Abstract 256TiP
Background
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.
Trial design
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.
Clinical trial identification
NCT05501769.
Editorial acknowledgement
Medical writing support: Justine Lempart, PhD, of Apollo Medical Communications, and funded by Arvinas Operations, Inc.
Legal entity responsible for the study
Arvinas Estrogen Receptor, Inc.
Funding
Arvinas Estrogen Receptor, Inc.
Disclosure
A. Schott: Financial Interests, Personal, Other, Contracted Research: Pfizer, Takeda, Genentech, Arvinas; Financial Interests, Personal, Other, Receipt of Intellectual Property Rights/Patent Holder: Imbio, LLC. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp& Dohme, GSK, Leuko, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardant Health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca. S. Ivie: Financial Interests, Personal, Full or part-time Employment: Arvinas Operations, Inc. R. Gedrich: Financial Interests, Personal, Full or part-time Employment: Arvinas Operations, Inc.; Financial Interests, Personal, Stocks/Shares: Arvinas Operations, Inc. E. Zhi: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas; Financial Interests, Personal, Project Lead: Arvinas. J. Ranciato: Financial Interests, Personal, Full or part-time Employment: Arvinas. J. Perkins: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Other, Patent Holder: Pfizer. E. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, Arcus, AstraZeneca, Daiichi Sankyo, Seagen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Immunomedics, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, InventisBio, Verastem, eFFECTOR Therapeutics, CytomX, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Jacobio, Atlas MedX, Ellipses, Incyte, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Cascadian Therapeutics, Artios, BeiGene, Bliss BioPharmaceuticals, Context Therapeutics, Cullinan-Florentine, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Relay Therapeutics, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Tolmar, Torque Therapeutics. All other authors have declared no conflicts of interest.