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(3S)-3-[6-[4-[[1-[4-[(1R,2S)-6-Hydroxy-2-Phenyl-1,2,3,4-Tetrahydronaphthalen-1-Yl]Phenyl]Piperidin-4-Yl]Methyl]Piperazin-1-Yl]-3-Oxo-1H-Isoindol-2-Yl]Piperidine-2,6-Dione

This article summarizes several clinical trials investigating vepdegestrant (ARV-471), an oral medication being studied for the treatment of advanced or metastatic estrogen receptor-positive (ER+), HER2-negative breast cancer. Vepdegestrant is a new type of drug called a proteolysis targeting chimera (PROTAC) that works by degrading the estrogen receptor. The trials are evaluating vepdegestrant alone and in combination with other cancer drugs to determine its safety, effectiveness, and optimal dosing in patients whose cancer has progressed after prior treatments.

Table of Contents

Introduction

Vepdegestrant, also known as ARV-471 or PF-07850327, is an innovative drug being developed for the treatment of advanced breast cancer. It belongs to a new class of medications called oral proteolysis targeting chimeras (PROTACs)[1]. This article will provide an overview of vepdegestrant, its potential benefits, and ongoing clinical trials for patients with breast cancer.

Mechanism of Action

Vepdegestrant works by targeting and degrading the estrogen receptor (ER) in breast cancer cells[2]. The estrogen receptor plays a crucial role in the growth and survival of many breast cancers. By breaking down this receptor, vepdegestrant may help slow or stop the growth of ER-positive breast tumors.

Indications

Vepdegestrant is being studied for the treatment of estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer[3]. This type of breast cancer is hormone-sensitive and accounts for a significant proportion of breast cancer cases.

Clinical Trials

Several clinical trials are currently evaluating the safety and efficacy of vepdegestrant:

  • VERITAC-2: A Phase 3 study comparing vepdegestrant to fulvestrant in patients who have progressed after prior endocrine-based treatment[1].
  • VERITAC-3: A Phase 3 study comparing vepdegestrant plus palbociclib to letrozole plus palbociclib in patients who have not received prior systemic treatment for advanced disease[2].
  • TACTIVE-U: An umbrella study investigating vepdegestrant in combination with other anticancer treatments, including abemaciclib, ribociclib, samuraciclib, and PF-07220060[3][4][5][6].
  • A Phase 1b trial studying vepdegestrant in combination with everolimus[7].

Efficacy

The ongoing clinical trials aim to assess the efficacy of vepdegestrant through various endpoints, including:

  • Progression-free survival (PFS): The time from the start of treatment until the cancer progresses or the patient dies[1].
  • Overall survival (OS): The length of time patients live after starting treatment[1].
  • Objective response rate (ORR): The proportion of patients whose tumors shrink or disappear with treatment[3].
  • Clinical benefit rate (CBR): The percentage of patients who achieve a complete response, partial response, or stable disease for at least 24 weeks[3].
  • Duration of response (DOR): How long the tumor response lasts[3].

Results from these trials will help determine how effective vepdegestrant is compared to existing treatments and in combination with other therapies.

Safety and Side Effects

The safety profile of vepdegestrant is still being evaluated in clinical trials. Researchers are monitoring for adverse events, laboratory abnormalities, and ECG changes[3]. Common side effects of breast cancer treatments may include fatigue, nausea, and changes in blood cell counts. However, the specific side effects of vepdegestrant will become clearer as more data from clinical trials become available.

Combination Therapies

Vepdegestrant is being studied in combination with several other cancer drugs to potentially enhance its effectiveness:

  • CDK4/6 inhibitors: Such as palbociclib, abemaciclib, and ribociclib[2][3][4].
  • mTOR inhibitors: Like everolimus[7].
  • Other investigational drugs: Including samuraciclib and PF-07220060[5][6].

These combinations aim to target multiple pathways involved in cancer growth and potentially overcome resistance to single-agent treatments.

