⁶⁸Ga-FAPI as a Diagnostic Tool in Sarcoma: Data from the ⁶⁸Ga-FAPI PET Prospective Observational Trial

Bone and soft-tissue sarcomas express fibroblast activation protein (FAP) on tumor cells and associated fibroblasts. Therefore, FAP is a promising therapeutic and diagnostic target. Novel radiolabeled FAP inhibitors (e.g., ⁶⁸Ga-FAPI-46) have shown high tumor uptake on PET in sarcoma patients. Here, we report the endpoints of the ⁶⁸Ga-FAPI PET prospective observational trial. Methods: Forty-seven patients with bone or soft-tissue sarcomas undergoing clinical ⁶⁸Ga-FAPI PET were eligible for enrollment into the ⁶⁸Ga-FAPI PET observational trial. Of these patients, 43 also underwent ¹⁸F-FDG PET. The primary study endpoint was the association between ⁶⁸Ga-FAPI PET uptake intensity and histopathologic FAP expression analyzed with Spearman r correlation. Secondary endpoints were detection rate, positive predictive value (PPV), interreader reproducibility, and change in management. Datasets were interpreted by 2 masked readers. Results: The primary endpoint was met, and the association between ⁶⁸Ga-FAPI PET uptake intensity and histopathologic FAP expression was significant (Spearman r = 0.43; P = 0.03). By histopathologic validation, PPV was 1.00 (95% CI, 0.87-1.00) on a per-patient and 0.97 (95% CI, 0.84-1.00) on a per-region basis. In cases with histopathologic validation, 27 of 28 (96%) confirmed patients and 32 of 34 (94%) confirmed regions were PET-positive, resulting in an SE of 0.96 (95% CI, 0.82-1.00) on a per-patient and 0.94 (95% CI, 0.80-0.99) on a per-region basis. The detection rate on a per-patient basis in ⁶⁸Ga-FAPI and ¹⁸F-FDG PET was 76.6% and 81.4%, respectively. In 8 (18.6%) patients, ⁶⁸Ga-FAPI PET resulted in an upstaging compared with ¹⁸F-FDG PET. ⁶⁸Ga-FAPI PET readers showed substantial to almost perfect agreement for the defined regions (Fleiss κ: primary κ = 0.78, local nodal κ = 0.54, distant nodal κ = 0.91, lung κ = 0.86, bone κ = 0.69, and other κ = 0.65). Clinical management changed in 13 (30%) patients after ⁶⁸Ga-FAPI PET. Conclusion: We confirm an association between tumoral ⁶⁸Ga-FAPI PET uptake intensity and histopathologic FAP expression in sarcoma patients. Further, with masked readings and independent histopathologic validation, ⁶⁸Ga-FAPI PET had a high PPV and sensitivity for sarcoma staging.