Preclinical data of IBI3028, the first clinical-stage bispecific dual-payload ADC, targeting EGFR/c-MET–positive advanced solid tumors.

e15020 Background: Acquired and intrinsic resistance to topoisomerase-1i ADCs are emerging as key unmet need, driven by heterogeneous target expression, impaired internalization/lysosomal processing, altered DNA damage response, and drug efflux. Dual-payload ADCs are designed to mitigate these escape mechanisms by co-delivering a mechanistically distinct cytotoxin along a Topo1i within a single, tumor-targeted construct. This strategy can broaden intra-tumoral coverage, enhance bystander killing, and reduce reliance on multi-agent combinations. Both EGFR and c-Met are transmembrane tyrosine kinase receptors that play critical roles in tumorigenesis, metastasis, and treatment. Aberrant EGFR activation or overexpression, common in various cancers, drives uncontrolled cell proliferation and tumor progression, while dysregulated c-Met signaling is associated with EGFR-TKI resistance, enhancing tumor invasion and drug resistance through pathway cross-talking. Methods: Aimded at addressing the emerging challenges of Topo1i ADC & EGFR TKI resistance, we developed IBI3028, the first bispecific dual-payload ADC in clinical development, targeting EGFR/c-MET-positive advanced solid tumors. Preclinical efficacy and safety of IBI3028 was comprehensively evaluated via in vitro cytotoxicity, in vitro by-stander, in vivo efficacy, monkey toxicology and PK studies. Results: IBI3028 exhibited superior in vitro cytotoxicity on cancer cell lines with various EGFR/c-Met expression profile. Notably, IBI3028 maintained high efficacy in EGFR-TKI-resistant cell lines. It also showed good in vitro bystander killing effects in the mixture of EGFR/c-Met-positive and EGFR/c-Met-negative cells, due to the cleavable linker design. IBI3028 demonstrated superior efficacy to AZD9592 in xenograft models with varying EGFR/c-Met expression levels. Furthermore, IBI3028 shows good efficacy in Topo1i-resistant model. IBI3028 was well tolerated in GLP-compliant toxicology studies in cynomolgus monkeys. Conclusions: IBI3028 demonstrates outstanding preclinical efficacy and safety profile, and is well positioned as a promising broad-spectrum therapeutic for advanced solid tumors with EGFR/c-MET expression or EGFR/c-Met-driven pathogenesis.