A phase 1, open-label study evaluating the pharmacokinetics, safety, and tolerability of vepdegestrant in Chinese patients with ER+/HER2- advanced breast cancer

Purpose: Vepdegestrant is an investigational, orally administered PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader being evaluated for the treatment of ER+/HER2- advanced breast cancer, with promising results in prior studies of Western and Japanese patients. Vepdegestrant had not been previously evaluated in Chinese patients. Methods: This phase 1 study (NCT05732428) assessed pharmacokinetics (PK) of vepdegestrant and its epimer (ARV-473), and safety and preliminary efficacy of vepdegestrant monotherapy (200 mg once daily [QD] in 28-day cycles) in Chinese adults with ER+/HER2- advanced breast cancer who had received ≥ 1 prior line of endocrine therapy. Results: Nine female Chinese patients were treated (median age, 56.0 [range: 42.0–69.0] years; six received ≥ 3 prior anticancer therapies in the advanced setting). Geometric mean area under the plasma concentration–time curve over the dosing interval was 9575 ng*h/mL following a single dose and 18,340 ng*h/mL following multiple daily doses on day 15; maximum observed concentration of vepdegestrant was 633.2 ng/mL and 1035 ng/mL after single and multiple doses, respectively. Vepdegestrant was well tolerated. Most treatment-related adverse events (TRAEs) were grade 1 or 2. Two patients experienced grade 3 TRAEs; no patients discontinued due to AEs. Objective response and clinical benefit rates were 33.3% and 44.4%, respectively. Three patients had partial responses; all three subsequently had progressive disease at the final data cutoff. Conclusions: Vepdegestrant (200 mg QD) demonstrated a PK profile comparable to previous studies, a well-tolerated safety profile, and signs of preliminary antitumor activity in heavily pretreated Chinese patients with ER+/HER2- advanced breast cancer. Clinical trial registration number: ClinicalTrials.gov ID, NCT05732428.