Abstract PS17-08: Population pharmacokinetic and exposure-response modeling of the oral selective estrogen receptor degrader, rintodestrant (G1T48), in patients with ER+/HER2- advanced breast cancer
Authors: Beelen Andrew P , Li Chao , Jarugula Praneeth , Gopalakrishnan Mathangi , Sorrentino Jessica A , Wolfgang Curt D , Jain Sarika , Tao Wenli 
Published: February 2021

Background: Rintodestrant is an orally bioavailable, potent and selective estrogen receptor degrader (SERD) that competitively binds to the estrogen receptor (ER) and blocks ER signaling in tumors resistant to other endocrine therapies. Clinical trials have been conducted to evaluate the safety and efficacy of rintodestrant in healthy volunteers and patients with ER+/HER2- locally advanced or metastatic breast cancer (ABC). Population pharmacokinetic (PK) and exposure-response (Ex/Re) analyses were performed to further characterize the PK profile of rintodestrant and identify potential Ex/Re relationships. Methods: The present analyses include data from two studies: (1) G1T48-01, a Phase 1 first-in-human study of rintodestrant monotherapy (200-1000 mg once daily [QD]) in women with ER+/HER2- ABC after progression on endocrine therapy (NCT03455270), and (2) G1T48-10, a study in healthy volunteers investigating potential drug-drug interactions between rintodestrant (200 mg QD) and palbociclib (125 mg QD). A PK model was developed using nonlinear mixed effects methodology to estimate PK parameters for individual patients. A tumor dynamic model was built to characterize the relationship between rintodestrant concentrations and the longitudinal tumor sizes according to RECIST v1.1. Ex/Re for key pharmacodynamic markers, including ER target engagement (18F-fluoroestradiol positron emission tomography [FES-PET]), dynamics of cell-free DNA mutational burden, ER degradation and proliferation (Ki67) in tumors, and enumeration of circulating tumor cells are being evaluated. Relationships between model-predicted exposures and study endpoints (objective response rate, clinical benefit rate) are also being evaluated. Results: Rintodestrant PK was best described using a linear two-compartment model with a mixed absorption model. The predicted population mean trough concentration of rintodestrant at the recommended Phase 2 dose (800 mg QD) exceeded the IC90 value for ER degradation established in vitro. A positive Ex/Re relationship was identified between total exposure and target ER engagement as measured by FES-PET. A clear Ex/Re relationship was not identified between any PK parameters and ER degradation or proliferation, potentially due to confounding effects from covariates in the model (eg, prior SERD treatment, ESR1 mutations, etc). Additional exploration of these covariates is ongoing. The final PK, Ex/Re and PK/tumor dynamics model results will be presented. Conclusions: A population PK model was developed and Ex/Re relationship analyses were performed to support the development of rintodestrant for the treatment of patients with ER+ breast cancer. Initial results identified an Ex/Re relationship with target ER engagement via FES-PET analysis.

Citation Format: Andrew P Beelen, Chao Li, Praneeth Jarugula, Mathangi Gopalakrishnan, Jessica A Sorrentino, Curt D Wolfgang, Sarika Jain, Wenli Tao. Population pharmacokinetic and exposure-response modeling of the oral selective estrogen receptor degrader, rintodestrant (G1T48), in patients with ER+/HER2- advanced breast cancer [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 PS17-08.