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Vepdegestrant Demonstrates Progression-Free Survival in Patients With ER+/HER2- Metastatic Breast Cancer
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Vepdegestrant is an experimental oral PROteolysis TArgeting Chimera that degrades estrogen receptor (ER) in patients with metastatic breast cancer.
Vepdegestrant (ARV-471; Arvinas, Inc) met its primary end point of progression-free survival (PFS) compared with fulvestrant (Faslodex; AstraZeneca) in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer (MBC) whose disease progressed following prior treatment with CDK 4/6 inhibitors and endocrine therapy. The clinically meaningful outcomes were observed in the phase 3 VERITAC-2 clinical trial (NCT05654623).1
Breast cancer cells | Image Credit: © Best - stock.adobe.com
In 2022, breast cancer (BC) was diagnosed in approximately 2.3 million individuals worldwide, and by 2025, nearly 320,000 new cases are projected in the United States. The most common subtype, ER+/HER2- BC, accounts for about 70% of all cases. Although many patients are initially diagnosed with early-stage disease, nearly 30% will eventually develop MBC. Treatment advancements have improved symptom management and slowed disease progression, but resistance to first-line therapies remains a significant challenge. ESR1 mutations, which contribute to acquired resistance, are present in approximately 40% of patients receiving second-line treatment.2
“Patients with advanced ER+/HER2- metastatic breast cancer face significant clinical challenges, with limited treatment options following disease progression and the development of resistance to available endocrine therapies,” Megan O’Meara, MD, interim chief development officer, Pfizer Oncology, said in a press release. “These data from VERITAC-2 support the potential of vepdegestrant to give patients whose tumors harbor ESR1 mutations additional time without disease progression, compared to fulvestrant.”2
Vepdegestrant is an experimental oral PROTAC (PROteolysis TArgeting Chimera) designed to selectively target and degrade the estrogen receptor (ER) in patients with ER+/HER2- breast cancer by utilizing the body’s natural protein disposal system. Vepdegestrant is being developed both as a potential standalone treatment and in combination with other therapies for various stages of ER+/HER2- metastatic breast cancer. It was granted fast track designation as a monotherapy for adults with ER+/HER2- advanced or MBC who have previously undergone endocrine-based therapy.2
In the phase 3 randomized, open-label, multicenter trial, researchers evaluated the efficacy and safety of vepdegestrant as a monotherapy compared with fulvestrant in patients with ER+/HER2- advanced or MBC. The patients, who had previously received treatment with a CDK 4/6 inhibitor and endocrine therapy, were randomized to receive either vepdegestrant once daily on a 28-day continuous dosing schedule or fulvestrant, administered intramuscularly on days 1 and 15 of cycle 1 and then on day 1 of each 28-day cycle starting from day 1 of cycle 2. The primary endpoint was PFS in the intent-to-treat (ITT) and ESR1-mutated (ESR1m) populations with a secondary end point of overall survival (OS); however, OS data were not mature at the time of analysis.2
When compared with fulvestrant, the trial's primary endpoint in the community of ESR1m patients showed a statistically significant and clinically relevant improvement in PFS. In the ESR1m population, the outcomes surpassed the predetermined goal hazard ratio of 0.60. In the ITT group, the trial's increase in PFS did not achieve statistical significance. Vepdegestrant was generally well tolerated during the trial, and its safety profile aligned with findings from earlier research.2
The phase 3 VERITAC-2 trial highlights vepdegestrant’s potential to offer meaningful improvements in PFS for patients with ER+/HER2- MBC, particularly those with ESR1 mutations who face limited treatment options after developing resistance to previous therapies. With its unique mechanism of action as a PROTAC protein degrader and its fast track designation, vepdegestrant represents a promising step forward in the ongoing effort to address the unmet needs of these patients.
