Abstract PS1-11-07: First-in-human, phase 1a/b study of GDC-4198 (RGT-419B), a next generation CDK4/2 inhibitor, in patients with hormone receptor positive HER2- locally advanced/metastatic breast cancer (LA/mBC) who progressed on prior CDK4/6 inhibitors

Abstract Introduction: GDC-4198 (also known as RGT-419B) is a CDK4/2 inhibitor, acting as an oral, highly potent small-molecule inhibitor of CDK4 with substantial activity against CDK2. Here we present interim data from a phase 1, first-in-human, multicenter trial of GDC-4198 as a monotherapy or in combination with endocrine therapy (ET) in patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) LA/mBC. Methods: Eligible patients received treatment for LA/mBC including ET and CDK4/6i. GDC-4198 monotherapy was administered orally in continuous 28-day cycles across four cohorts (25, 75, 150 mg once daily [QD], and 150 mg twice daily [BID]) using a standard 3+3 dose escalation design to identify the maximum tolerated dose (MTD) and recommended dose for expansion (RDE). Patients in the combination therapy cohort received GDC-4198 150 mg BID + aromatase inhibitor (AI). The primary objective was to assess safety and tolerability; secondary objectives included exploratory efficacy. Results: As of May 2025, 32 patients (28 monotherapy; 4 in combination with AI) received GDC-4198. The median age was 62 years (range 49-80). The median number of previous lines of therapy was 3 (range 1, 7). All patients received prior CDK4/6i and ET (100%). The most common (occurring in ≥10% of patients) treatment-emergent adverse events (TEAEs; all causality) were nausea, diarrhea, vomiting, white blood cell count decrease, neutrophil count decrease, fatigue, and headache. The incidence of grade ≥3 treatment-related adverse events (TRAEs) was low (16%). No patients have discontinued GDC-4198 due to TRAEs. There were no treatment-related SAEs. The MTD has not been reached. In patients with measurable disease and at least 1 post-baseline tumor assessment (n=24), 4 patients had confirmed partial responses in the monotherapy cohorts (1 at 150 mg QD; 3 at 150 mg BID). Conclusions: GDC-4198, with potent and selective activity against CDK4 and CDK2, was well-tolerated both as a single agent and in combination with AI. GDC-4198 demonstrated preliminary evidence of efficacy in a post-CDK4/6i setting. Further dose escalation with GDC-4198 as a single agent is ongoing and updated data will be presented at the meeting. Citation Format: S. A. Wander, R. Zuniga, H. Han, S. Sadeghi, R. Shatsky, K. Clifton, M. Dhawan, J. Xie, R. Xin, K. Kalinsky. First-in-human, phase 1a/b study of GDC-4198 (RGT-419B), a next generation CDK4/2 inhibitor, in patients with hormone receptor positive HER2- locally advanced/metastatic breast cancer (LA/mBC) who progressed on prior CDK4/6 inhibitors [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 PS1-11-07.