Abstract 205P
Background
The oral PROTAC protein degrader ARV-471 binds and degrades wild-type (WT) and mutant ER. The phase II expansion (VERITAC) of a phase I/II study (NCT04072952) tested 2 ARV-471 doses (200 mg once daily [QD] and 500 mg QD) in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer. ARV-471 200 mg QD was selected as the phase III monotherapy dose based on comparable efficacy and favorable tolerability vs 500 mg QD and robust ER degradation (data cutoff: Jun 6, 2022). We present updated data for ARV-471 200 mg QD after 5 additional months of follow-up.
Methods
ARV-471 was administered to pts with ER+/HER2- locally advanced/metastatic breast cancer who had received ≥1 prior endocrine therapy for ≥6 months, ≥1 cyclin-dependent kinase (CDK)4/6 inhibitor, and ≤1 chemotherapy regimen. The primary endpoint was clinical benefit rate (CBR; rate of confirmed complete or partial response or stable disease ≥24 weeks).
Results
As of Nov 1, 2022, 35 pts (median age: 63 y [range: 42–79]; 97% female) received ARV-471 200 mg QD. Pts had a median of 4 prior regimens (range: 1–9); 100% prior CDK4/6 inhibitors, 74% prior fulvestrant, and 74% prior chemotherapy (46% in metastatic setting). CBR with ARV-471 200 mg QD was 37.1% (95% CI: 21–55) in all evaluable pts (n=35) and 47.4% (95% CI: 24–71) in evaluable pts with mutant ESR1 (n=19). Median progression-free survival in all evaluable pts was 3.5 months (95% CI: 1.8–7.8). As of the data cutoff date, 14 pts were on treatment for ≥24 weeks (4 for ≥48 weeks) with 4 ongoing. Substantial on-treatment reductions in mutant ESR1 circulating tumor DNA levels were observed. Treatment-related adverse events in ≥10% of pts were fatigue (40%), hot flush (17%), nausea (14%), arthralgia (11%), and increased aspartate aminotransferase (11%); all were grade 1/2.
Conclusions
After longer follow-up, ARV-471 200 mg QD continued to show clinical activity and was well tolerated in heavily pretreated pts with ER+/HER2- advanced breast cancer. The ongoing phase III VERITAC-2 study (NCT05654623) is evaluating ARV-471 200 mg QD vs fulvestrant.
Clinical trial identification
NCT04072952.
Editorial acknowledgement
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
S.A. Hurvitz: Financial Interests, Personal, Research Grant: Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, OBI Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, Zymeworks; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, AstraZeneca. A. Schott: Financial Interests, Personal, Research Grant: Pfizer, Genentech, Arvinas, Takeda; Financial Interests, Personal, Proprietary Information: Imbio, LLC. C.X. Ma: Financial Interests, Personal, Other, Consulting Fees: Olaris, Novartis, Gilead, AstraZeneca, Sanofi-Genzyme, Biovica, Jacobio, Natera, Inivata, Athenex, Bayor, OncoSignal; Financial Interests, Personal, Funding: Pfizer, Puma. R. Nanda: Financial Interests, Personal, Advisory Board: AstraZeneca, BeyondSpring, Cardinal Health, Fujifilm, Immunomedics/Gilead, Infinity, iTeos, Merck, OBI, Oncosec, Seagen; Financial Interests, Personal, Other, Research Funding: Arvinas, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Odonate Therapeutics, OncoSec, Pfizer, Seattle Genetics, Taiho. G. Zahrah: Financial Interests, Personal, Research Grant: Arvinas. N. Hunter: Financial Interests, Personal, Research Grant: Arvinas. A. Tan: Financial Interests, Personal, Research Grant: Arvinas. M.L. Telli: Financial Interests, Personal, Other, Research: Arvinas; Financial Interests, Personal, Other, Consulting: Merck, Immunomedics, Genentech/Roche, G1 Therapeutics, Natera, Pfizer, OncoSec, Blueprint Medicines, Guardant Health, Novartis, AstraZeneca, Sanofi, RefleXion Medical, Gilead Sciences; Financial Interests, Institutional, Research Grant: Novartis, PharmaMar, AbbVie, Calithera Biosciences, Genentech, GSK, Medivation, OncoSec, Vertex, Biothera, Tesaro, Pfizer, EMD Serono, Bayer, Hummingbird Biosciences. J. Anampa: Financial Interests, Personal, Other, Research: Arvinas. R. Jeselsohn: Financial Interests, Personal, Research Grant: Pfizer, Lilly; Financial Interests, Personal, Advisory Board: Carrick Therapeutics, Luminex. P. Munster: Financial Interests, Institutional, Research Grant: Cyteir Therapeutics, Inc., InventisBio Co., Ltd., Amgen, PMV Pharmaceuticals, Genentech, Inc., Revolution Medicines, Inc., Bliss Biopharmaceutical (Hangzhou) Co., Ltd., Arvinas Estrogen Receptor, Inc., Arch Oncology, Hoffman-La Roche, JS InnoPharm, LLC, Seagen Inc., Tempest Therapeutics, Jannsen, Deciphera Pharmaceuticals LLC, Clovis Oncology, Inc., ORIC Pharmaceuticals, Merck Sharp & Dohme LLC, Pfizer, Novartis; Financial Interests, Personal, Other, Consulting Fees: Alessa, RasCal, AtlasMedx; Financial Interests, Personal, Ownership Interest: Alessa, RasCal, AtlasMedx, EpiAxis; Financial Interests, Personal, Royalties: Alessa, RasCal, AtlasMedx, EpiAxis; Financial Interests, Personal, Other: EpiAxis. E. Zhi: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas; Financial Interests, Personal, Project Lead: Arvinas. R. Gedrich: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas. C. Mather: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas. H. Han: Financial Interests, Personal, Advisory Board: Novartis, Gilead, AstraZeneca; Financial Interests, Personal, Other, Speaker's Bureau: Lilly; Financial Interests, Institutional, Invited Speaker: Zymeworks, arvinas, AbbVie, Daiichi Sankyo, Marker therapeutics, Pfizer, Seagen, Quantum Leap Healthcare Collaborative. 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, Millennium, Rgenix, Arqule, Clovis, 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.