Initial Clinical Experience with (90)Y-FAPI-46 Radioligand Therapy for Advanced-Stage Solid Tumors: A Case Series of 9 Patients

Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP ((68)Ga-FAPI-46) for PET imaging. Here, we report our initial experience of the feasibility and safety of (90)Y-FAPI-46 for radioligand therapy of extensively pretreated patients with solid tumors. Methods: Patients were considered for (90)Y-FAPI-46 therapy if they showed both an exhaustion of all approved therapies based on multidisciplinary tumor board decision, and high FAP expression, defined as SUV(max) greater than or equal to 10 in more than 50% of all lesions. If tolerated, (90)Y-FAPI-46 bremsstrahlung scintigraphy was performed after therapy to confirm systemic distribution and focal tumor uptake, and (90)Y-FAPI-46 PET scans were performed at multiple time points to determine absorbed dose. Blood-based dosimetry was used to determine bone marrow absorbed dose. Adverse events were graded using Common Terminology Criteria for Adverse Events (version 5.0). Results: Nine patients either with metastatic soft-tissue or bone sarcoma (n = 6) or with pancreatic cancer (n = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 GBq (interquartile range [IQR], 3.25–5.40 GBq) for the first cycle, and 3 patients received subsequent cycles with a median of 7.4 GBq (IQR, 7.3–7.5 GBq). Posttreatment (90)Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient (90)Y-FAPI-46 uptake in tumor lesions in 7 of 9 patients (78%). Mean absorbed dose was 0.52 Gy/GBq (IQR, 0.41–0.65 Gy/GBq) in the kidney, 0.04 Gy/GBq (IQR, 0.03–0.06 Gy/GBq) in bone marrow, and less than 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median, 1.28 Gy/GBq). New laboratory G3 or G4 toxicities were noted in 4 patients (44%, n = 2 patients with thrombocytopenia only, n = 2 patients with new onset of thrombocytopenia and anemia). Other G3 or G4 laboratory-based adverse events occurred in 2 patients or fewer. No acute toxicities attributed to (90)Y-FAPI-46 were noted. Radiographic disease control was noted in 4 patients (50%). Conclusion: FAP-targeted radioligand therapy with (90)Y-FAPI-46 was well tolerated, with a low rate of attributable adverse events. Low radiation doses to at-risk organs suggest feasibility of repeat cycles of (90)Y-FAPI-46. We observed signs of tumor response, but further studies are warranted to determine efficacy and the toxicity profile in a larger cohort.