264TiP TACTIVE-K: Phase Ib/II study of vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, in combination with PF-07220060, a cyclin-dependent kinase (CDK)4 inhibitor, in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer

Vepdegestrant (ARV-471) is an investigational, orally administered PROTAC ER degrader. Initial results from a phase Ib cohort of a first-in-human phase I/II study (NCT04072952) showed that vepdegestrant, in combination with the CDK4/6 inhibitor palbociclib, had robust clinical activity (clinical benefit rate CBR: 63.0%) in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer. PF-07220060 is an investigational CDK4-selective inhibitor, which in contrast to CDK4/6 inhibitors, spares CDK6 blockade and demonstrates less neutropenia in in vivo models. A first-in-human phase I/IIa study (NCT04557449) demonstrated promising antitumor activity with PF-07220060 in pts with advanced solid tumors with a CBR of 52.4%. Preclinical tumor models have shown that vepdegestrant + PF-07220060 effectively suppresses tumor growth to a greater extent than either agent alone. This open-label, multicenter phase Ib/II study (NCT06206837) will evaluate the combination of vepdegestrant + PF-07220060 in pts ≥18 y with confirmed ER+/HER2- advanced breast cancer. The phase Ib portion will use an escalation/de-escalation approach to determine the recommended phase II dose (RP2D) of the combination of vepdegestrant and PF-07220060. The phase II portion will further evaluate the preliminary antitumor activity, safety, and pharmacokinetics (PK) of the combination at the RP2D. Pts (N≈65) will receive vepdegestrant orally once daily continuously and PF-07220060 orally twice daily continuously. The primary endpoint of the phase Ib portion is the number of pts with dose-limiting toxicities; secondary endpoints are antitumor activity (objective response rate ORR, duration of response DOR, CBR), progression-free survival (PFS), safety, and PK. The primary endpoint of the phase II portion is ORR; secondary endpoints are antitumor activity (DOR, CBR), PFS, safety, plasma concentrations of study drugs, and changes in circulating tumor DNA. NCT06206837. Justine Lempart, PhD, of Apollo Medical Communications, part of the Helios Global Group. Pfizer Inc. Pfizer Inc. (sponsor) and Arvinas Estrogen Receptor, Inc. (collaborator).