Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the 
standard-of-care treatment for EGFR-mutant non-small cell lung cancers (NSCLC). 
However, most patients develop acquired drug resistance to EGFR TKIs. HER3 is a 
unique pseudokinase member of the ERBB family that functions by dimerizing with 
other ERBB family members (EGFR and HER2) and is frequently overexpressed in 
EGFR-mutant NSCLC. Although EGFR TKI resistance mechanisms do not lead to 
alterations in HER3, we hypothesized that targeting HER3 might improve efficacy 
of EGFR TKI. HER3-DXd is an antibody-drug conjugate (ADC) comprised of 
HER3-targeting antibody linked to a topoisomerase I inhibitor currently in 
clinical development. In this study, we evaluated the efficacy of HER3-DXd 
across a series of EGFR inhibitor-resistant, patient-derived xenografts and 
observed it to be broadly effective in HER3-expressing cancers. We further 
developed a preclinical strategy to enhance the efficacy of HER3-DXd through 
osimertinib pretreatment, which increased membrane expression of HER3 and led to 
enhanced internalization and efficacy of HER3-DXd. The combination of 
osimertinib and HER3-DXd may be an effective treatment approach and should be 
evaluated in future clinical trials in EGFR-mutant NSCLC patients. SIGNIFICANCE: 
EGFR inhibition leads to increased HER3 membrane expression and promotes 
HER3-DXd ADC internalization and efficacy, supporting the clinical development 
of the EGFR inhibitor/HER3-DXd combination in EGFR-mutant lung cancer.See 
related commentary by Lim et al., p. 18.