Background Alterations in the epidermal growth factor receptor (EGFR) gene are prevalent in non-small cell lung cancer (NSCLC) patients, accounting for 23% to 30% of activating mutations in NSCLC globally. Despite the initial dramatic tumor growth control with third-generation EGFR tyrosine kinase inhibitors (TKIs), acquired resistance due to spontaneous mutations or activation of signalling pathways is inevitable. Vascular endothelial growth factor (VEGF) and mesenchymal epithelial transition factor (c-Met) signalling pathways are alternative activation pathways to EGFR, which may account for the resistance to EGFR-TKIs. Many gastric, TNBC, and pancreatic cancer subtypes are difficult to treat with diverse aetiologies that are largely driven by abnormal EGFR signalling, increased cMET activation, and VEGF linked angiogenesis which are responsible for tumor growth and metastasis.

Methods and Results In preclinical xenograft models, TAVO412 demonstrated strong tumor growth inhibition effects on NSCLC, GC, PDAC, or TNBC cell line-derived tumors. The mechanisms of action included selective and potent binding to EGFR, cMet, and VEGF at lower pH values found in the solid tumor environment; effective blocking of EGFR and cMet pathways that drove cancer cell growth and proliferation; shutdown of VEGF mediated angiogenesis; and potent and efficacious Fc effector function that enhanced ADCC, ADCP, and CDC. TAVO412 had better TGI than analogous molecules. TAVO412 also demonstrated strong tumor growth inhibition against NSCLC patient derived xenograft (PDX) models with mutant EGFR and cMet genotypes. Each of the binding arms had cross reactivity with the cynomolgus monkey orthologues allowing the cyno model to be a relevant toxicology model. In the pivotal Good Laboratory Practices toxicology study in cynomolgus monkeys, TAVO412 was well tolerated, had no major organ toxicities, observations were mostly consistent with EGFR-related effects and recoverable.

Conclusions TAVO412 was successfully discovered and developed for hard-to-treat solid tumors. This drug is expected to be safe and efficacious in cancer patients. Our studies indicated that, through multiple mechanisms of action, TAVO412 has the potential to prevent or delay resistance when combined with SOCs in treating patients with NSCLC, Gastric cancer, TNBC, PDAC, making it a promising candidate for further clinical development.

Ethics Approval This study was approved by CRADL-Suzhou’s Ethics Board; Ethical number: P202302160002.