683P Preclinical evaluation of HLX42, a novel EGFR-targeting ADC, for cetuximab or TKI resistant cancer

EGFR is highly expressed in various tumour types and is a driving force in tumourigenesis and progression. Although anti-EGFR and EGFR TKIs have demonstrated success in cancer treatment, a considerable medical need remains for patients who do not respond to or experience relapse following standard care. EGFR ADCs in clinical evaluation displayed preliminary efficacy, but conventional EGFR ADCs could pose considerable toxicity risks due to the universal expression of EGFR in normal epithelial tissues. HLX42, a next-generation EGFR ADC, is comprised of a highly specific humanized IgG1 anti-EGFR connected to a novel topoisomerase-I inhibitor payload, whose cleavage and release are tumour microenvironment dependent and do not necessitate internalisation of ADC. This distinct mechanism of payload release grants HLX42 a superior therapeutic index compared to its predecessors. HLX42 was examined in antigen binding, internalisation, and plasma stability assays; efficacy analyses were also performed in multiple CDX and PDX models. In vitro evaluations verified that HLX42 possessed a similar binding affinity and internalisation rate as its parental antibody. Additionally, the ADC remained stable in rat and cynomolgus monkey plasma. HLX42 exhibited robust tumour suppression in several CDX and PDX models that were resistant to anti-EGFR or TKIs. In comparison to conventional ADC technologies such as vc-MMAE and GGFG-Dxd, HLX42 displayed superior efficacy and elicited more durable antitumour responses. In the NCI-H1993 model, weekly administration of HLX42 at 8 mg/kg for three times resulted in a 91.5% TGI compared to 79.8% TGI induced by anti-EGFR-GGFG-Dxd. Furthermore, the combination of HLX42 and osimertinib exhibited strong synergy in the LU3075 PDX model which poorly responded to osimertinib alone. In our pilot toxicity studies, HLX42 was well tolerated in rats and non-human primates (severely toxic dose in 10% of animals = 50 mpk in rats; highest non-severely toxic dose = 20 mpk in non-human primates). Taken together, these preclinical data strongly suggest that HLX42 is a potential best-in-class EGFR-targeting ADC which is worth further clinical investigations.