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.