Conclusion

Vepdegestrant (ARV-471) represents a promising new approach to treating ER-positive, HER2-negative advanced breast cancer. As a PROTAC molecule, it offers a novel mechanism for targeting the estrogen receptor. Ongoing clinical trials will provide crucial information about its efficacy, safety, and potential role in breast cancer treatment, both as a single agent and in combination with other therapies. Patients interested in learning more about vepdegestrant should discuss potential clinical trial opportunities with their oncologist.

Trial Name Phase Combination Drug Key Objectives Patient Population
VERITAC-2 3 Fulvestrant (comparator) Compare progression-free survival and overall survival ER+/HER2- advanced breast cancer after prior endocrine therapy
VERITAC-3 3 Palbociclib Compare progression-free survival to letrozole plus palbociclib ER+/HER2- advanced breast cancer, no prior systemic therapy for advanced disease
TACTIVE-U (Sub-study A) 1b/2 Abemaciclib Assess safety, tolerability, and antitumor activity ER+/HER2- advanced breast cancer after 1-2 prior therapies including CDK4/6 inhibitor
TACTIVE-U (Sub-study B) 1b/2 Ribociclib Assess safety, tolerability, and antitumor activity ER+/HER2- advanced breast cancer after 1-2 prior therapies including CDK4/6 inhibitor
TACTIVE-U (Sub-study C) 1b/2 Samuraciclib Assess safety, tolerability, and antitumor activity ER+/HER2- advanced breast cancer after 1-2 prior therapies including CDK4/6 inhibitor
Unnamed 1b/2 PF-07220060 Assess safety, tolerability, and antitumor activity ER+/HER2- advanced breast cancer after prior endocrine therapy and CDK4/6 inhibitor
Unnamed 1b Everolimus Evaluate safety, tolerability, and select recommended Phase 2 dose ER+/HER2- advanced breast cancer after 1-3 prior therapies including CDK4/6 inhibitor

FAQ

  • What is vepdegestrant (ARV-471)? Vepdegestrant, also known as ARV-471 or PF-07850327, is an oral medication being studied for advanced breast cancer. It belongs to a new class of drugs called proteolysis targeting chimeras (PROTACs) that work by degrading specific proteins in cancer cells, in this case the estrogen receptor.
  • What type of breast cancer is vepdegestrant being studied for? Vepdegestrant is being investigated for estrogen receptor-positive (ER+), HER2-negative advanced or metastatic breast cancer. This means the cancer is fueled by estrogen and has spread beyond the breast to other parts of the body.
  • How is vepdegestrant being studied in clinical trials? Vepdegestrant is being evaluated in several Phase 1b and Phase 2 clinical trials, both as a single agent and in combination with other cancer drugs like CDK4/6 inhibitors (palbociclib, abemaciclib, ribociclib), samuraciclib, and everolimus. The trials are assessing its safety, effectiveness, and optimal dosing.
  • What are the main goals of these clinical trials? The main goals are to evaluate the safety and tolerability of vepdegestrant, determine the recommended dose for future studies, assess its effectiveness in shrinking tumors or slowing cancer growth, and study how the drug behaves in the body when given alone or with other medications.
  • Who is eligible to participate in these clinical trials? In general, eligible participants are adults with ER+/HER2- advanced breast cancer that has progressed after prior treatments. Most trials require patients to have received prior endocrine therapy and a CDK4/6 inhibitor. Specific eligibility criteria vary between trials.

Ongoing Clinical Trials on (3S)-3-[6-[4-[[1-[4-[(1R,2S)-6-Hydroxy-2-Phenyl-1,2,3,4-Tetrahydronaphthalen-1-Yl]Phenyl]Piperidin-4-Yl]Methyl]Piperazin-1-Yl]-3-Oxo-1H-Isoindol-2-Yl]Piperidine-2,6-Dione

  • Study on the Safety of ARV-471 and Everolimus for Patients with Advanced or Metastatic ER+, HER2- Breast Cancer

    Not recruiting

    1 1 1 1
    Investigated drugs:
    Spain

  • Study on the Safety and Effectiveness of Vepdegestrant and Samuraciclib for Adults with ER+ Advanced or Metastatic Breast Cancer

