Translational PET Imaging of Nectin-4 Expression in Multiple Different Cancers with ⁶⁸Ga-N188

Nectin cell adhesion molecule 4 (nectin-4) is a transmembrane protein overexpressed on a variety of cancers and plays an important role in oncogenic and metastatic processes. The nectin-4-targeted antibody-drug conjugate enfortumab vedotin has been approved for treating locally advanced or metastatic urothelial cancer, but the efficacy in other types of cancer remains to be explored. The aim of this study was to evaluate the feasibility of nectin-4-targeted PET imaging with ⁶⁸Ga-N188 as a noninvasive method to quantify membranous nectin-4 expression in multiple tumor types-an approach that may provide insight for patient stratification and treatment selection. Methods: Sixty-two patients with 16 types of cancer underwent head-to-head ⁶⁸Ga-N188 and ¹⁸F-FDG PET/CT imaging for initial staging or detection of recurrence and metastases. Correlation between lesion SUV_max and nectin-4 expression determined by immunohistochemistry staining was analyzed in 36 of 62 patients. Results: The SUV_max of ⁶⁸Ga-N188 had a positive correlation with membranous nectin-4 expression in the various tumor types tested (r = 0.458; P = 0.005), whereas no association was observed between the SUV_max and cytoplasmic nectin-4 expression. The detection rates for patient-based analysis of ⁶⁸Ga-N188 and ¹⁸F-FDG PET/CT examinations were comparable (95.00% [57/60] vs. 93.33% [56/60]). In patients with pancreatic cancer, ⁶⁸Ga-N188 exhibited a potential advantage for detecting residual or locally recurrent tumors; this advantage may assist in clinical decision-making. Conclusion: The correlation between nectin-4-targeted ⁶⁸Ga-N188 PET imaging and membranous nectin-4 expression indicates the potential of ⁶⁸Ga-N188 as an effective tool for selecting patients who may benefit from enfortumab vedotin treatment. The PET imaging results provided evidence to explore nectin-4-targeted therapy in a variety of tumors. ⁶⁸Ga-N188 may improve the restaging of pancreatic cancer but requires further evaluation in a powered, prospective setting.