Abstract P4-08-17: First-in-human Phase 1 study of BTX-9341, a first-in-class, CDK4/6 bifunctional degrader, as a monotherapy and in combination with fulvestrant in patients with advanced and/or metastatic HR+/HER2- breast cancer

Abstract Background: BTX-9341 is a first-in-class, oral bifunctional degrader of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6), both clinically validated cell cycle targets in hormone receptor (HR)-positive (+)/human epidermal growth factor receptor 2 (HER2)-negative (-) breast cancer. Preclinical data highlight the superiority of BTX-9341compared to CDK4/6 inhibitors in terms of robust inhibition of retinoblastoma (RB) phosphorylation and CDK2 and Cyclin E transcription, cell cycle arrest, in vivo efficacy in breast cancer xenografts and, ultimately, in the ability to overcome key resistance mechanisms that limit the impact of CDK4/6 inhibitors in second-line (2L) HR+/HER2- breast cancer. Methods: This first-in-human (FIH), Phase 1 trial of BTX-9341 (BTX-9341-101) will be a multicenter, nonrandomized, open-label trial to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of BTX-9341 in patients with advanced and/or metastatic HR+/HER2- breast cancer who received prior CDK4/6 inhibitor therapy and have no mutations in RB. The trial will consist of initial dose escalation using accelerated titration and a Bayesian Optimal Interval (BOIN) design (Part A) of BTX-9341, both as monotherapy and in combination with fulvestrant. The dose expansion (Part B) of BTX-9341 in combination with fulvestrant will use a Bayesian Optimal Phase 2 (BOP2) design. The primary objective of Part A is to determine the maximum tolerated dose (MTD)/maximum evaluable dose (MED) of BTX-9341 monotherapy and/or combination therapy. The primary objectives of Part B are to obtain preliminary evidence of BTX-9341 efficacy and to confirm the recommended phase 2 dose (RP2D) of BTX-9341 combination therapy. Secondary objectives include characterization of the plasma PK profile of BTX-9341 following single and multiple doses of the drug administered as a single agent and/or in combination with fulvestrant and exploratory objectives will assess pharmacodynamic (PD) effects and PK/PD correlations. Approximately 82 patients will be enrolled and non-randomly assigned initially to Part A (dose escalation; ∼36 participants) and later to Part B (dose expansion; ∼46 participants). BTX-9341 will be evaluated as an oral therapeutic administered once a day (QD) in 28-day treatment cycles. Note: Dr. Rachel M. Layman and Dr. Matthew Goetz have contributed equally to this abstract. Citation Format: Amita Patnaik, Danette Powell, Aparajita H. Chourasia, Massimo Cristofanilli, Ewelina Morawa, Jeremy Barton, Rachel M. Layman, Matthew Goetz. First-in-human Phase 1 study of BTX-9341, a first-in-class, CDK4/6 bifunctional degrader, as a monotherapy and in combination with fulvestrant in patients with advanced and/or metastatic HR+/HER2- breast cancer [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 P4-08-17.