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Pfizer Oncology
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The safety and efficacy of this agent(s), or use in this setting, has not been established or is subject to confirmation. For an agent(s) whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.

Vepdegestrant (ARV-471)*

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Vepdegestrant (ARV-471)*

Vepdegestrant is an investigational compound. Its safety and efficacy have not been established. * Vepdegestrant is being co-developed with Arvinas.

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Overview + Rationale

  • Worldwide, female breast cancer has now surpassed lung cancer as the most commonly diagnosed cancer 
    • ~310,720 women are expected to be diagnosed with invasive breast cancer in the US in 2024 1
    • Metastatic breast cancer accounts for ~6% of newly diagnosed cases 
  • Estrogen receptor (ER)-positive breast cancers make up ~80% of all breast cancers 2
  • There is an unmet need for patients with ER-positive breast cancers who progress on endocrine therapy and CDK 4/6 inhibitors 3
  • There is a need for novel agents to treat ER+ breast cancer4
  • In preclinical studies, vepdegestrant: 
    • Induced ER degradation in ER+ breast cancer cell lines, MCF-7 
  • Showed promising activity against tumor growth compared to fulvestranta
    • An oral daily dose of vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%–123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%–80% TGI)

    • In corresponding quantitative western blots, ER was reduced by 79% and 88% in the 10 mpk and 30 mpk arms, respectively, vs. 63% for fulvestrant

      a Fulvestrant schedule: 2x weekly x2 / q7dx2 nM = nanomolar; mpk = milligrams per kilogram

Mechanism of Action

  • PROteolysis TArgeting Chimera (PROTAC) protein degraders are bifunctional small molecules  consisting of a ligand for a target protein (the ER for vepdegestrant) and another ligand, which serves as a substrate for an E3 ubiquitin ligase complex
  • vepdegestrant creates a trimer complex with the E3 ubiquitin ligase and ER to directly induce ubiquitination of ER and its subsequent proteasomal degradation

Stage of Development

small icon representing breast cancer
ER+/HER2- Metastatic Breast Cancer
Phase 1B Combination§

Phase 1B/2 Combination

Phase 1/2 Monotherapy and Combination§

Phase 1/2 Combination

Phase 3 Monotherapy

Phase 3 Combination§
small icon representing breast cancer
ER+/HER2- Early Breast Cancer
Phase 2 Monotherapy§
This information is current as of October 30th 2024.

*Vepdegestrant is being co-developed with Arvinas. §Closed to Enrollment

REFERENCES: 1.  https://www.cancer.net/cancer-types/breast-cancer/statistics; 2. National Cancer Institute, Hormone Therapy for Breast Cancer; Malmgren, J.A., Breast Cancer Res Treat (2018) 167:579–590; Snyder, et al. AACR 2021 Presentation; 3,  Hamilton E., et al. SABCS 2021 Poster #PD13-08; Snyder et al. Virtual Presentation AACR 2021; 4.  Hanker A et al. Cancer Cell, Volume 37, Issue 4, 2020, Pages 496-513; 5. Gough SM, et al. Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Modelsl . Clin Cancer Res. 2024 Aug 15;30(16):3549-3563. doi: 10.1158/1078-0432.CCR-23-3465. PMID: 38819400; PMCID: PMC11325148. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05501769;  https://clinicaltrials.gov/study/NCT05548127; https://clinicaltrials.gov/study/NCT05573555; https://clinicaltrials.gov/study/NCT06125522; https://clinicaltrials.gov/study/NCT06206837; https://clinicaltrials.gov/study/NCT04072952;; https://clinicaltrials.gov/study/NCT05654623; https://clinicaltrials.gov/study/NCT05909397.; https://clinicaltrials.gov/study/NCT05549505   Accessed October 22, 2024.