DIET & NUTRITION 
PATIENT EDUCATION 
OBESITY/WEIGHT MANAGEMENT 
EXERCISE/TRAINING 
LEGAL MATTERS 
GUIDELINES/RECOMMENDATIONS The FDA approved vepdegestrant (Veppanu) on May 1, 2026, for ER-positive, HER2-negative advanced or metastatic breast cancer with ESR1 mutations after endocrine therapy progression. This marks the first PROTAC drug approval, with Guardant360 CDx as companion diagnostic.
Clinical Considerations
- Phase 3 VERITAC-2 enrolled 624 patients post-CDK4/6 inhibitor; 270 had ESR1 mutations identified via ctDNA testing.
- Vepdegestrant more than doubled median PFS versus fulvestrant in ESR1-mutated disease (5.0 vs 2.1 months; HR 0.57).
- Objective response rate reached 19% with vepdegestrant versus 4% with fulvestrant; overall survival data remain immature at 16% event maturity.
- Tolerability profile showed 3% discontinuation for treatment-emergent adverse events; fatigue (27%) was most common, with QTc prolongation warning in labeling.
Practice Applications
- Integrate ctDNA-based ESR1 testing into progression workup after first-line endocrine therapy.
- Consider vepdegestrant 200 mg daily for ESR1-mutated patients progressing on CDK4/6-containing regimens.
- Monitor QTc intervals and hepatic enzymes per prescribing information during treatment.
- Recognize PROTAC mechanism as a novel therapeutic class entering oncology practice.
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