Fibroblast Activation Protein-Directed Imaging Outperforms ¹⁸F-FDG PET/CT in Malignant Mesothelioma: A Prospective,...

The fibroblast activation protein (FAP) is highly expressed in tumor and stromal cells of mesothelioma and thus is an interesting imaging and therapeutic target. Previous data on PET imaging with radiolabeled FAP inhibitors (FAPIs) suggest high potential for superior tumor detection. Here, we report the data of a large malignant pleural mesothelioma cohort within a ⁶⁸Ga-FAPI46 PET observational trial (NCT04571086). Methods: Of 43 eligible patients with suspected or proven malignant mesothelioma, 41 could be included in the data analysis of the ⁶⁸Ga-FAPI46 PET observational trial. All patients underwent ⁶⁸Ga-FAPI46 PET/CT, contrast-enhanced CT, and ¹⁸F-FDG PET/CT. The primary study endpoint was the association of ⁶⁸Ga-FAPI46 PET uptake intensity and histopathologic FAP expression. Furthermore, secondary endpoints were detection rate and sensitivity, specificity, and positive and negative predictive values as compared with ¹⁸F-FDG PET/CT. Datasets were interpreted by 2 masked readers. Results: The primary endpoint was met, and the association between ⁶⁸Ga-FAPI46 SUV_max or SUV_peak and histopathologic FAP expression was significant (SUV_max: r = 0.49, P = 0.037; SUV_peak: r = 0.51, P = 0.030).⁶⁸Ga-FAPI46 and ¹⁸F-FDG showed similar sensitivity by histopathologic validation on a per-patient (100.0% vs. 97.3%) and per region (98.0% vs. 95.9%) basis. Per-region analysis revealed higher ⁶⁸Ga-FAPI46 than ¹⁸F-FDG specificity (81.1% vs. 36.8%) and positive predictive value (87.5% vs. 66.2%). Conclusion: We confirm an association of ⁶⁸Ga-FAPI46 uptake and histopathologic FAP expression in mesothelioma patients. Additionally, we report high sensitivity and superior specificity and positive predictive value for ⁶⁸Ga-FAPI46 versus ¹⁸F-FDG.