FDA Approves Arvinas and Pfizer's Veppanu for ESR1-Mutated Advanced Breast Cancer

The FDA on May 1 approved vepdegestrant (Veppanu) for adults with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer whose disease has progressed after at least one line of endocrine therapy, according to the agency's announcement. The mutation must be detected by an FDA-authorized test, and the FDA approved Guardant360 CDx as a companion diagnostic to identify eligible patients.

Vepdegestrant was discovered by Arvinas and developed jointly with Pfizer. The FDA describes it as a heterobifunctional protein degrader. Arvinas said it is the first PROteolysis TArgeting Chimera (PROTAC) therapy the FDA has approved, in the company's announcement, distributed by GlobeNewswire and read via BioSpace. It is also the company's first approved medicine.

The VERITAC-2 trial

The FDA said efficacy was evaluated in VERITAC-2 (NCT05654623), a randomized, open-label Phase 3 trial in 624 adults with ER-positive, HER2-negative advanced or metastatic breast cancer, 270 of whom had tumors with ESR1 mutations. Patients had progressed on one or two lines of endocrine therapy, including one with a CDK4/6 inhibitor. They were randomized to oral vepdegestrant once daily or to fulvestrant given by intramuscular injection. ESR1 status was determined from circulating tumor DNA in the blood.

In patients with ESR1 mutations, median progression-free survival assessed by blinded independent central review was 5 months with vepdegestrant and 2.1 months with fulvestrant (hazard ratio 0.57; 95% CI, 0.42 to 0.77; p = 0.0001), the FDA said. The objective response rate was 19% and 4%. Overall survival data were immature, with 16% of patients in that group having died at the time of the analysis. The FDA's announcement reported the statistically significant result for the ESR1-mutated population; progression-free survival in the overall trial population was also a major efficacy measure.

"For patients living with ESR1 mutant, ER+/HER2 advanced breast cancer, there have been minimal second-line treatment options once standard therapies are no longer effective," said Erika Hamilton of the Sarah Cannon Research Institute, a principal investigator of VERITAC-2, in the Arvinas release.

Safety and next steps

The prescribing information includes warnings and precautions for QTc interval prolongation and embryo-fetal toxicity, the FDA said. The recommended dose is 200 mg taken orally once daily with food. Arvinas said most adverse events were grade 1 or 2; the most common adverse reactions included decreased white blood cells, increased liver enzymes, musculoskeletal pain, fatigue and nausea.

The FDA approved the application one month ahead of its goal date, which Arvinas said was June 5. The company said it and Pfizer are on track to announce a third-party partner to commercialize the drug. "Today's FDA approval is a transformative moment for Arvinas as we achieve our first approved medicine and the first-ever approved PROTAC therapy based on the technology we've pioneered since 2013," said Randy Teel, Arvinas' president and chief executive.