Population Pharmacokinetics and Exposure–Response Analyses of Vepdegestrant, a First‐in‐Class PROteolysis‐TArgeting Chimera Estrogen Receptor Degrader

Abstract

Population pharmacokinetic (PK) and exposure–response analyses were performed to characterize the PK and exposure–response relationships of vepdegestrant, a first‐in‐class, oral PROteolysis‐TArgeting Chimera estrogen receptor degrader. Population PK and exposure–response analyses for safety utilized data from the first‐in‐human study (ARV‐471‐mBC‐101, NCT04072952) and the registrational VERITAC‐2 study (NCT05654623), which included patients with ER‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer. Safety endpoints of clinical interest were evaluated using logistic regression and included grade ≥3 treatment‐emergent adverse events (TEAEs) and TEAEs of any grade (arthralgia, fatigue, nausea, aspartate aminotransferase or alanine aminotransferase elevations, anemia, and neutrophil count decreased). Exposure–efficacy analysis included patients with estrogen receptor‐1 (ESR1)‐mutated, ER‐positive, HER2‐negative advanced breast cancer from the VERITAC‐2 vepdegestrant arm only. Progression‐free survival (PFS) as assessed by blinded independent central review, the primary efficacy endpoint in VERITAC‐2, was assessed via Cox proportional hazards modeling. Vepdegestrant PK was described by a two‐compartment model with linear elimination and sequential zero‐, first‐order absorption. None of the evaluated covariates significantly influenced the disposition of vepdegestrant. There was no statistically significant relationship between vepdegestrant exposure and any of the evaluated safety endpoints across 30‐500 mg total daily doses. In patients with ESR1‐mutated, ER‐positive, HER2‐negative advanced breast cancer treated with vepdegestrant 200 mg once daily in the VERITAC‐2 study, exposure was not a statistically significant predictor of PFS. Overall, integrated analyses adequately characterized the PK of vepdegestrant, with no clinically meaningful covariate effects. No exposure–response relationships were identified between vepdegestrant exposure and efficacy or safety outcomes.