DM005: An anti-EGFR/c-MET bispecific antibody-drug conjugate for advanced solid tumors.

e15010 Background: Bispecific ADCs (BsADCs) enhance efficacy, reduce toxicity, and overcome drug resistance by increasing internalization and tumor specificity. EGFR and c-MET are frequently co-expressed in various solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), head and neck cancer, etc. DM005 is a BsADC conjugated to BLD1102 (linker/DNA topoisomerase I inhibitor BCPT02), targeting EGFR and c-MET with an average drug-to-antibody ratio (DAR) of 4. Preclinical studies shows DM005 has robust anti-tumor activity in PDX/CDX models and favorable safefy/tolerance in monkeys. Methods: The first-in-human clinical trial is a multi-center, open-label, dose-escalation/expansion study to assess safety, tolerability, preliminary efficacy, pharmacokinetics and immunogenicity of DM005 in advanced solid tumors (NCT06515990). Part 1 (dose escalation): Determine maximum tolerated dose (MTD) and/or the recommended dose for expansion (RDE) via 3+3 dose-escalation algorithm. Part 2 (dose expansion): Evaluate safety, tolerability, efficacy, PK and immunogenicity in 3 cohorts: a) subjects with metastatic or locally advanced EGFR mut NSCLC who have been treated ≥1 prior systemic anticancer therapy. b) subjects with metastatic or locally advanced EGFR wt NSCLC (± other actionable genomic alterations), who have been treated ≥ 1 prior line of systemic anticancer therapy. c) subjects with head and neck squamous cell carcinoma (HNSCC) who have experienced disease progression on or after treatment with 1 or 2 systemic lines, including chemotherapy and immune checkpoint inhibitors. Patient recruitment ongoing in Australia, USA, China. Preliminary data from Part 1 is expected late 2025. Results: The first-in-human clinical trial of DM005 has been successfully initiated, with patient recruitment actively ongoing in Australia, the USA, and China. Building on extensive preclinical studies, DM005 has demonstrated strong anti-tumor activity, a favorable safety profile, and well-tolerated toxicokinetics in animal models, establishing a solid foundation for clinical development. This ongoing multi-center trial is designed to evaluate DM005's safety, pharmacokinetics, and efficacy in patients with advanced solid tumors, with preliminary data from the dose-escalation phase expected by late 2025. Conclusions: DM005, a bispecific ADC targeting EGFR and c-MET, is a promising therapy for advanced solid tumors. With strong preclinical data, this trial marks a milestone in its clinical development. The ongoing study aims to address significant unmet oncology needs and guide future applications. Clinical trial information: NCT06515990 .