Dr Hamilton on Vepdegestrant vs Fulvestrant in ER+/HER2-Negative Advanced Breast Cancer

"VERITAC-2 met its primary end point. Vepdegestrant significantly improved progression free survival [at] 5.0 months compared [with] 2.1 months with fulvestrant among patients with ESR1 mutations."

Erika Hamilton, MD, director of the Breast Cancer Research Program at Sarah Cannon Research Institute, discussed findings from the phase 3 VERITAC-2 study (NCT05654623), which evaluated vepdegestrant (ARV-471), a novel PROTAC estrogen receptor (ER) degrader, vs fulvestrant (Faslodex) in patients with ER-positive/HER2-negative advanced breast cancer.

The study included patients who received first-line treatment with a CDK4/6 inhibitor plus endocrine therapy; were administered no more than 1 additional line of endocrine therapy; were on their last line of endocrine therapy for at least 6 months; had no prior treatment with a selective ER degrader; and had no prior chemotherapy in the advanced setting.

The trial met its primary end point, with vepdegestrant demonstrating a statistically significant improvement in progression-free survival (PFS) in patients harboring ESR1 mutations (HR, 0.57; 95% CI, 0.42-0.77; 2-sided P < .001). In this population, the median PFS was 5.0 months (95% CI, 3.7-7.4) with vepdegestrant (n = 136) compared with 2.1 months (95% CI, 1.9-3.5) with fulvestrant (n = 134). At the 6-month landmark analysis, the PFS rates were 45.2% (95% CI, 36.1%-53.9%) and 22.7% (95% CI, 15.1%-31.2%), respectively.

Hamilton noted that the PFS benefit with vepdegestrant was limited to patients with ESR1 mutations. The improvement in PFS was not statistically significant in the overall population, which included patients without ESR1 mutations (HR, 0.83; 95% CI, 0.68-1.02; 2-sided P = .07). The median PFS was 3.7 months (95% CI, 3.6-5.3) for vepdegestrant (n = 313) vs 3.6 months (95% CI, 2.2-3.8) for fulvestrant (n = 311).

Vepdegestrant was well tolerated. The rate of treatment discontinuation due to treatment-emergent adverse effects (TEAEs) was 3% in the experimental arm vs 1% in the fulvestrant arm. Two percent of patients in the vepdegestrant arm required dose reductions due to TEAEs. The most frequently reported any-grade TEAEs with vepdegestrant were fatigue (27%), elevated aspartate aminotransferase levels (14%), elevated alanine aminotransferase levels (14%), nausea (13%), anemia (12%, neutropenia (12%), back pain (11%), arthralgia (11%), and decreased appetite (11%).