Abstract 218P
Background
Preliminary phase Ib cohort results from a phase 1/2 study (NCT04072952) evaluating vepdegestrant (ARV-471) plus palbo showed promising clinical activity in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer (data cutoff: 6 Jun 2023). We present updated data after 6 additional mo of follow-up (data cutoff: 18 Dec 2023).
Methods
Eligible pts had ER+/HER2- advanced breast cancer with ≥1 prior endocrine therapy and ≤2 chemotherapy regimens for advanced disease. Vepdegestrant was given orally once daily (QD) continuously (180 mg [n=2], 200 mg [n=21], 400 mg [n=3], or 500 mg [n=20]); palbo 125 mg was given orally QD for 21 days followed by 7 days off treatment in 28-day cycles.
Results
Of 46 pts in the phase Ib cohort (median 4 prior therapies [range: 1–11] in any setting; 87% with cyclin-dependent kinase 4/6 inhibitors; 80% with fulvestrant; and 78% with chemotherapy), 12 (26%) are ongoing. Grade 3/4 treatment-related adverse events (TRAEs) ≥10% to either vepdegestrant or palbo were neutropenia (91%) and decreased white blood cell count (15%); no grade 5 TRAEs or febrile neutropenia were reported. CBR, ORR, and mPFS are summarized in all pts and by ESR1 mutation status (Table). Based on 27 (59%) events, mPFS was 11.2 mo (95% CI: 8.2–16.5). Median duration of response in 13 responders was 14.6 mo (95% CI: 9.5–NR). Exploratory circulating tumor DNA (ctDNA) analyses found marked reduction in tumor fraction after 1 treatment cycle (all dose groups); substantial on-treatment decreases in mutant ESR1 ctDNA levels were sustained for multiple treatment cycles (200 mg dose). Table: 218P
Summary of clinical activity
| Total (N=46) | Mutant ESR1 a (n=29) | Wild-type ESR1 a (n=15) | |
| CBRb | |||
| % (95% CI) | 63.0 (47.6–76.8) | 72.4 (52.8–87.3) | 53.3 (26.6–78.7) |
| ORRc | |||
| % (95% CI) | 41.9 (24.6–60.9)(n=31) | 47.1 (23.0–72.2)(n=17) | 41.7 (15.2–72.3)(n=12) |
| PFS | |||
| Events, n (%) | 27 (58.7) | 16 (55.2) | 10 (66.7) |
| mPFS, mo (95% CI) | 11.2 (8.2–16.5) | 13.7 (8.2–NR) | 11.1 (2.8–19.3) |
aBaseline ESR1 status was missing for 2 pts.bRate of confirmed complete response, partial response, or stable disease ≥24 weeks.cIn pts with measurable disease at baseline.CBR: clinical benefit rate; ESR1: estrogen receptor 1 gene; mo: months; NR: not reached; ORR: objective response rate; mPFS: median progression-free survival
Conclusions
With longer follow-up, vepdegestrant plus palbo continued to show robust clinical activity in pts with ER+/HER2- advanced breast cancer who had received extensive prior treatment, regardless of ESR1 mutation status. Safety was consistent with that previously reported.
Clinical trial identification
NCT04072952.
Editorial acknowledgement
Justine Lempart, PhD, of Apollo Medical Communications, part of the Helios Global Group, and funded by Arvinas Operations, Inc.
Legal entity responsible for the study
Pfizer Inc.
Funding
Pfizer Inc. (sponsor) and Arvinas Estrogen Receptor, Inc. (collaborator).
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. 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. N.P. McAndrew: Financial Interests, Personal and Institutional, Principal Investigator: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator: Novartis, Dizal Pharmaceuticals, Arvinas Operations, Inc., Loxo, Seattle Genetics; Financial Interests, Personal and Institutional, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: AstraZeneca, GoodRx. M.L. Telli: Financial Interests, Advisory Role: AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Genentech, Gilead (DSMC), GSK Smith Kline, Guardant, Merck, Natera, Novartis, RefleXion, Sanofi Aventis; Financial Interests, Institutional, Research Grant: Arvinas Operations, Inc., AstraZeneca, Genentech/Roche, GSK Smith Kline, Hummingbird Biosciences, Merck, OncoSec Medical, Pfizer Inc. D. Juric: Financial Interests, Advisory Role: Eisai, EMD Serono, Genentech, Ipsen, Mapkure, Novartis, Petra Pharma, Syros Pharmaceuticals, Vibliome Therapeutics; Financial Interests, Institutional, Research Grant: Amgen, Eisai, EMD Serono, Genentech, Infinity Pharmaceuticals, InventisBio, Novartis, Pfizer Inc., Placon, Syros Pharmaceuticals, Takeda. H.S. Han: Financial Interests, Institutional, Research Grant: Arvinas Operations, Inc., AbbVie, Celcuity, GSK, G1 Therapeutics, Quantum Leap Healthcare Collaborative, Marker, Mersana, Senhwa, Pfizer Inc., Zymeworks, Department of Defense. R. Nanda: Financial Interests, Personal, Advisory Role: Merck, Seattle Genetics, AstraZeneca, Gilead Sciences, GE Healthcare, Sanofi, Daiichi Sankyo, Exact Science, Guardant Health, Moderna Therapeutics; Financial Interests, Institutional, Research Grant: Corcept Therapeutics, Celgene, Merck, Seattle Genetics, Genentech/Roche, Odonate Therapeutics, Pfizer, AstraZeneca, Immunomedics, OncoSec, Arvinas Operations, Inc., Taiho Oncology, OBI Pharma, Sun Pharma. G.F. Zahrah: Financial Interests, Personal, Other, Research Support: Arvinas Operations, Inc. Y. Zhang: Financial Interests, Personal, Stocks/Shares: Arvinas Operations, Inc. W. Tan: Financial Interests, Institutional, Stocks/Shares: Pfizer Inc. E. Duperret: Financial Interests, Personal, Other, employee: Arvinas Operations, Inc., Adaptimmune. E. Zhi: Financial Interests, Personal, Other, employee: Arvinas Operations, Inc.; Financial Interests, Personal, Project Lead: Arvinas Operations, Inc.; Financial Interests, Personal, Stocks/Shares: Arvinas Operations, Inc. C. Mather: Financial Interests, Personal, Other, employee: Arvinas Operations, Inc.; Financial Interests, Personal, Stocks/Shares: Arvinas Operations, Inc. R.M. Jeselsohn: Financial Interests, Other, Research Support: Pfizer Inc., Eli Lilly; Financial Interests, Advisory Role: Carrick Therapeutics, Luminex, Eli Lilly, Pfizer Inc., Novartis.