Abstract B012: Results From the Phase 1 Dose Escalation and Dose Expansion Study of Azenosertib, a WEE1 Inhibitor, in Patients With Advanced Solid Tumors

Abstract Background: WEE1, a tyrosine kinase with a role in several stages of the cell cycle, is a promising target in patients with solid tumors with increased levels of Cyclin E1 protein. Azenosertib is a potential best-in-class, highly selective oral WEE1 kinase inhibitor. This first-in-human phase 1 dose escalation/expansion study evaluated safety, tolerability and efficacy of azenosertib monotherapy in heavily pre-treated patients with advanced/metastatic solid tumors including gynecologic malignancies. Methods: This open-label, dose escalation/dose expansion Phase 1 study enrolled patients ≥18 years with advanced/metastatic solid tumors including platinum-resistant ovarian cancer (PROC) and uterine serous carcinoma (USC) who had received ≥1 prior line of therapy. Azenosertib monotherapy was administered continuously or intermittently (5 days on, 2 days off [5:2] or 4 days on, 3 days off [4:3]). The primary objective for dose escalation was to evaluate the safety and tolerability of azenosertib and identify the maximum tolerated dose with continuous and intermittent dosing. The primary objective for dose expansion was to investigate the clinical activity of azenosertib by objective response rate (ORR) per RECIST version 1.1. Duration of response (DOR) and safety were key secondary objectives. Biomarkers of replicative stress, such as Cyclin E1 protein expression, were explored retrospectively by immunohistochemistry. Results: As of December 2, 2024, 193 patients (PROC, n=69; USC, n=35; other solid tumors, n=89) received a total daily dose (300-500mg) of azenosertib, continuously or intermittently (5:2 or 4:3). The median age was 65 years and 98% of patients had ECOG PS ≤1; median number of prior lines of therapy was 5 (PROC), 3 (USC) and 4 (other solid tumors). The most common treatment-related adverse events (TRAEs) were nausea (61%), fatigue (59%), and diarrhea (52%). Most frequent Grade ≥3 TRAEs were fatigue and neutropenia (13% each), and anemia and thrombocytopenia (11% each). These adverse events were clinically manageable. TRAEs led to treatment interruption in 78 patients (40%), discontinuation in 10 patients (5%), and one death (cause unknown at 175mg twice a day 5:2). In patients with PROC who received azenosertib intermittently, ORR was 35% (8/23) in patients with Cyclin E1 positive tumors vs 21% (12/58) overall (median DOR, 5.2 [range 2.8-6.9, Cyclin E1 positive] and 5.1 months [range 3.0-5.9, overall]). In patients with USC who received azenosertib intermittently, ORR was 36% (4/11) in patients with Cyclin E1 positive tumors vs 26% (5/19) overall (median DOR, 5.5 months [range 5.4-NE] for both groups). Conclusion: WEE1 inhibitor azenosertib demonstrated a manageable safety profile at total daily doses (300-500mg), continuously or intermittently (5:2 or 4:3). Promising anti-tumor activity was observed in Cyclin E1 positive PROC and USC tumors, supporting further assessment of azenosertib in these patient populations. The DENALI Part 2 study (NCT05128825) is currently evaluating azenosertib in patients with Cyclin E1 positive PROC. Citation Format: Funda Meric-Bernstam, Gini F. Fleming, Deborah Doroshow, Jennifer Segar, Shiraj Sen, Hirva Mamdani, Alberto A. Mendivil, Jing-Yi Chern, Matthew L. Anderson, Cara A. Mathews, Natraj R. Ammakkanavar, David Miller, Matthew Whitehurst, Ryan Kendle, Alexander Spira, Shanta Chawla, Thejonatha Annareddy, Dongliang Zhuang, Jianhui Ma, Anthony W. Tolcher. Results From the Phase 1 Dose Escalation and Dose Expansion Study of Azenosertib, a WEE1 Inhibitor, in Patients With Advanced Solid Tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B012.