Abstract P4-12-03: Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader, Plus Abemaciclib in ER-Pos/Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced or Metastatic Breast Cancer: TACTIVE-U Prelim Pha

Abstract Background: Vepdegestrant (ARV-471), an oral PROTAC ER degrader, was well tolerated and showed evidence of clinical activity in the first-in-human phase 1/2 study in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer (NCT04072952). In xenograft models, vepdegestrant plus the cyclin-dependent kinase (CDK)4/6 inhibitor abemaciclib showed greater tumor growth inhibition vs fulvestrant plus abemaciclib. The open-label, phase 1b/2 TACTIVE-U umbrella study is evaluating the safety, efficacy, and pharmacokinetics (PK) of vepdegestrant in combination with other anticancer treatments in pts with ER+ advanced or metastatic breast cancer. Here, we report preliminary phase 1b results from the ongoing TACTIVE-U sub-study A (NCT05548127) investigating vepdegestrant plus abemaciclib. Methods: Eligible pts were aged ≥18 years with confirmed ER+/HER2- advanced or metastatic breast cancer and had received up to 2 lines of prior therapy, including a CDK4/6 inhibitor-based regimen in any setting (pts with prior CDK4/6 inhibitor dose reductions due to adverse events [AEs] were excluded). Following a 7-day PK lead-in with abemaciclib administered alone, pts received vepdegestrant 200 mg orally once daily and abemaciclib 150 mg orally twice daily (both continuously). The primary endpoint of the phase 1b portion of the study was dose-limiting toxicities (DLTs) during the first cycle. Secondary endpoints of phase 1b are assessments of safety (type, frequency, and severity of AEs), PK (plasma concentrations of study drugs), and antitumor activity (objective response, clinical benefit rate). Results: As of April 4, 2024, 16 female pts (median age: 56 years [range: 38–79]) received vepdegestrant plus abemaciclib, with 9 pts treated for ≥5 cycles; 12 remain on treatment. All pts (100%) received prior CDK4/6 inhibitors (ribociclib [n=8], palbociclib [n=7], and abemaciclib [n=1]), 14 (88%) prior aromatase inhibitors, 11 (69%) prior chemotherapy, and 5 (31%) prior fulvestrant. There were no DLTs or treatment discontinuations due to treatment-emergent AEs (TEAEs). TEAEs led to dose reduction of vepdegestrant and abemaciclib in 1 pt (neutropenia) and dose reductions of abemaciclib in 6 pts (fatigue [n=2] and fatigue/muscular weakness, neutropenia, diarrhea, and anemia [n=1 each]). Treatment-related AEs (TRAEs) to either vepdegestrant or abemaciclib that occurred in ≥20% of pts were diarrhea (69%), nausea (44%), fatigue (44%), and decreased appetite (25%). The majority of TRAEs were grade 1/2; grade 3 TRAEs were neutropenia or neutrophil count decreased in 5 pts and fatigue in 2 pts. There were no grade ≥4 TRAEs. Observed PK of vepdegestrant and abemaciclib was consistent with historical data reported in single-agent clinical studies. The exposure of abemaciclib (Cmax and AUCtau) increased slightly (15% and 13%, respectively) when dosed with vepdegestrant compared with abemaciclib alone. Conclusions: The safety profile of vepdegestrant plus abemaciclib in pts with ER+/HER2- advanced or metastatic breast cancer was generally consistent with the known profiles of each agent, and no DLTs were observed. Neutropenia was manageable with dose modifications. The impact of vepdegestrant on abemaciclib exposure was minor and indicated no significant drug interaction. These data support further evaluation of this combination at the full standard doses of vepdegestrant 200 mg once daily and abemaciclib 150 mg twice daily in the phase 2 portion of this sub-study. Additional ongoing sub-studies for TACTIVE-U are evaluating vepdegestrant plus ribociclib (sub-study B; NCT05573555) and samuraciclib (sub-study C; NCT06125522). Citation Format: John Hilton, Katarzyna J. Jerzak, A. Jo Chien, Jose L.M. Guimaraes, Colombe Chappey, Hechuan Wang, Stefanie K. Drescher, Elisa Dall’O’, Julia Perkins Smith, Swapnil Parmar, Rachel M. Layman, Cynthia Ma. Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader, Plus Abemaciclib in ER-Pos/Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced or Metastatic Breast Cancer: TACTIVE-U Prelim Phase 1b Results [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-12-03.