256TiP TACTIVE-E: Phase Ib study of ARV-471, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in combination with everolimus in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer

ARV-471 is an oral PROTAC ER degrader that binds to and degrades both wild-type ESR1 mutants. was well tolerated showed clinical activity in a phase I/II study heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer. Everolimus, inhibitor of mammalian target rapamycin (mTOR), approved exemestane for pts cancer after progression on aromatase inhibitors has shown cyclin-dependent kinase 4 6 (CDK4/6) treatment. In prior CDK4/6 therapy, the combination everolimus may offer additional advantages as can degrade mutant forms ER, mutations are enriched this setting. Preclinical studies ER-expressing cell lines evidence growth inhibition plus everolimus, including cells expressing Y537S or D538G mutations. demonstrated greater tumor xenograft model than either monotherapy. Here we describe open-label, Ib TACTIVE-E (NCT05501769) Eligible (aged ≥18 years) have histologically cytologically confirmed metastatic, recurrent, unresectable cancer; received 1–3 systemic therapy advanced/metastatic setting, ≥1 endocrine ≤1 chemotherapy; intolerance inhibitor. Pts not mTOR-targeting therapy. combined administered orally 28-day cycles. The primary endpoints dose-limiting toxicities determine recommended II dose type, frequency, severity adverse events laboratory abnormalities. Secondary preliminary antitumor (overall response rate, benefit duration response) pharmacokinetic parameters everolimus. NCT05501769. Medical writing support: Justine Lempart, PhD, Apollo Communications, funded by Arvinas Operations, Inc. Estrogen Receptor,