Abstract PS1-10-25: Pharmacodynamic effects of the first-in-class CDK4-selective inhibitor atirmociclib (PF-07220060) in combination with endocrine therapy in tumors of patients with HR+/HER2− metastatic breast cancer

Abstract Background: The cyclin-dependent kinase 4 (CDK4)-selective inhibitor atirmociclib (PF-07220060) in combination with endocrine therapy (ET) has demonstrated favorable tolerability and promising clinical activity, as well as strong pharmacodynamic effects in inhibiting serum thymidine kinase activity (TKa) and early ctDNA decrease in an ongoing phase 1 trial (NCT04557449). We performed further exploratory analysis of pharmacodynamic biomarker modulation in tumor biopsies collected from patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC) treated with atirmociclib plus fulvestrant. Methods: Tumor biopsy samples were collected before the first dose (baseline) and at Cycle 2 Day 1 (C2D1) from patients with HR+/HER2− mBC treated with 100, 300, or 400 mg BID atirmociclib in combination with fulvestrant. Formalin-fixed paraffin-embedded tumor samples were analyzed for phospho-Rb (Ser807/811, pRb), Ki67, and FOXM1 expression by immunochemistry (IHC), and RNA expression by whole transcriptome RNA-seq. Gene set variation analysis (GSVA), PAM50 molecular subtype, and BayesPrism bulk RNA-seq deconvolution were performed with the RNA-seq data. Results: At data cutoff (Feb 21, 2025), results from baseline and C2D1 were available for IHC (pRb, Ki67, or FOXM1) in 14 patients and RNA-seq in 14 patients. Median changes of pRb, Ki67, and FOXM1 expression from baseline to C2D1 were −86%, −88%, and −100%, respectively. GSVA showed strong inhibition of cell cycle-related pathways (e.g., E2F, G2M, DNA repair, and Myc), largely in patients who achieved stable disease or better as best overall response. Atirmociclib plus fulvestrant treatment also resulted in upregulation of immune and inflammation response gene sets. Cell type fraction estimation based on BayesPrism bulk RNA-seq deconvolution showed a decrease in tumor cell fraction and an increase in cancer-associated fibroblasts (CAFs) fraction. An increase in macrophage fraction and expression of genes associated with antigen presentation was also observed. No significant change in CD4+ or CD8+ T-cell fraction was detected. Among 13 tumors with Luminal B or HER2-enriched PAM50 intrinsic molecular subtype at baseline, 10 (77%) switched to the less proliferative Luminal A subtype at C2D1. Conclusions: Atirmociclib, in combination with fulvestrant, showed strong effects in inhibiting cell cycle-related pharmacodynamic protein biomarkers and gene sets in HR+/HER2− mBC tumors, consistent with its mechanism of CDK4 inhibition. The analyses also revealed potential immune-modulatory effects of atirmociclib, including increased macrophage infiltration and enhanced antigen presentation pathway gene expression. Citation Format: A. Giordano, F. Liu, W. Roh, H. Zhang, D. Fabiola Flores Diaz, C. A. Hernandez, X. Wu, M. C. Sanchez, J. Park, M. Delioukina, R. A. Moss, T. A. Yap. Pharmacodynamic effects of the first-in-class CDK4-selective inhibitor atirmociclib (PF-07220060) in combination with endocrine therapy in tumors of patients with HR+/HER2− 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 PS1-10-25.