Vepdegestrant (PROTAC ER degrader) + atirmociclib (selective CDK4 inhibitor) delivers 9–12mo mPFS post-CDK4/6i in ER+/HER2− ABC

Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) designed to degrade estrogen receptor, combined here with atirmociclib (ATI; a selective CDK4 inhibitor) in the open-label, multicenter TACTIVE-K Phase 1b/2 study (NCT06206837) for previously treated ER+/HER2− advanced breast cancer after 1–2 prior ABC lines; Phase 2 required 1 prior CDK4/6i-based regimen (n=70; median age 60; median 1.0 prior ABC regimen; 94–100% had prior CDK4/6i). At the recommended regimen vepdegestrant 200mg QD + ATI 100mg BID (n=36) or 300mg BID (n=34), confirmed ORR was 16.1% (measurable n=31) and 24.2% (measurable n=33), CBR 44.4% vs 52.9%, and mPFS 9.3 vs 11.5 months (both with upper CI NE); outcomes in baseline ESR1-mutant disease were similar with ORR 15.4% and 21.4% and CBR 46.2% and 64.3% (ESR1-mutant n=27 overall). Safety was largely grade 1/2, with dose-limiting grade 3 thrombocytopenia (ATI100) and grade 3 neutropenia (ATI300); grade 3/4 neutropenia was 16.7% (ATI100) and 35.3% (ATI300), and PK suggested no clinically meaningful drug–drug interaction—efficacy looks well above endocrine monotherapy benchmarks post-CDK4/6i such as elacestrant (EMERALD mPFS ~2.8 months overall; ~3.8 months in ESR1-mutant), and in the ballpark of targeted combos in selected biomarker subsets (e.g., capivasertib+fulvestrant in PIK3CA/AKT1/PTEN-altered tumors mPFS 7.3 vs 3.1 months).