Vepdegestrant, a proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader, plus atirmociclib (ATI) in ER+/HER2− advanced breast cancer (ABC): TACTIVE-K phase 1b/2 results.

1075 Background: There is unmet need for therapies that improve clinical outcomes in patients (pts) with ER+/HER2− ABC and disease progression on existing endocrine therapies (ETs). Both vepdegestrant, and ATI, a selective cyclin-dependent kinase (CDK) 4 inhibitor (CDK4i), have shown antitumor activity in pts with ER+/HER2− ABC previously treated with CDK4/6i plus ET. This study evaluated the efficacy and safety of vepdegestrant plus ATI in pts with ER+/HER2− ABC. Methods: This open-label, multicenter, phase 1b/2 study (NCT06206837) enrolled pts with ER+/HER2− ABC who received >1 (phase 1) or 1–2 (phase 2) prior lines of therapy in the ABC setting; 1 prior CDK4/6i-based regimen in any setting was required in phase 2. The study included a dose escalation/de-escalation phase 1b to select recommended doses, and a randomized phase 2 to further assess efficacy, safety, and PK. Baseline ESR1 mutation status (via ctDNA) and its association with efficacy outcomes were also assessed in phase 2. Results: As of Sep 5, 2025, 70 pts (median age, 60 y) received vepdegestrant 200 mg daily plus ATI 100 mg BID (ATI100; n = 36), or 300 mg BID (ATI300; n = 34). Pts received a median of 1.0 prior regimens in the ABC setting. Most pts previously received an aromatase inhibitor (ATI100, n = 33, 91.7%; ATI300, n = 26, 76.5%) and/or a CDK4/6i (ATI100, n = 36, 100%; ATI300, n = 32, 94.1%). Confirmed objective response rate (ORR), clinical benefit rate (CBR; complete response, partial response, or stable disease for ≥ 24 wks), and median progression-free survival (mPFS) are shown in the Table. Efficacy outcomes for pts with baseline ESR1 mutations (n = 27) were consistent with the total population (Table). Two dose-limiting toxicities were reported in phase 1b: a grade (G) 3 platelet count decreased (ATI100) and a G3 neutrophil count decreased (ATI300). Most treatment-related adverse events (TRAEs) were G1/2; G3/4 TRAEs were mainly neutropenia (ATI100, 16.7%; ATI300, 35.3%). PK parameters including AUC tau and C max for vepdegestrant and ATI100/300 at steady state were consistent with previous reports, indicating no clinically impactful drug-drug interactions. Conclusions: In previously treated pts with ER+/HER2− ABC, vepdegestrant plus ATI showed clinical activity in the full pt population and in pts with ESR1 mutations. The safety profile of the combination was consistent with each agent. Clinical trial information: NCT06206837 . Vepdegestrant + ATI 100 mg Vepdegestrant + ATI 300 mg Pts with measurable disease at baseline n = 31 n = 33 Confirmed ORR, % (95% CI) 16.1 (7.1–32.6) 24.2 (12.8-41.0) All pts n = 36 n = 34 CBR, % (95% CI) 44.4 (29.5–60.4) 52.9 (36.7–68.5) mPFS, mo (95% CI) 9.3 (5.4–NE) 11.5 (7.2–NE) Pts with ESR1 mutation n = 13 n = 14 Confirmed ORR, % (95% CI) 15.4 (4.3–42.2) 21.4 (7.6-47.6) CBR, % (95% CI) 46.2 (23.2–70.9) 64.3 (38.8–83.7) mPFS, mo (95% CI) NR (3.0–NE) NR (3.7–NE) NE, not estimable; NR, not reached.