PII-157 - THE EFFECT OF ITRACONAZOLE ON THE PHARMACOKINETICS (PK) OF VEPDEGESTRANT, A PROTEOLYSIS TARGETING CHIMERA (PROTAC) ESTROGEN RECEPTOR (ER) DEGRADER, IN HEALTHY ADULT PARTICIPANTS.

L. Tran¹, J. Winton², K. Matschke³, A. Stouffs⁴, K. Lee², Y. Zhang⁵, W. Tan¹; ¹Pfizer, Inc., San Diego, CA, USA, ²Pfizer, Inc., Groton, CT, USA, ³Pfizer, Inc., Collegeville, PA, USA, ⁴Pfizer, Inc., 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+/human epidermal growth factor receptor 2- breast cancer. The objective of this study was to evaluate the impact of itraconazole, a strong cytochrome P450 (CYP)3A inhibitor, on the PK of vepdegestrant in healthy adult participants (NCT05538312).

Methods: This phase 1, open-label, 2-period, fixed-sequence study was conducted in healthy male and female adults; female participants were of non-childbearing potential. In period 1, a single oral dose of vepdegestrant 200 mg was administered alone in the fed state. In period 2, itraconazole 200 mg orally once daily was administered from day 1 to day 11; a single oral dose of vepdegestrant 200 mg was administered in the fed state on day 5. Blood samples for vepdegestrant PK were collected up to 120 h (period 1) and 168 h (period 2) after dosing.

Results: A total of 12 participants were enrolled and treated. Co-administration of itraconazole with vepdegestrant increased the plasma area under the curve from time 0 extrapolated to infinite time (AUC_inf) of vepdegestrant by 69% and the maximum plasma concentration (C_max) of vepdegestrant by 52% (primary endpoints). For vepdegestrant administration with itraconazole (test) compared with vepdegestrant alone (reference), the test/reference ratios of the adjusted geometric means (90% CI) for vepdegestrant AUC_inf and C_max were 168.90% (157.66%–180.94%) and 152.19% (136.90%–169.18%), respectively. Treatment-emergent adverse events (TEAEs) occurred in 2 (16.7%; vepdegestrant), 3 (25.0%; itraconazole), and 2 (16.7%; vepdegestrant+itraconazole) participants, respectively. All AEs were mild to moderate; no serious or severe AEs occurred and no discontinuations or dose reductions due to AEs were reported. Two treatment-related AEs of mild abdominal pain and diarrhea were reported after vepdegestrant treatment in 1 (8.3%) participant.

Conclusion: Co-administration of multiple doses of the potent CYP3A inhibitor itraconazole modestly increased vepdegestrant exposure. A single dose of vepdegestrant 200 mg was well tolerated when administered alone and with itraconazole in healthy adult participants.