Abstract
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Objectives ARN-810 is a novel, potent ERα antagonist and degrader that is being developed for the treatment of postmenopausal women with ER+ advanced breast cancer. We apply ligand displacement PET with 18F-Fluoroestradiol (FES) to validate ER target engagement.
Methods This data was obtained as part of a multicenter, Phase I, dose-finding, safety and pharmacokinetic clinical trial of ARN-810 in women with advanced or metastatic ER+ breast cancer. Baseline imaging prior to initiation of ARN-810 was performed for all patients. Each patient subsequently underwent either PET imaging at peak or trough plasma concentration of continuous daily dosing, orally administered ARN-810 to confirm duration of receptor engagement. Mean and maximum standardized uptake values (SUVmean and SUVmax) for up to five index FES avid lesions were recorded for each scan. Threshold for FES avidity was SUVmax≥1.5; SUVmax was corrected for physiologic background (SUVmax_corr). SUVmax_corr was defined as SUVmax(lesion)-SUVmax(background). Change in uptake for each FES avid site was defined as (preSUVmax_corr - postSUVmax_corr)/preSUVmax_corr. Median change for each time point was calculated by aggregating the percentage change across individual FES avid lesions.
Results Thirty patients underwent baseline and inter-treatment imaging. Mean time for peak concentration PET scanning was 7 hours (range 2-12 hours), while mean time for trough concentration PET scanning was 20 hours (range 18-24 hours). Number of FES avid lesions on baseline scan ranged from 1 to greater than 10. SUVmax of FES avid lesions ranged from 1.5 to 17.2. All except 3 post-therapy 18-FES scan showed complete or near complete (>90%) suppression of FES uptake to background levels.
Conclusions FES-PET/CT successfully demonstrates target engagement in clinical trials of ARN-810.
Research Support This study was sponsored by Seragon/Genentech.