390P - Vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: Update of dose escalation results from a phase I/II trial

Background

Vepdegestrant (ARV-471), an oral PROTAC ER degrader, was well tolerated and had clinical activity in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer in the phase 1 dose escalation (data cutoff: Sep 30, 2021) and phase 2 expansion cohort portions of a phase 1/2 study (NCT04072952). We present updated phase 1 dose escalation data after an additional 13 months of follow-up.

Methods

Eligible pts had ER+/HER2- advanced breast cancer, ≥1 prior cyclin-dependent kinase (CDK)4/6 inhibitor, and ≥2 prior endocrine therapies. Primary endpoints were safety, tolerability, and recommended phase 2 dose.

Results

As of Nov 1, 2022, 83 pts (median age: 64 y [range: 36–80]; 99% female) received vepdegestrant (30–700 mg total daily dose). Pts had a median of 4 prior regimens (range: 0–10; 100% prior CDK4/6 inhibitors, 81% prior fulvestrant, and 82% prior chemotherapy [60% in metastatic setting]). There were no dose-limiting toxicities. Treatment-related adverse events were mostly grade 1/2 (Table). Clinical benefit rate (rate of confirmed complete or partial response [PR] or stable disease ≥24 wks) for evaluable pts (n=76) was 37% (95% CI: 26–49). Of 64 pts with baseline measurable disease, 6 had a confirmed and 4 an unconfirmed PR. At data cutoff, 27 pts had treatment for ≥24 wks (7 for ≥48 wks) with 10 pts ongoing. Pharmacokinetics (PK) showed dose-dependent exposure for 30–500 mg daily doses. Substantial on-treatment reductions in mutant ESR1 circulating tumor DNA levels were observed.

Conclusions

Vepdegestrant continued to be well tolerated across all doses and showed clinical activity in heavily pretreated pts with ER+/HER2- advanced breast cancer; PK was dose-dependent up to 500 mg daily. Data support further development of vepdegestrant; the ongoing phase 3 VERITAC-2 study (NCT05654623) is evaluating vepdegestrant 200 mg once daily vs fulvestrant. Table: 390P

TRAEs reported in ≥10% of pts overall

^aNo grade ≥4 TRAEs occurred in any pts ^bOther grade 3 TRAEs not listed were headache (n=1), increased aspartate aminotransferase (n=1), increased amylase (n=1), increased lipase (n=1), QT prolongation (n=1), and venous embolism (n=1); pts may have experienced more than one TRAE TRAE=treatment-related adverse event

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 Operations, Inc.

Funding

Arvinas Estrogen Receptor, Inc.

