FDA Approves Vepdegestrant for ESR1-Mutated Advanced Breast Cancer

Key Takeaways

• The FDA approved vepdegestrant for adults with ER-positive, HER2-negative advanced or metastatic breast cancer with an ESR1 mutation after disease progression on endocrine therapy, with Guardant360 CDx approved as the companion diagnostic.
• VERITAC-2 showed longer progression-free survival and a higher objective response rate with vepdegestrant than with fulvestrant in the ESR1-mutated subgroup.
• Overall survival was immature at analysis, and safety findings included low discontinuation and dose-reduction rates, fatigue as the most common adverse event, and warnings for QTc prolongation and embryo-fetal toxicity.

On May 1, the FDA approved vepdegestrant for adults with ER-positive, HER2-negative, advanced or metastatic breast cancer with an ESR1 mutation after disease progression on endocrine therapy. In the ESR1-mutated subgroup, median progression-free survival was 5 months with vepdegestrant and 2.1 months with fulvestrant. Guardant360 CDx was also approved to identify ESR1 mutations in eligible patients, aligning the approval with a defined biomarker-selected population.

Phase 3 VERITAC-2, the trial supporting the decision, was a randomized, open-label, active-controlled, multicenter study with progression-free survival as the primary outcome measure. It enrolled 624 adults with ER-positive, HER2-negative advanced or metastatic breast cancer whose disease had progressed on 1 or 2 lines of endocrine therapy, including a CDK4/6 inhibitor. Among them, 270 had ESR1-mutated disease identified by blood circulating tumor DNA using central or local testing. Patients were assigned 1:1 to oral vepdegestrant once daily or intramuscular fulvestrant on days 1 and 15 of cycle 1, then monthly. Randomization was stratified by ESR1 mutation status and visceral metastasis.

In the ESR1-mutated subgroup, progression-free survival favored vepdegestrant, with a hazard ratio of 0.57 and a 95% confidence interval of 0.42 to 0.77. The reported P value was .0001. Objective response rate was 19% with vepdegestrant and 4% with fulvestrant, with corresponding confidence intervals of 12% to 27% and 1.6% to 10%. Overall survival was immature at the time of the progression-free survival analysis, with 16% of deaths recorded.

Treatment-emergent adverse events led to discontinuation in 3% of vepdegestrant recipients and 1% of fulvestrant recipients. Dose reductions occurred in 2% of patients receiving vepdegestrant. Fatigue was the most common treatment-emergent adverse event, occurring in 27% of those receiving vepdegestrant. Other adverse events included increased alanine aminotransferase, nausea, anemia, neutropenia, back pain, arthralgia, and decreased appetite. Prescribing information carries warnings and precautions for QTc interval prolongation and embryo-fetal toxicity.