First-in-Class Vepdegestrant Approved in Advanced Breast Cancer

The FDA approved oral vepdegestrant (Veppanu) for adults with advanced or metastatic estrogen receptor (ER)-positive/HER2-negative breast cancer, the agency announced on Friday.

Approval of the first-in-class proteolysis targeting chimera (PROTAC) — a type of heterobifunctional protein degrader therapy — stipulates use in patients with ESR1-mutated disease that has progressed following at least one line of endocrine therapy.

Findings of the global phase III VERITAC-2 trial showed that among patients with ESR1-mutated disease, vepdegestrant reduced the risk of disease progression or death by 43% compared with fulvestrant (Faslodex), with a median progression-free survival (PFS) of 5 months versus 2.1 months, respectively (HR 0.57, 95% CI 0.42-0.77, P=0.0001).

“For patients living with ESR1 mutant, [ER-positive/HER2-negative] advanced breast cancer, there have been minimal second-line treatment options once standard therapies are no longer effective,” investigator Erika Hamilton, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee, said in a press release from drugmaker Arvinas.

“The introduction of a new, targeted treatment is an encouraging development for this community and highlights meaningful innovation in the way this disease is treated,” Hamilton added. “The approval of vepdegestrant gives clinicians another tool in the breast cancer treatment arsenal and brings renewed hope to individuals who need additional options.”

Of note, patients in VERITAC-2 were required to have disease progression on one to two lines of endocrine therapy, including one line with a CDK4/6 inhibitor. Other efficacy data showed an objective response rate of 19% with vepdegestrant versus 4% with fulvestrant. Overall survival data were immature at the time of the PFS analysis.

The most common adverse events with vepdegestrant (at least 10%) included musculoskeletal pain; fatigue; nausea; decreased appetite; constipation; electrocardiogram QT prolonged; decreases in white blood cells, hemoglobin, neutrophils, blood potassium, and platelets; and increases in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin.

Prescribing information includes warnings and precautions for QTc interval prolongation and embryo-fetal toxicity. The drug has no contraindications, though a list of several possible drug interactions are noted.

FDA also approved Guardant360 CDx as a companion diagnostic device to identify patients with breast cancer with ESR1 mutations for treatment with vepdegestrant.