Prognostic Value of Fibroblast Activation Protein–Directed PET Imaging in Pleural Mesothelioma

High expression of fibroblast activation protein (FAP) has been associated with inferior survival in several tumor entities. Novel ⁶⁸Ga-radiolabeled FAP inhibitors (⁶⁸Ga-FAPIs) allow noninvasive measurement of FAP, which enables the development of prognostic imaging parameters from ⁶⁸Ga-FAPI PET/CT. In this study, we compared the prognostic value of ⁶⁸Ga-FAPI-46 with ¹⁸F-FDG PET in a cohort of patients with malignant pleural mesothelioma from the FAPI PET observational trial (NCT04571086). <b>Methods:</b> Between May 2020 and January 2024, 49 patients with suspected or proven malignant mesothelioma were recruited, 39 of whom were eligible for data analysis. All patients underwent ⁶⁸Ga-FAPI-46 and ¹⁸F-FDG PET/CT less than 4 wk apart. Tumor burden was measured semiautomatically, and SUV_max, SUV_mean, and volumetric parameters (metabolic tumor volume [MTV], total lesion glycolysis/total lesion fibroblast activation, and total tumor SUV) were calculated. The FAP immunoreactive score (IRS) was calculated for tumor samples from a subset of patients (<i>n</i> = 19). Overall survival and progression-free survival were assessed per revised mRECIST (version 1.1). Survival analyses were performed with univariate and multivariate Cox regression and with Kaplan-Meier curves for clinical and imaging parameters, stratified by median. <b>Results:</b> Univariate analysis showed significant survival differences for all volumetric parameters for ⁶⁸Ga-FAPI-46 and ¹⁸F-FDG (e.g., ⁶⁸Ga-FAPI-46 MTV, 262 d vs. 737 d; <i>P</i> = 0.008 vs. ¹⁸F-FDG MTV, 336 d vs. 760 d; <i>P</i> = 0.012). Multivariate analysis revealed that MTV was an independent prognostic marker for ⁶⁸Ga-FAPI-46 (hazard ratio, 4.44; 95% CI, 1.20-16.43; <i>P</i> = 0.025) and ¹⁸F-FDG (hazard ratio, 7.01; 95% CI, 1.29-38.2; <i>P</i> = 0.024). Kaplan-Meier analysis of the FAP IRS found that a higher IRS was associated with poorer survival (438 d with an IRS of 0-3 vs. 1,076 d with an IRS of 4-12; <i>P</i> = 0.04), but no significant difference was observed in univariate and multivariate analyses. <b>Conclusion:</b> In this modest exploratory cohort of patients with malignant pleural mesothelioma, MTV determined by ⁶⁸Ga-FAPI-46 and ¹⁸F-FDG PET/CT had similar prognostic value, and high MTV was an independent risk factor. ⁶⁸Ga-FAPI-46 not only complements a diagnostic work-up but also provides prognostic value and could offer alternative theranostic strategies for these patients.