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 
    • ~297,790 women are expected to be diagnosed with invasive breast cancer in the US in 2023 
    • Metastatic breast cancer accounts for ~6% of newly diagnosed cases 
  • Estrogen receptor (ER)-positive breast cancers make up ~80% of all breast cancers 
  • There is an unmet need for patients with ER-positive breast cancers who progress on endocrine therapy and CDK 4/6 inhibitors 
  • There is a need for novel agents to treat ER+ breast cancer R

In preclinical studies, vepdegestrant: 

  • Induced ER degradation in multiple ER+ breast cancer cell lines, including MCF-7 cells and ESR1-mutant linesA
  • DC50 = 1.8 nM in MCF7 cellsB 

Showed promising activity against tumor growth compared to fulvestrantC

  • An oral daily dose of vepdegestrant decreased tumor growth by 99% at 10 mpk and 106% at 30 mpk in an ESR1 mutant patient-derived xenograft (PDX) model (shown at right) 

  • 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 Also tested: MB-134-VI, T47D, D538G, Y537S, ZR-75-1, BT474, CAMA-1; BDC50 = Half-maximal degradation concentration; C Fulvestrant schedule: 2x weekly x2 / q7dx2 nM = nanomolar; mpk = milligrams per kilogram

Mechanism of Action

  • PROteolysis TArgeting Chimera (PROTAC) protein degraders are heterobifunctional molecules that consist 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 
  • Upon binding to ER, the PROTAC vepdegestrant recruits an E3 ubiquitin ligase complex, which marks ER with ubiquitin tags for 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 3 Monotherapy

Phase 3 Combination§
small icon representing breast cancer
ER+/HER2- Early Breast Cancer
Phase 2 Monotherapy§

*Vepdegestrant is being co-developed with Arvinas Estrogen Receptor, Inc. §Closed to Enrollment

REFERENCES: https://www.cancer.net/cancer-types/breast-cancer/statistics Accessed May 8, 2023; 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; Hamilton E., et al. SABCS 2021 Poster #PD13-08; Snyder et al. Virtual Presentation AACR 2021; Hanker A et al. Cancer Cell, Volume 37, Issue 4, 2020, Pages 496-513; 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/NCT05549505; https://clinicaltrials.gov/study/NCT05654623; https://clinicaltrials.gov/study/NCT05909397.  Accessed July 23, 2024.