PS5-09-30: A phase 1/2 trial evaluating the safety, tolerability, and efficacy of the KAT6 inhibitor, PF-07248144, in combination with vepdegestrant in patients with ER+/HER2− locally advanced or metastatic breast cancer

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy are standard for the first-line (1L) treatment of estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2−) advanced/metastatic breast cancer (ABC). Although CDK4/6 inhibitors significantly prolong progression-free survival (PFS) in patients with ER+/HER2− ABC, resistance ultimately occurs. For patients who develop resistance to CDK4/6i-based therapy, there is no universal standard of care, highlighting a key unmet need for this patient population. PF-07248144 is a novel, oral, selective inhibitor of KAT6A and KAT6B, two histone lysine acetyltransferases that regulate lineage-specific gene transcription via H3K23 acetylation. Vepdegestrant (ARV-471/PF-07850327) is an oral PROteolysis TArgeting Chimera (PROTAC) ER degrader that has exhibited clinical activity as monotherapy in heavily pretreated patients with ER+/HER2− ABC. Here, we describe a phase 1/2 study that aims to evaluate the safety, tolerability, and efficacy of the KAT6 inhibitor, PF-07248144, in combination with vepdegestrant in patients with ER+/HER2− ABC (NCT04606446). Methods: This is an open-label, multicenter, phase 1/2 study of PF-07248144 as monotherapy or in combination for patients with advanced or metastatic solid tumors, including breast cancer. The study is comprised of two parts: dose escalation (Part 1) and dose expansion (Part 2). Parts 1E and 2E are focused herein and are evaluating PF-07248144 plus vepdegestrant in patients with ER+/HER2− ABC. Patients are eligible to participate in Parts 1E and 2E if they are ≥18 years of age (or per local regulatory requirements) and have histologically or cytologically confirmed ER+/HER2− ABC. Other eligibility criteria include disease progression after ≥1 prior line of treatment with CDK4/6i and endocrine therapy. Patients may have received fulvestrant. Other inclusion criteria are measurable disease as defined by Response Evaluation Criteria in Solid Tumor version 1.1, adequate organ function, asymptomatic/stable brain metastasis and Eastern Cooperative Oncology Group performance status of 0 or 1. Females must meet postmenopausal criteria, and premenopausal women with ovarian suppression (via chemical menopause) are allowed. Key exclusion criteria are prior malignancies within 3 years of enrollment; prior major surgery, radiation therapy, or systemic anticancer therapy within 3 weeks of study entry; major ECG abnormalities or cardiac disorders; symptomatic brain metastasis or visceral metastasis; active infection; active inflammatory gastrointestinal diseases or conditions; and pregnancy or breastfeeding. The recommended dose for expansion for PF-07248144 plus vepdegestrant will be determined in Part 1E and evaluated in Part 2E. Primary endpoints are dose-limiting toxicities (Part 1E only), safety, and tolerability. Secondary endpoints include pharmacokinetics of PF-07248144 and vepdegestrant in both Parts 1E and 2E, and best overall response, duration of response, clinical benefit rate, progression-free survival, time to progression, and overall survival in Part 2E. Citation Format: F. Yan, T. Mukohara, Y. Park, S. Im, G. Kim, T. Yamashita, D. Sommerhalder, R. Layman, E. Hamilton, S. Kim, F. Hara, S. Wang, J. Chien, J. Kim, T. Clay, R. Joshi, Y. Chae, C. Oakman, B. Holbrook, B. Dong, Y. Cheng, H. Li, J. Yang, S. Kent, L. Liu, K. Kowalski, S. Badhrinarayanan, A. Skoura, L. Howie, P. Lorusso. A phase 1/2 trial evaluating the safety, tolerability, and efficacy of the KAT6 inhibitor, PF-07248144, in combination with vepdegestrant in patients with ER+/HER2− locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-30.