Neoadjuvant ET provides an effective and less toxic alternative to chemotherapy for patients with localized estrogen receptor (ER)-positive/HER2-negative disease. Vepdegestrant is a selective, oral PROTAC ER degrader that targets wild-type and mutant ER. This article summarizes results from the TACTIVE-N trial (NCT05549505), which is an open-label, noncomparative phase 2 study evaluating the biological and clinical activity of vepdegestrant, an oral proteolysis-targeting chimera ER degrader, in comparison with anastrozole as neoadjuvant therapy for postmenopausal women with ER-positive/HER2-negative localized breast cancer amenable to surgical resection.
Postmenopausal patients with ER-positive/HER2-negative localized breast cancer were randomized 2:1 to receive vepdegestrant (200 mg once daily) or anastrozole (1 mg once daily) for approximately 5.5 months until surgical resection. Tumor tissue samples were collected at screening, week 2 (cycle 1, day 15), and surgery (cycle 6, day 18). The primary endpoint was the percentage change from baseline in Ki-67 score at cycle 1, day 15. Secondary endpoints included pathologic complete response, modified preoperative endocrine prognostic index score at surgery, breast-conserving surgery rate, radiographic response, and safety. Exploratory endpoints included assessments of ER and progesterone receptor protein (PgR) levels.
As of November 18, 2024, 152 patients were randomized to vepdegestrant (n=102) or anastrozole (n=50). The median age of both populations was 66 years, with 65% of patients presenting with tumors >2 cm in the vepdegestrant cohort and 68% in the anastrozole cohort, with 51% having Ki-67 <20% at baseline in the vepdegestrant cohort and 50% in the anastrozole cohort. Patients receiving vepdegestrant demonstrated a significant reduction in Ki-67 score, with a geometric mean change from baseline of −71.4% (95% confidence interval [CI], −60.6% to −79.3%) versus anastrozole (−72.9% [95% CI, −57.8% to −82.6%)]) at week 2, and −84.5% (95% CI, −75.6% to −90.2%) versus anastrozole (−82.8% [95% CI, −67.4% to −90.9%]) at surgery. Median tumor ER protein levels decreased by 76.1% at week 2, and by 94.4% at surgery in the vepdegestrant group, confirming robust ER degradation. Median tumor PgR protein levels decreased by 100% at week 2, and by 100.0% at surgery in the vepdegestrant group. A pathological complete response was seen in 1% of patients who received vepdegestrant and in 0 patients who received anastrozole. The breast-conserving surgery rate radiographic response was 70% (95% CI, 60%-78%) in the vepdegestrant cohort and 54% (95% CI, 40%-67%) in the anastrozole cohort.
Treatment-emergent adverse events (TRAEs) led to dose reductions in 7 vepdegestrant-treated patients (dose reduction was not permitted for anastrozole) and treatment discontinuation in 3 vepdegestrant patients versus 8 anastrozole patients. The most common TRAEs in the vepdegestrant group included hot flush (24%), asthenia (19%), and constipation (14%). There were no grade >4 TRAEs.
Neoadjuvant vepdegestrant was well tolerated and demonstrated significant biological and clinical activity in postmenopausal women with ER-positive/HER2-negative localized breast cancer. The robust reduction in Ki-67 scores and tumor ER protein levels supports the pharmacodynamic effect of vepdegestrant and its potential as an effective neoadjuvant therapy. Further studies are warranted to confirm these findings and to explore the long-term impact of vepdegestrant on clinical outcomes.
Source: Fasching PA, Bermejo B, Arkania E, et al. TACTIVE-N: phase 2 study of neoadjuvant vepdegestrant, a PROteolysis TArgeting chimera (PROTAC) estrogen receptor (ER) degrader, or anastrozole in postmenopausal ER+/human epidermal growth factor receptor 2 (HER2)- localized breast cancer (BC). Presented at: ESMO Congress 2025. October 19, 2025; Berlin, Germany. Abstract 293MO.