Nectin-4 PET for predicting enfortumab vedotin dose-response in urothelial carcinoma
- Akhilesh Mishra
- Ajay Kumar Sharma
- Kuldeep Gupta
- Dhanush S. Banka
- Burles A. Johnson
- Jean Hoffman-Censits
- Peng Huang
- David J. McConkey
- Sridhar Nimmagadda
2026-01-07
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 noninvasively quantify the real-time interaction of the ADC enfortumab vedotin (EV) with tumors in urothelial carcinoma. Using the imaging agent [ 68 Ga]AJ647, dynamic changes in the interaction of EV with Nectin-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.