    Not recruiting

    1 1 1
    Investigated drugs:
    Belgium France Italy Spain

  • Study on the Safety and Effectiveness of Vepdegestrant and PF-07220060 for Adults with ER+/HER2- Advanced or Metastatic Breast Cancer

    Not recruiting

    1 1 1
    Investigated drugs:
    Belgium France Spain

  • Study Comparing ARV-471 and Palbociclib with Letrozole and Palbociclib for Patients with Estrogen Receptor Positive, HER2-Negative Advanced Breast Cancer

    Not recruiting

    3 1 1 1
    Investigated drugs:
    Hungary Italy Slovakia Spain

  • Study Comparing ARV-471 and Fulvestrant for Patients with Advanced Estrogen Receptor-Positive, HER2-Negative Breast Cancer After Endocrine Treatment

    Not recruiting

    3 1 1 1
    Investigated drugs:
    Austria Belgium Bulgaria Czechia Finland France +9

  • Study on the Safety and Antitumor Effects of Vepdegestrant and Abemaciclib in Adults with ER+ Advanced or Metastatic Breast Cancer

    Not recruiting

    1 1 1 1
    Investigated drugs:
    Italy Spain

  • Study on the Safety and Antitumor Activity of ARV-471 and Ribociclib in Adults with ER+ Advanced or Metastatic Breast Cancer

    Not recruiting

    1 1 1 1
    Investigated drugs:
    Italy Spain

Glossary

  • Advanced breast cancer: Cancer that has spread beyond the breast to nearby tissues or other parts of the body. Also called metastatic breast cancer.
  • Estrogen receptor-positive (ER+): Breast cancer cells that have proteins (receptors) that attach to the hormone estrogen, allowing it to fuel cancer growth.
  • HER2-negative: Breast cancer cells that do not have high levels of a protein called HER2 on their surface.
  • Proteolysis targeting chimera (PROTAC): A type of drug that works by marking specific proteins in cancer cells for destruction.
  • CDK4/6 inhibitor: A class of drugs that block proteins called CDK4 and CDK6, which are involved in cell division.
  • Endocrine therapy: Treatment that adds, blocks, or removes hormones to slow or stop the growth of hormone-sensitive cancer cells.
  • Pharmacokinetics (PK): The study of how a drug moves through the body, including how it is absorbed, distributed, metabolized, and excreted.
  • Dose-limiting toxicity (DLT): Side effects that are severe enough to prevent increasing the dose of a drug in a clinical trial.
  • Recommended Phase 2 Dose (RP2D): The dose of a drug determined to be safe and potentially effective for further study in larger clinical trials.
  • RECIST: Response Evaluation Criteria in Solid Tumors – a standard way to measure how well a cancer treatment is working.

References

  1. http://clinicaltrials.eu/trial/study-comparing-arv-471-and-fulvestrant-for-patients-with-advanced-estrogen-receptor-positive-her2-negative-breast-cancer-after-endocrine-treatment/
  2. http://clinicaltrials.eu/trial/study-comparing-arv-471-and-palbociclib-with-letrozole-and-palbociclib-for-patients-with-estrogen-receptor-positive-her2-negative-advanced-breast-cancer/
  3. http://clinicaltrials.eu/trial/study-on-the-safety-and-antitumor-effects-of-vepdegestrant-and-abemaciclib-in-adults-with-er-advanced-or-metastatic-breast-cancer/
  4. http://clinicaltrials.eu/trial/study-on-the-safety-and-effectiveness-of-arv-471-and-ribociclib-in-adults-with-er-advanced-or-metastatic-breast-cancer/
  5. http://clinicaltrials.eu/trial/study-on-the-safety-and-effectiveness-of-vepdegestrant-and-samuraciclib-for-adults-with-er-advanced-or-metastatic-breast-cancer/
  6. http://clinicaltrials.eu/trial/study-on-the-safety-and-effectiveness-of-vepdegestrant-and-pf-07220060-for-adults-with-er-her2-advanced-or-metastatic-breast-cancer/
  7. http://clinicaltrials.eu/trial/study-on-the-safety-of-arv-471-and-everolimus-for-patients-with-advanced-or-metastatic-er-her2-breast-cancer/