Abstract A119: ALX2004, a novel topoisomerase I inhibitor antibody-drug conjugate for the treatment of EGFR-expressing solid tumors

Abstract EGFR remains one of the most validated and clinically actionable targets in oncology. Past attempts to develop EGFR targeted ADCs have resulted in failures and no approvals. Toxicity associated with the previously utilized payloads (e.g. tubulin inhibitors and cross-linking DNA agents) as well as off tumor skin toxicity associated with this target, have significantly limited the therapeutic window and clinically meaningful dose. ALX2004 is an anti-EGFR topoisomerase I inhibitor ADC with a lysosomal protease-cleavable linker and payload linked to native IgG1 inter-chain cysteines with DAR 8, resulting in a homogenous product. ALX2004 utilizes an affinity-tuned EGFR antibody with a wider therapeutic window and a binding epitope different from currently FDA approved EGFR antibodies. Our proprietary topoisomerase 1 inhibitor payload is designed and selected to offer similar cytotoxic potency with enhanced bystander effect compared to the clinical standard, DXd. The linker payload was designed with improved stability in circulation to minimize off-tumor payload release, leading to decreased off-tumor deconjugation from antibody, increased protease-mediated release of the payload in the tumor microenvironment. In a non-human primate (NHP) exploratory study, ALX2004 had a higher DAR in circulation compared to the DXd linker payload. Multiple mechanisms of action may contribute to ALX2004 anti-tumor activity and have been demonstrated in either or both in-vitro and in-vivo models. These include direct tumor cell killing by its cytotoxic payload via inhibition of topoisomerase I, payload mediated bystander killing of neighboring cells in the tumor, payload mediated immunogenic cell death, and ADCC and ADCP mediated by IgG1 Fc domain and inhibition of EGFR signaling pathway. ALX2004 demonstrated potent anti-tumor activity across ten CDX models with varying levels of EGFR expression, different EGFR signaling pathway mutations and five tumor types. Toxicity was evaluated as 6-week repeat dose (Q3W dosing) with 6-week recovery period in NHP. No dose limiting major target organ toxicity, including on-target toxicity (i.e. skin or other EGFR expressing cells) was observed. No observed adverse event level (NOAEL) was 10 mg/kg. No evidence of payload-related interstitial lung disease was observed. All observations are clinically monitorable and reversible. This favorable safety profile in combination with potent tumor activity across multiple tumor types supports future clinical development. A Phase 1 dose escalation study in patients with relapsed/refractory EGFR-expressing solid tumors including non-small cell lung cancer, colorectal cancer, head and neck squamous cell carcinoma and esophageal squamous cell carcinoma, is ongoing. Citation Format: Janica Wong, Ana Monegal-Granados, Hanako Daino-Laizure, Jia-Xu Li, Jessica L. Morgan, Sarah Bolton, Andrew Olson, Yin Labson, Connie Lu, Sen Xu, Venita De Almedia, Hadi Falahatpisheh, Peter Strop, Jaume Pons, Marija Vrljic. ALX2004, a novel topoisomerase I inhibitor antibody-drug conjugate for the treatment of EGFR-expressing 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 A119.