% CI = 90.61, 117.33) and 104.16 (90% CI = 94.00, 115.42), respectively.The HER2/ECD concentrations were a significant covariate of trastuzumab clearance.

Conclusion: Pop PK profiles of MYL-1401O vs. Herceptin® were similar in patients with HER2positive mBC. Model-based exposure measures were similar between treatments. HER2/ECD concentrations were a strong determinant of trastuzumab clearance, and clearance was similar between treatments. The observed trough concentrations were similar between treatments at the end of Cycle 1 and at Cycle 6.Clinical trial identification: EudraCT Number: 2011-001965-42Legal entity responsible for the study: Mylan GmbHFunding: Mylan GmbH

Table 1:Bayesian Parameter Based Exposure Estimates at Cycle 6MYL-1401O (N=245)Herceptin®(N=240)Total(N=485)Parametern*213202415Dose (mg)Mean (SD)420.70 (90.46)421.25 (97.67)420.97 (93.92)Clearance (L/day)0.27 (0.10)0.28 (0.08)0.27 (0.09)Volume of Central Compartment (L)3.16 (0.60)3.20 (0.60)3.18 (0.60)Volume at Steady State (L)6.36 (1.19)6.32 (1.14)6.34 (1.16)AUC (ug*day/mL)40501.40 (13037.04)38816.90 (11966.26)39681.40 (12540.58)Dose-normalized AUC (ug*day/mL/mg)98.50 (30.56)94.41 (28.90)96.51 (29.80)Cmax,ss (ug/mL)177.00 (37.76)171.52 (34.61)174.33 (36.32)Dose-normalized Cmax,ss (ug/mL/mg)0.43 (0.10)0.42 (0.09)0.43 (0.10)Half-life (day)Median (SD)25.12 (7.50)24.34 (6.89)24.74 (7.21)*concentrations below lower limit of quantification and samples before first dose with values &gt;zero were excluded from Pop PK analysis, as were some patients with incomplete information for covariates significant in the final model.

Citation Format: Joel Owen, Russell Rackley, Mark Liu, Adolfo Fuentes-Alburo, Tazeen Idris, Subramanian Loganathan, Abhijit Barve, Cornelius F. Waller, Hope S. Rugo. Population pharmacokinetics (Pop PK) of MYL-1401O (a trastuzumab biosimilar) and reference trastuzumab (Herceptin®) in patients with HER2-positive metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-23.