Dose optimization of PF-07248144, a first-in-class KAT6 inhibitor, in patients (pts) with ER+/HER2− metastatic breast cancer (mBC): Results from phase 1 study to support the recommended phase 3 dose (RP3D).

作者：Patricia LoRusso, Toru Mukohara, David Sommerhalder, Kan Yonemori, Erika Hamilton, Rachel M. Layman, Sung‐Bae Kim, Seock‐Ah Im, Hope S. Rugo, Toshinari Yamashita, Fengting Yan, Fumikata Hara, Gun Min Kim, Shusen Wang, Sean Kent, Li Liu, Athanasia Skoura, Karen Kowalski, M. Li, Yeon Hee Park · 发表于：Journal of Clinical Oncology · 年份：2025 · DOI：10.1200/jco.2025.43.16_suppl.1020 · 被引用次数：5 · 研究领域：Radiopharmaceutical Chemistry and Applications、PARP inhibition in cancer therapy、Lung Cancer Treatments and Mutations

1020 Background: PF-07248144 is a selective catalytic inhibitor of KAT6, a histone lysine acetyltransferase. To inform the RP3D, we evaluated two pharmacokinetically distinguishable doses of PF-07248144 in combination with fulvestrant (FUL) from a phase 1 study in ER+/HER2− mBC in a dose expansion phase. Methods: Pts with ER+/HER2− mBC after prior CDK4/6i and endocrine therapy (ET) received PF-07248144 at recommended doses for expansion (RDEs) of 5 mg QD alone, 5 mg QD plus FUL, or 1 mg QD plus FUL (N = 107) and were followed up (at least 6 months across all cohorts) to assess for safety and efficacy. Primary objective wassafety/tolerability per CTCAE 5.0 and RDE selection. Other objectives included antitumor activity per RECIST 1.1, PK, PD, and predictive biomarkers. Results: 5 mg QD was identified as the RDE for both PF-07248144 monotherapy (35 pts treated) and FUL combination (43 pts treated) based on safety, PK, PD, and antitumor activity. 1 mg PF-07248144 plus FUL (29 pts treated) was selected as the lower RDE based on a distinguishable PK and safety profile while achieving maximal blood and tumor PD marker reduction and efficacious concentrations supported by preclinical models. As of Oct 11, 2024, a total of 107 pts were treated at RDEs. Baseline pt characteristics from the two RDEs plus FUL were comparable. All pts received prior CDK4/6i and ET in the metastatic setting. Positive dose-response relationships were identified for both safety (neutropenia) and efficacy (o...