Fibroblast activation protein alpha (FAPα) directed imaging and radioligand therapy in patients with solitary fibrous tumor (SFT)

Introduction: FAPα shows high expression levels in several tumor types and novel FAPα-targeted radioligands are emerging in theranostic approaches. Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms with limited therapeutic options in metastatic disease. Here, we report the expression pattern of FAPα in SFT and the potential as theranostic target.

Methods: 19 patients with advanced SFT who received clinical 68Ga-FAPI-46 and 18F-FDG PET/CT between 07/2020 and 02/2022 were enrolled in a prospective observational study. Two blinded nuclear medicine physicians and one radiologist performed independently a lesion-based analysis. Disagreement was resolved by joint consensus read. Standard of reference were follow-up and contrast-enhanced CT scans. Wilcoxon-Test was performed to compare SUVmax/SUVmean and Tumor-to-Background Ratios (TBR; blood pool, liver, muscle). Change in management was determined by pre- and post-imaging questionnaires. 90Y-FAPI-46 radioligand therapy (RLT) was initiated at tumor progression, exhaustion of approved therapies, and high FAP expression (SUVmax ≥ 10 in more than 50% of tumor lesions) under consensus by a local tumor board. Safety, RECIST/PERCIST response and survival were retrospectively evaluated. FAPα protein expression was analyzed in a separate patient cohort by immunohistochemical staining.

Results: In 19 patients, 388 lesions were detected across all imaging modalities. 68Ga-FAPI-46 PET (94.6%) demonstrated highest detection efficacy compared to 18F-FDG PET (67.5%) and contrast-enhanced CT (87.1%). 68Ga-FAPI-46 PET showed significantly higher tumor uptake (SUVmax/SUVmean) (average (SD): 21.7 (25.3)/13.1 (15.5) vs. 4.5 (4.0)/2.8 (2.5); both p<0.001) and TBR (average (SD): TBRbloodpool: 13.7 (17.0) vs. 2.3 (2.3); TBRliver: 21.0 (30.8) vs. 1.9 (1.8); TBRmuscle: 13.0 (15.5) vs. 5.6 (5.8); all p<0.001) when compared to standard 18F-FDG PET. Change in management, i.e. additional surgery, was noted in 3 of 19 patients (15.8%). 11 patients received a total of 34 cycles (median 3 cycles) 90Y-FAPI-46 RLT with a median progression free survival of 403 days. Grade 3 or higher adverse events under RLT were Anemia in n=2 and thrombocytopenia in n=1. Interestingly, in a separate patient cohort we observed FAPα protein expression in 30 of 38 tumor samples (79%) by immunohistochemical staining, which was primarily located on the tumor cell surface.

Conclusions: FAPα is expressed at high levels on SFT. 68Ga-FAPI-46 PET demonstrates superior tumor uptake and detection efficacy compared to 18F-FDG PET or contrast-enhanced CT. Furthermore, we demonstrate feasibility of FAPα-directed radioligand therapy in a case series of SFT.