On May 1, the U.S. Food and Drug Administration (FDA) approved vepdegestrant (Veppanu), a heterobifunctional protein degrader, for the treatment of adult patients with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy.
The FDA simultaneously approved the Guardant360 CDx as a companion diagnostic device to identify patients with breast cancer with ESR1 mutations for treatment with vepdegestrant.
VERITAC-2
Efficacy for vepdegestrant was evaluated in VERITAC-2 (ClinicalTrials.gov identifier NCT05654623), a randomized, open-label, active-controlled, multicenter phase III trial of 624 patients with ER-positive, HER2-negative, advanced or metastatic breast cancer, including 270 patients harboring an ESR1 mutation. In the study, patients were required to have disease progression on one to two lines of endocrine therapy, including one line with a CDK4/6 inhibitor. Patiently were randomly assigned 1:1 to receive vepdegestrant orally once daily or fulvestrant intramuscularly on days 1 and 15 of cycle 1 and then once a month thereafter. Random assignment was stratified by ESR1 mutation status and visceral metastasis. ESR1 mutational status was determined by blood circulating tumor DNA status using central or local testing.
The major efficacy outcome measure was progression-free survival as assessed by blinded independent central review in the population of patients whose tumors had an ESR1 mutation, and in the overall population. Additional efficacy outcome measures included overall survival and objective response rate, as assessed by blinded independent central review.
In the population of patients with an ESR1 mutation, a statistically significant difference was observed in blinded independent central review–assessed progression-free survival for vepdegestrant as compared with fulvestrant. The median progression-free survival was 5 months (95% confidence interval [CI] = 3.7–7.4 months) in the vepdegestrant arm and 2.1 months (95% CI = 1.9–3.5 months) in the fulvestrant arm (hazard ratio = 0.57; 95% CI = 0.42–0.77; P = .0001). The objective response rate was 19% (95% CI = 12%–27%) in the vepdegestrant arm and 4% (95% CI = 1.6%–10%) in the fulvestrant arm. Overall survival was immature with 16% of deaths in this population at the time of the progression-free survival analysis.
Warnings and Precautions
The prescribing information includes warnings and precautions for QTc interval prolongation and embryo-fetal toxicity.
The recommended vepdegestrant dose is 200 mg taken orally once daily with food until disease progression or unacceptable toxicity.
The review used the voluntary Assessment Aid submission from applicant Arvinas Operations, Inc. to facilitate the FDA's assessment. The agency also noted that this application was approved 1 month ahead of the target action date.
