EGFR-directed antibodies promote HER2 ADC internalization and efficacy

Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody drug conjugate that has remarkable activity in HER2-positive cancers. However, the degree of benefit of T-DXd is not uniform among solid tumors even with high levels of HER2. Despite high HER2 expression, the HER2/T-DXd complex may not always undergo internalization and payload release dependent on the receptor’s conformation and context. We hypothesize that epidermal growth factor receptor (EGFR), a dimerization partner of HER2, can modulate HER2 trafficking through endocytic pathways and affect T-DXd uptake. We demonstrate that elevated EGFR expression levels can promote EGFR/HER2 heterodimer formation and suppress T-DXd internalization and efficacy. Knockdown of EGFR expression or pharmacologic stimulation of EGFR endocytosis with EGFR monoclonal antibodies restores T-DXd trafficking and antitumor activity in EGFR-overexpressing cancers in vivo . Our results reveal EGFR overexpression to be a potential mechanism of resistance to T-DXd, which can be overcome by combination therapy strategies targeting EGFR. • EGFR expression mediates resistance to the HER2 antibody drug conjugate (ADC) T-DXd • Overexpressed EGFR reduces HER2 homodimerization and HER2/ADC internalization • EGFR monoclonal antibodies (mAbs) restore HER2/ADC trafficking • Addition of EGFR mAbs enhances T-DXd efficacy in multiple cancer types Gupta et al. demonstrate that high EGFR expression mediates resistance to HER2 antibody drug conjugates (ADCs) including trastuzumab deruxtecan (T-DXd) by limiting HER2/ADC internalization. The addition of EGFR monoclonal antibodies enhances the antitumor activity of T-DXd in preclinical models of various tumor types, including KRAS- mutant tumors.