Purpose: Sarcomas are aggressive mesenchymal malignancies with high recurrence rates and poor prognosis, particularly in advanced, metastatic stages where conventional therapies have been exhausted. Fibroblast activation protein (FAP), highly expressed in the tumor microenvironment of sarcomas, presents a promising theranostic target. This study aimed to evaluate the safety and efficacy of ¹⁷⁷Lu-FAPI-2286 radioligand therapy (RLT) in patients with advanced metastatic sarcoma and to compare the diagnostic utility of ⁶⁸Ga-FAPI-46 PET/CT with ¹⁸F-FDG PET/CT in these patients.
Methods: This single-center exploratory study enrolled 6 patients (median age, 29 y) with histologically confirmed treatment-refractory metastatic sarcoma. All patients underwent baseline ⁶⁸Ga-FAPI-46 and ¹⁸F-FDG PET/CT, followed by 2 to 4 cycles of ¹⁷⁷Lu-FAPI-2286 (3.7-7.4 GBq per cycle). Organ-level dosimetry was performed using serial planar and SPECT/CT imaging. Treatment response was evaluated using PET response criteria in solid tumors (PERCIST), and toxicity was graded according to CTCAE v5.0. Quantitative image-derived metrics, including the standardized uptake value (SUV), metabolic tumor volume (MTV), total lesion glycolysis (TLG), FAP expression tumor volume (FTV), total lesion FAP expression (TLF), and tumor-to-liver ratio (TLR) were extracted.
Results: On the basis of the quantitative imaging data from the 6 sarcoma patients, there was no statistically significant difference between ⁶⁸Ga-FAPI-46 and ¹⁸F-FDG across the measured parameters (SUVmean, SUVmax, MTV/FTV, TLG/TLF, and TLR). However, ¹⁸F-FDG showed slightly higher MTVs. RLT was well-tolerated, with no grade ≥3 treatment-related toxicities observed. Adverse events were limited to low-grade hematological toxicities, including grade 2 leukopenia (n=1), grade 1 anemia (n=2), and grade 1 thrombocytopenia (n=1). Among 6 patients, 3 died due to disease progression before follow-up imaging could be completed. Among the 3 evaluable patients, one patient showed a mixed response pattern with metabolic improvement, but volumetric progression [partial response (PR) based on a decrease in SUVmax and SUVmean, progressive disease (PD) based on an increase in FTV, and stable disease (SD) based on minimal change in TLF], another patient showed SD, and the last patient demonstrated PD. The median overall survival was 4 months (95% CI: 0-8.8 mo).
Conclusion: 177Lu-FAPI-2286 RLT was safe, well-tolerated, and demonstrated disease stabilization in heavily pretreated sarcoma patients. 68Ga-FAPI-46 PET/CT provides superior delineation of FAP-rich tumor areas, but smaller tumor volumes compared with 18F-FDG PET/CT. Prospective multicenter studies are warranted to confirm these findings and optimize FAP-targeted theranostic strategies in sarcoma.
