Vepdegestrant (PROTAC ER degrader) + abemaciclib delivers 30.6% ORR (45.0% in ESR1m) post-CDK4/6 in ER+/HER2− ABC

Vepdegestrant is an oral proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader combined with abemaciclib, an oral CDK4/6 inhibitor, in Substudy A of the open-label Phase 1b/2 TACTIVE-U umbrella study (NCT05548127) in ER+/HER2− advanced breast cancer after 1–2 prior metastatic lines and required prior CDK4/6i exposure (n=37; ESR1-mutated 54.1%). As of October 10, 2025, in patients with measurable disease, ORR was 30.6% overall and 45.0% in ESR1-mutant tumors; median PFS was 7.2 months overall and 10.9 months in ESR1-mutant tumors—numerically above typical single-agent endocrine therapy outcomes post-CDK4/6 (e.g., EMERALD SOC mPFS ~1.9 months; elacestrant mPFS ~2.8 months overall and ~3.8 months in ESR1-mutated). Discontinuations for TEAEs were 13.5%; common TRAEs included diarrhea 73.0% (G3/4 2.7%), fatigue 54.1% (G3/4 13.5%), and neutropenia 54.1% (G3/4 32.4%), with frequent abemaciclib dose reductions (51.4%), broadly consistent with a CDK4/6i-containing safety profile (postMONARCH abemaciclib+fulvestrant mPFS 6.0 vs 5.3 months; HR 0.73).