[68Ga]Ga-NY104 PET/CT and [18F]FDG PET/CT in patients with metastatic clear cell renal cell carcinoma (NYCRM): A prospective, single-center, single-arm, comparative imaging trial.

PURPOSE: This study aimed to compare the diagnostic performance of CAIX-targeted [68Ga]Ga-NY104 PET/CT versus standard [18F]FDG PET/CT in metastatic clear cell renal cell carcinoma (ccRCC). METHODS: In this prospective single-center trial (NYCRM), 45 patients with histologically confirmed metastatic ccRCC underwent paired [68Ga]Ga-NY104 and [18F]FDG PET/CT scans within 7 days. Lesions were evaluated using a standardized composite reference (histopathology, imaging, and follow-up). Primary endpoints were lesion- and region-level sensitivity/specificity; secondary endpoints included SUVmax, tumor-to-background ratios (TBR), and clinical management impact. RESULTS: Among 682 analyzed lesions, [68Ga]Ga-NY104 demonstrated superior sensitivity (94.4% vs. 78.2%, P < 0.001) and specificity (98.9% vs. 5.5%, P < 0.001) compared to [18F]FDG. Region-level analysis confirmed these findings (sensitivity: 97.0% vs. 82.2%; specificity: 97.5% vs. 10.0%). [68Ga]Ga-NY104 showed higher ccRCC lesion uptake (SUVmax: 12.4 ± 11.8 vs. 7.5 ± 10.7; TBR: 15.3 ± 14.6 vs. 4.7 ± 5.5, both P < 0.001) and lower non-ccRCC uptake (P < 0.001). Notably, [68Ga]Ga-NY104 identified 47 additional metastatic regions in 53% of patients and altered clinical management in 24% (11/45), including treatment intent or modality changes. CONCLUSION: This prospective head-to-head comparison between [68Ga]Ga-NY104 and [18F]FDG PET/CT in 45 patients with metastatic ccRCC shows superior sensitivity and specificity with [68Ga]Ga-NY104 PETCT than with [18F]FDG. It indicates that CAIX-targeting PET should be the PET tracer of choice over [18F]FDG in restaging ccRCC.