Vepdegestrant Gains FDA Fast Track Designation in ER+/HER2- Breast Cancer

• The fast track designation from the FDA to vepdegestrant (ARV-471), a new oral drug, aims to expedite the development and approval process for the agent.

• Vepdegestrant works by specifically targeting and degrading the estrogen receptor (ER) protein in cancer cells.

• Vepdegestrant is currently being evaluated in several clinical trials, including the phase 3 VERITAC-2 trial (NCT05654623) for patients with ER-positive/HER2-negative (ER+/HER2-) breast cancer.

The FDA has granted a fast track designation to vepdegestrant as a monotherapy for the treatment of adult patients with ER+/HER2- locally advanced or metastatic breast cancer that received prior treatment with endocrine-based therapy.¹

Vepdegestrant is a novel oral PROteolysis Targeting Chimera (PROTAC) ER degrader that was designed to specifically target and degrade the ER protein for patients with ER+/HER2- breast cancer.

The ongoing phase 3 VERITAC-2 clinical trial is evaluating vepdegestrant as a monotherapy or fulvestrant in the second-line setting for this patient population. Additional trials are and will plan to monitor vepdegestrant to further assess its safety and antitumor activity among patients with ER+/HER2- locally advanced or metastatic breast cancer previously treated with endocrine-based therapy.

“The receipt of fast track designation reinforces the potential of vepdegestrant to provide an important new therapeutic option for people with ER+/HER2- breast cancer whose disease has progressed,” said Roger Dansey, MD, chief development officer, oncology, Pfizer, in a press release. “We are proud to continue our legacy of developing innovative treatment options for people impacted by metastatic breast cancer and look forward to working with the FDA as we advance our development program for vepdegestrant.

Breast Cancer Image: © Giovanni Cancemi- stock.adobe.com

Jointly developed by Arvinas and Pfizer, vepdegestrant, the investigational, orally bioavailable PROTAC® protein degrader, has shown promise in preclinical studies by demonstrating up to 97% ER degradation in tumor cells. In multiple ER-driven xenograft models, the agent produced robust tumor shrinkage when given to patients as a single agent. Vepdegestrant also increased antitumor activity as a single agent and when given in combination with a CDK4/6 inhibitor vs fulvestrant.

Vepdegestrant as a monotherapy is being evaluated in the second-line setting in the ongoing phase 3 VERITAC-2 trial. In combination with palbociclib, vepdegestrant is also being studied in the first-line setting in the lead-in cohort of the phase 3 VERITAC-3 clinical trial. Vepdegestrant is being combined with abemaciclib, ribociclib, samuraciclib, everolimus, and with an investigational novel CDK4 inhibitor developed by Pfizer, PF-07220060, in other studies.

About VERITAC-2

The phase 3, randomized, open-label, multicenter VERITAC-2 trial is evaluating vepdegestrant vs fulvestrant in patients with advanced breast cancer.² Patients enrolled in the trial will be treated with vepdegestrant orally, once daily on a 28-day continuous dosing schedule or fulvestrant intramuscularly on days 1 and 15 of cycle 1, followed by day 1 of each cycle in a 28-day cycle.

Enrollment in the study is open to adult patients with loco-regional recurrent or metastatic breast disease not amenable to surgical resection or radiation therapy who have a confirmed diagnosis of ER+/HER2- breast cancer. For locoregional recurrent or metastatic disease, prior therapies must include 1 line of CDK4/6 inhibitor therapy in combination with endocrine therapy with only 1 line of CDK4/6 inhibitor allowed in any setting and ≤ 1 endocrine therapy in addition to CDK4/6 inhibitor with endocrine therapy.The most recent length of endocrine treatment must have been given for ≥6 months prior to disease progression.

Further, patients must have radiological progression during or after the last line of therapy, have measurable disease evaluable per RECIST v.1.1 or non-measurable bone-only disease, an ECOG performance status 0 to 1, and be willing to provide blood and tumor tissue.

The primary end point of the study is progression-free survival with secondary end points of overall survival, objective response rate, clinical benefit rate, number of patients with treatment-emergent adverse events (AEs), serious AEs, electrocardiogram and laboratory abnormalities, QT interval, pharmacokinetics, health state utility and health status, disease-related quality-of-life (QOL), treatment-related QOL, clinical pain and its impact on functioning, and circulating DNA.

"We are focused on the persisting unmet needs of people with ER+/HER2- breast cancer and doing all that we can to expedite the development of vepdegestrant as a novel, oral ER-targeted potential therapy for this patient community,” said John Houston, PhD, Arvinas chairperson, chief executive officer, and president, in a press release.¹ “We are pleased the FDA has granted fast track designation for vepdegestrant, and we continue to believe this investigational drug has the potential to harness the body’s own natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins."

REFERENCES:

1. Arvinas and Pfizer’s vepdegestrant (ARV-471) receives FDA fast track designation for the treatment of patients with ER+/HER2- metastatic breast cancer. News release. Arvinas, Inc. February 5, 2024. Accessed February 6, 2024. http://tinyurl.com/4hp95z77

2. A study to learn about a new medicine called ARV-471 (PF-07850327) in people who have advanced metastatic breast cancer. (VERITAC-2). ClinicalTrials.gov. Updated September 21, 2023. Accessed February 6, 2024. https://clinicaltrials.gov/study/NCT05654623