Disclosure

E.P. 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, AstraZeneca, Daiichi Sankyo, SeaGen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science, Theratechnologies; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Inst, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, 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, Atlas MedX, Ellipses Pharma, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics, Context Therapeutics, Cullinan, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics H. Han: Financial Interests, Institutional, Funding: Arvinas; Financial Interests, Institutional, Research Grant: Abbvie, GSK, G1 Therapeutics, Quantum Leap Healthcare Collaborative, Marker, Pfizer, Zymeworks; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Gilead. A. Schott: Financial Interests, Personal, Research Grant: Pfizer, Takeda, Genentech, Arvinas; Financial Interests, Personal, Other, Receipt of Intellectual Property Rights/Patent Holder: Imbio, LLC. A. Tan: Financial Interests, Personal, Research Grant: Arvinas. R. Nanda: Financial Interests, Personal, Advisory Board: AstraZeneca, BeyondSpring, Cardinal Health, Fujifilm, Immunomedics/Gilead, Infinity, iTeos, Merck, OBI, Oncosec, Seagen; Financial Interests, Funding: Arvinas, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Odonate Therapeutics, OncoSec, Pfizer, Seattle Genetics, Taiho. D. Juric: Financial Interests, Personal, Advisory Role: Eisai, EMD Serono, Genentech, Ipsen, MapKure, Novartis, Petra Pharma, Syros Pharmaceuticals, Vibliome Therapeutics; Financial Interests, Institutional, Research Funding: Amgen, Eisai, EMD Serono, Genentech, Infinity Pharmaceuticals, InventisBio, Novartis, Pfizer, Placon, Syros Pharmaceuticals, Takeda. N. Hunter: Financial Interests, Funding, Research: Arvinas. P. Munster: Financial Interests, Institutional, Funding: Cyteir Therapeutics, Inc, InventisBio Co., Ltd, Amgen, PMV Pharmaceuticals, Inc, Genentech, Inc, Revolution Medicines, Inc, Hoffman-La Roche, JS InnoPharm, LLC, Seagen Inc, Tempest Therapeutics, Janssen, Deciphera Pharmaceuticals LLC, Clovis Oncology, Inc, ORIC Pharmaceuticals, Merck Sharp & Dohme LLC, Pfizer, Novartis; Financial Interests, Personal, Royalties: Alessa, RasCal, AtlasMedx; Financial Interests, Personal, Other, Consulting Fees: Alessa, RasCal, AtlasMedx. B. Fang: Financial Interests, Personal, Full or part-time Employment: Astera Cancer Care; Financial Interests, Personal, Leadership Role: Astera Cancer Care; Financial Interests, Institutional, Research Funding: Abbvie, Arvinas, Bristol Myers Squibb/Pfizer, Daiichi Sankyo/AstraZeneca, Epizyme, Exelixis, Gilead/Forty Seven, ImmunityBio, Janssen Oncology, Mirati Therapeutics, Natera, Novartis, Novocure, POINT Biopharma, Roche/Genentech, Veru, Zymeworks. G. Zahrah: Financial Interests, Other, Research: Arvinas. J. Ranciato: Financial Interests, Personal, Full or part-time Employment: Arvinas. R. Gedrich: Financial Interests, Personal, Full or part-time Employment: Arvinas, Inc; Financial Interests, Personal, Stocks/Shares: Arvinas, Inc. E. Zhi: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Project Lead: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas. Y. Zhang: Financial Interests, Personal, Full or part-time Employment: Arvinas, Inc; Financial Interests, Personal, Stocks/Shares: Arvinas, Inc. W. Tan: Financial Interests, Personal, Full or part-time Employment: Pfizer, Inc; Financial Interests, Personal, Stocks/Shares: Pfizer, Inc. C. Mather: Financial Interests, Personal, Full or part-time Employment: Arvinas, Inc; Financial Interests, Personal, Stocks/Shares: Arvinas, Inc. J. Perkins: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Ownership Interest: Pfizer. S. Anderson: Financial Interests, Personal, Full or part-time Employment: Arvinas Operations, Inc; Financial Interests, Personal, Stocks/Shares: Arvinas Operations, Inc. S.A. Hurvitz: Financial Interests, Personal, Invited Speaker: Clinical Care Options, axis medical, cancer expert now, ICHE, MJH Associates, PER, Primo, Projects in Knowledge, Prova Education, Research to Practice, Ultimate Medical Academy, Vaniam, WebMD, Peer Education, PrecisCA; Financial Interests, Personal, Stocks/Shares, spouse owns: ROM Tech; Financial Interests, Personal, Ownership Interest, spouse: Ideal Implant; Financial Interests, Personal, Royalties, author medical book: McGraw; Financial Interests, Personal, Royalties: Elsevier, Springer, Sage, Wolters Kluwer, Wiley; Financial Interests, Institutional, Invited Speaker: Ambrx, AstraZeneca, Arvinas, Daiichi Sankyo, Genentech/Roche, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA, Radius, sanofi, Seattle Genetics, Dignitana, Zymeworks, Phoenix Molecular Designs, Ltd, Celcuity, cytomx, Dantari, G1 Therapeutics, Greenwich Life Sciences, Loxo Oncology, orinove, Orum; Financial Interests, Institutional, Research Grant: Samumed, Ambrx; Financial Interests, Invited Speaker: Greenwich Life Sciences, Orum; Non-Financial Interests, Advisory Role: Daiichi Sankyo, Novartis, Ambrx, 4DPharma, Dantari, Macrogenics, Lilly, Artios, Roche, Pyxis, Amgen, Pieris, Arvinas, Immunomedics/Gilead; Non-Financial Interests, Principal Investigator: Daiichi Sankyo, Genentech, Seattle Genetics; Non-Financial Interests, Member: ASCO, AACR; Non-Financial Interests, Other, speaker: National Breast Cancer Coalition; Non-Financial Interests, Member, site representative for breast cancer guidelines: National Comprehensive Cancer Network.