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

Abstract

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