A phase 1/2, first-in-human study of AVZO-021, a selective cyclin-dependent kinase 2 inhibitor (CDK2i), as 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 (BC) and cyclin E1 (CCNE1)–amplified solid tumors: Updated safety and efficacy results.

Abstract

1094 Background: AVZO-021 is a potent, once-daily, oral CDK2i with high selectivity against CDK1, thus minimizing off-target toxicity. Initial Phase 1 data from the ongoing first-in-human Phase 1/2 study of AVZO-021 (NCT05867251) showed clinical responses and a favorable tolerability profile. Methods: The ongoing Phase 1 portion of the study is evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of AVZO-021 alone and in combination with fulvestrant. As of January 20, 2026, the safety population included all patients treated with AVZO-021 monotherapy (n=50) or in combination with fulvestrant (n=13). Efficacy evaluable population included patients treated at ≥150 mg once daily (QD) with HR+/HER2- breast cancer or CCNE1-amplified solid tumors with at least 1 post-baseline scan (n=23 in monotherapy and n=12 in combination with fulvestrant). Results: The median age was 63 years for monotherapy patients and 60 years for combination with fulvestrant. Overall, 95% of patients were female, 78% had BC, 10% had ovarian/fallopian tube cancer, and 5% had endometrial/uterine cancer. AVZO-021 monotherapy patients had a median of 3 prior lines of systemic therapy and those in combination therapy had a median of 4 prior lines, in the metastatic setting. All patients with HR+/HER2- BC received prior CDK4/6i and hormonal therapy. Most common (>25%) all-grade treatment-emergent adverse events (TEAEs) were nausea (51%), fatigue (43%), anemia (33%), and vomiting (32%); 13 patients required dose reductions due to TEAEs and 2 patients discontinued due to TEAEs (1 unrelated Grade 3 intestinal obstruction, 1 related Grade 4 neutropenia). Four patients with HR+/HER2- BC and CCNE1-amplified solid tumors had confirmed partial responses and remain ongoing, demonstrating prolonged clinical benefit. Additionally, 23 patients had stable disease for a disease control rate of 77%. Continuous CDK2 target coverage and significant decreases in ctDNA were observed at ≥90 mg QD monotherapy and in combination with fulvestrant. Conclusions: With longer follow-up, AVZO-021 as monotherapy and in combination with fulvestrant continues to show an encouraging tolerability profile and clinically meaningful efficacy. Gastrointestinal and hematologic adverse events continue to be of low incidence and severity allowing for prolonged treatment and potential safe combination with AVZO-023, a highly potent and selective CDK4i currently enrolling patients with HR+/HER2- BC in combination with fulvestrant. Clinical trial information: NCT05867251 .