Vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, plus abemaciclib (ABE) in ER+/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC): TACTIVE-U phase 1b/2 results.

1067 Background: Substudy A of the open-label, phase 1b/2 TACTIVE-U umbrella study is evaluating vepdegestrant, an oral PROTAC ER degrader, in combination with ABE for treatment of ER+/HER2− ABC (NCT05548127). Here, we report results for all patients (pts) in phases 1b and 2 treated with vepdegestrant (200 mg orally once daily) plus ABE (150 mg orally twice daily). Methods: Eligible pts were adults (age ≥18 years) with ER+/HER2− ABC who had received 1–2 prior lines of therapy in the ABC setting; 1 prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)-based regimen (in any setting) was required. The primary endpoint of phase 1b was dose-limiting toxicities during the first cycle. The primary endpoint of phase 2 was objective response rate (ORR); secondary endpoints included clinical benefit rate (CBR), progression-free survival (PFS), safety, and pharmacokinetics (PK). Results: As of October 10, 2025, 37 female pts (median age, 59 years range, 38–84; 20 pts 54.1% had ESR1 -mutated ESR1 m tumors) received vepdegestrant plus ABE in phases 1b and 2, with 26 pts treated for ≥5 28-day cycles; 10 remain on treatment. All pts received prior CDK4/6i (ribociclib, 48.6%; palbociclib, 43.2%; ABE, 8.1%) in any setting; prior treatments in the metastatic setting included aromatase inhibitors (64.9%), fulvestrant (35.1%), and chemotherapy (21.6%). Among pts with measurable disease at baseline, the ORR was 30.6% (95% CI, 18.0–46.9) in all pts and 45.0% (95% CI, 25.8–65.8) in pts with ESR1 m tumors. The CBR was 59.5% (95% CI, 43.5–73.7) in all pts and 65.0% (95% CI, 43.3–81.9) in pts with ESR1 m tumors. Median PFS was 7.2 months (95% CI, 5.5–16.5) in all pts and 10.9 months (95% CI, 5.5–not estimable) in pts with ESR1 m tumors. Five pts (13.5%) discontinued treatment due to treatment-emergent adverse events (TEAEs). TEAEs led to dose reduction of vepdegestrant in 6 pts (16.2%) and dose reduction of ABE in 19 pts (51.4%). Treatment-related adverse events of any grade that occurred in ≥20% of pts were diarrhea (73.0% grade 1/2, 70.3%; grade 3/4, 2.7%), fatigue (54.1% grade 1/2, 40.5%; grade 3/4, 13.5%), neutropenia (54.1% grade 1/2, 21.6%; grade 3/4, 32.4%), nausea (35.1% grade 1/2, 32.4%; grade 3/4, 2.7%), anemia (32.4% grade 1/2, 29.7%; grade 3/4, 2.7%), vomiting (24.3% grade 1/2, 21.6%; grade 3/4, 2.7%), and decreased appetite (21.6% grade 1/2, 18.9%; grade 3/4, 2.7%). There were no grade 5 TEAEs. PK data showed that vepdegestrant was associated with a modest 22% increase in exposure of ABE and its active metabolites, indicating no significant drug-drug interaction. Conclusions: In this phase 1b/2 study of pts with ER+/HER2− ABC, vepdegestrant plus ABE demonstrated antitumor activity and a safety profile that was generally consistent with the known profiles of each agent. Clinical trial information: NCT05548127 .