Abstract PS4-06-08: A phase 1/2, first-in-human study of AVZO-021, a selective cyclin-dependent kinase 2 inhibitor (CDK2i), as a monotherapy and in combination for patients with advanced solid tumors, including hormone receptor-positive (HR+)/human e

Abstract Background: Resistance to CDK4/6 inhibitors (CDK4/6i) in HR+/ HER2− metastatic breast cancer (mBC) is frequently associated with CCNE1 overexpression and CDK2 activation. Targeting CDK2 may overcome this resistance and enhance the efficacy of CDK4/6i-based regimens. AVZO-021 is a potent CDK2i with high selectivity for CDK2 over CDK1, thus minimizing off-target toxicity. We present preliminary results from the Phase 1 segment of the ongoing first-in-human Phase 1/2 study of AVZO-021 (NCT05867251). Methods: The ongoing Phase 1 open-label, dose-escalation segment of this study is evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of AVZO-021 alone and in combination with endocrine therapy [(ET) fulvestrant], CDK4/6i (ribociclib/abemaciclib) + ET (fulvestrant/letrozole), an antibody-drug conjugate (sacituzumab govitecan-hziy), or chemotherapy (carboplatin) in patients with advanced solid tumors, including HR+/HER2− mBC and CCNE1-amplified solid tumors. AVZO-021 is administered orally once daily (QD) across escalating dose levels (20 to 220 mg in monotherapy dose escalation). Results: As of May 14, 2025, 47 patients have received at least 1 dose of AVZO-021 (27 in monotherapy; 20 in combination). The median age was 63 years for patients who received AVZO-021 in monotherapy and 59 years for patients who received AVZO-021 in combination with ET ± CDK4/6i, sacituzumab govitecan-hziy, or chemotherapy. Overall, 96% of patients were female, 68% had breast cancer, 15% had ovarian/fallopian tube cancer, and 6% had endometrial/uterine cancer. Patients who received AVZO-021 in monotherapy had a median of 4 prior lines of systemic therapy, and those treated with combination therapy had a median of 6 prior lines. All patients with HR+/HER2− mBC (n = 30) had received prior CDK4/6i and hormonal therapy. No dose-limiting toxicities (DLTs) or treatment discontinuations due to adverse events (AEs) were observed with AVZO-021 monotherapy up to a dose of 220 mg. The most common (>25%) all-grade treatment-emergent AEs (TEAEs) with monotherapy were fatigue (41%), nausea (37%), anemia (26%), and vomiting (26%); 2 patients required dose reductions due to AEs (Grade 2 thrombocytopenia [n = 1, 180 mg dose level]; Grade 2 worsening fatigue [n = 1, 120 mg dose level]). No new safety signals or DLTs were reported in the combination cohorts. AVZO-021 monotherapy demonstrated a favorable PK profile with a low peak-to-trough ratio, robust target coverage, and mean half-life of 14 hours. Updated clinical data will be presented at the conference, including ctDNA analysis and preliminary efficacy of monotherapy and combination therapy in HR+/HER2− mBC and CCNE1-amplified solid tumors. Conclusions: AVZO-021 is a novel CDK2i with high selectivity for CDK2 over CDK1 and a favorable preliminary clinical profile. Together with the mechanistic rationale, the emerging clinical data support the continued development of AVZO-021 as a monotherapy and in combinations, including with ET ± CDK4/6i and selective CDK4i. Citation Format: A. J. Montero, M. R. Patel, A. I. Spira, B. Bashir, D. L. Richardson, S. Thamake, D. Trone, B. Veresh, P. LoRusso. A phase 1/2, first-in-human study of AVZO-021, a selective cyclin-dependent kinase 2 inhibitor (CDK2i), as a monotherapy and in combination for patients with advanced solid tumors, including hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer and cyclin E1 (CCNE1)-amplified solid tumors: preliminary safety and efficacy results [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 PS4-06-08.