PII-039 - THE EFFECT OF CARBAMAZEPINE ON THE PHARMACOKINETICS (PK) OF VEPDEGESTRANT, A PROTEOLYSIS TARGETING CHIMERA (PROTAC) ESTROGEN RECEPTOR (ER) DEGRADER IN HEALTHY ADULTS.

H. Wang¹, J. Winton², K. Matschke³, A. Stouffs⁴, K. Lee², Y. Zhang⁵, W. Qiao¹, W. Tan¹; ¹Pfizer, Inc., La Jolla, CA, USA, ²Pfizer, Inc., Groton, CT, USA, ³Pfizer, Inc., Collegeville, PA, United States, ⁴Pfizer Clinical Research Unit, Brussels, Belgium, ⁵Arvinas Operations, Inc., New Haven, CT, USA.

Background: In a first-in-human phase 1/2 study (NCT04072952), the oral PROTAC ER degrader vepdegestrant (ARV-471) had encouraging clinical activity and was well tolerated in patients with ER-positive/human epidermal growth factor receptor 2–negative breast cancer. The objective of this study was to evaluate the effect of a strong cytochrome P450 (CYP)3A4 inducer, carbamazepine, on the PK and safety of vepdegestrant (NCT06005688).

Methods: This was a phase 1, open-label, fixed-sequence study in healthy adults. During period 1, a single oral dose of vepdegestrant 200 mg was administered alone in a fed state. During period 2, carbamazepine dosing was titrated from 200 mg orally once a day (days 1–3) to 200 mg twice a day (days 4–7) to the final dose of 200 mg 3 times a day (days 8–19). A single oral dose of vepdegestrant 200 mg was administered in a fed state on day 14. Blood samples for vepdegestrant PK analysis were collected up to 144 hours after dosing in both periods.

Results: A total of 12 healthy male participants were enrolled and treated in this study. After administration of vepdegestrant with carbamazepine (test) or alone (reference), test/reference ratios (90% CIs) of the adjusted geometric means for vepdegestrant area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) and maximum observed plasma concentration (Cmax) were 64.05% (60.02–68.35) and 80.15% (74.00–86.81), respectively. Treatment-emergent adverse events (AEs) occurred in 6 (50%; vepdegestrant), 12 (100%; carbamazepine), and 9 (75%; vepdegestrant + carbamazepine) participants. Two participants reported mild treatment-related AEs of diarrhea and somnolence (1 [8.3%] each) following the administration of vepdegestrant alone. Following administration of carbamazepine with vepdegestrant, 2 serious AEs (SAEs) of increased hepatic enzyme levels, related to carbamazepine, were reported in 2 participants. Two participants discontinued from the study, 1 due to the SAE of increased hepatic enzyme levels and the other due to an AE of moderate maculopapular rash. No dose reductions due to AEs were reported.

Conclusion: Coadministration of multiple doses of carbamazepine, a strong CYP3A4 inducer, with a single dose of vepdegestrant resulted in a 36% decrease in plasma vepdegestrant AUCinf.