Nectin-4 PET for predicting enfortumab vedotin dose-response in urothelial carcinoma

Optimizing dosing strategies is critical to balance effectiveness and
toxicity, especially for drugs with narrow therapeutic windows such as
antibody-drug conjugates (ADCs). This study evaluates whether positron
emission tomography (PET) imaging targeting Nectin-4 can non-invasively
quantify the real-time interaction of the ADC enfortumab vedotin (EV) with
tumors in urothelial carcinoma (UC). Using the imaging agent [68Ga]AJ647,
dynamic changes in interaction of EV with Necin-4 were measured across
preclinical models and correlated with therapeutic responses. PET imaging
identified dose-dependent variations in Nectin-4 engagement, with
suboptimal EV doses resulting in incomplete Nectin-4 engagement and
increased tumor growth. Crucially, PET measured target engagement
predicted therapeutic outcomes more reliably than either drug dose or
baseline target expression. By defining effective target engagement levels
needed for optimal therapeutic outcomes, PET imaging provides a clear
benchmark for dosing decisions, maximizing efficacy while potentially
reducing exposure to higher, toxic doses and thereby enhancing patient
safety.