Abstract B009: Trial in Progress: Phase 1 Study of Trastuzumab Deruxtecan (DS-8201a) in Combination with Azenosertib (ZN-c3) in HER2-Expressing/ Amplified Gastric/ Gastroesophageal Junction Cancer and Other Solid Tumors with HER2 Expression

Abstract Background: Azenosertib (ZN-c3) is a selective, orally bioavailable WEE1 kinase inhibitor. Trastuzumab deruxtecan (T-DXd; DS-8201a) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate that delivers a topoisomerase 1 inhibitor payload. In preclinical studies, we demonstrated that WEE1 inhibition enhances the antitumor efficacy of T-DXd in tumors with low HER2 expression (IHC 0 or 1+) and prolongs disease control in HER2-high expressing models (PMID: 37279095). We sought to evaluate whether combining T-DXd with azenosertib is safe and whether the combination potentiates antitumor activity in HER2-expressing/ amplified solid tumors. Methods: This Phase 1 dose escalation and dose expansion study will evaluate the safety and preliminary efficacy of azenosertib in combination with T-DXd in HER2-expressing/ amplified solid tumors. In dose escalation, a Bayesian optimal interval design will be used to determine the combination’s maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). T-DXd will be administered intravenously at 5.4 mg/kg on Day 1 of each 21-day cycle. Azenosertib will be given orally starting at 150 mg and escalating up to 250 mg once per day on an intermittent schedule. In dose expansion, 16 evaluable patients will be randomized to one of two cohorts to evaluate the safety and preliminary efficacy at the RP2D, as well as to evaluate the pharmacodynamic effects of T-DXd alone and in combination with azenosertib (e.g. DNA damage response and immune markers). In cohort 1, T-DXd will begin on Cycle 1 Day 1 (C1D1) and azenosertib will be added on C1D8. In cohort 2, both agents will start on C1D1. The primary endpoints are: 1) find the MTD and RP2D as well as the dose limiting toxicities of T-DXd and azenosertib, and 2) determine the incidence of adverse events. The secondary endpoints are: 1) assess the objective response rate, progression free survival, and duration of response for the T-DXd and azenosertib combination, 2) assess the pharmacodynamic effects, and 3) determine predictors of response and acquired resistance. Major inclusion criteria include: 1) Dose escalation: locally advanced, unresectable, or metastatic HER2-expressing (IHC 1+, 2+, or 3+) or amplified solid tumors that are T-DXd naïve and have progressed after at least one prior metastatic therapy. 2) Dose expansion: locally advanced, unresectable, or metastatic HER2-expressing (IHC 1+, 2+, or 3+) or amplified gastric/ gastroesophageal junction cancer that is T-DXd naïve and has progressed after at least 1 prior metastatic therapy. 3) ECOG performance status of 0 or 1. 4) Evaluable or measurable disease. 5) Patients with treated brain metastases with no evidence of progression on follow-up imaging are eligible. Major exclusion criteria include: 1) Severe pulmonary disease and/or history of or current non-infectious pneumonitis/ interstitial lung disease. 2) Significant corneal disease. 3) Prior treatment with a WEE1 inhibitor or T-DXd. The study is recruiting in the United States through the NCI ETCTN (NCT06364410). Citation Format: Alexandria M. Doerfler, Ecaterina E. Dumbrava, Ying Yuan, Cheryl Pickett-Gies, Steven Gore, Shannon N. Westin, Jaffer A. Ajani, Ann-Marie Cimo, Siqing Fu, Catherine Lee, Quan Lin, Ronald Fleming, Timothy A. Yap, Khandan Keyomarsi, Funda Meric-Bernstam. Trial in Progress: Phase 1 Study of Trastuzumab Deruxtecan (DS-8201a) in Combination with Azenosertib (ZN-c3) in HER2-Expressing/ Amplified Gastric/ Gastroesophageal Junction Cancer and Other Solid Tumors with HER2 Expression [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 B009.