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Updated: Oct 24, 2025
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Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment
Published on: April 25, 2025
Initial Clinical Experience with 90Y-FAPI-46 Radioligand Therapy for Advanced-Stage Solid Tumors: A Case Series of 9
Justin Ferdinandus1,2, Pedro Fragoso Costa1,2, Lukas Kessler1,2
1Department of Nuclear Medicine, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and Uital Essen, Essen, Germany.
Abstract:
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 (68Ga-FAPI-46) for PET imaging. Here, we report our initial experience of the feasibility and safety of 90Y-FAPI-46 for radioligand therapy of extensively pretreated patients with solid tumors. Methods: Patients were considered for 90Y-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 SUVmax greater than or equal to 10 in more than 50% of all lesions. If tolerated, 90Y-FAPI-46 bremsstrahlung scintigraphy was performed after therapy to confirm systemic distribution and focal tumor uptake, and 90Y-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 90Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient 90Y-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 90Y-FAPI-46 were noted. Radiographic disease control was noted in 4 patients (50%). Conclusion: FAP-targeted radioligand therapy with 90Y-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 90Y-FAPI-46. We observed signs of tumor response, but further studies are warranted to determine efficacy and the toxicity profile in a larger cohort.
Insights
Fibroblast activation protein (FAP) targeted radioligand therapy using 90Y-FAPI-46 shows promise for treating advanced solid tumors. This therapy was well-tolerated with minimal side effects, suggesting potential for repeat treatments.
Area of Science:
- Oncology
- Nuclear Medicine
- Radiopharmaceutical Therapy
Background:
- Fibroblast activation protein (FAP) is overexpressed in various solid tumors, making it a viable target for radiotheranostics.
- Small-molecule FAP inhibitors like 68Ga-FAPI-46 have shown rapid and high uptake for PET imaging.
Purpose of the Study:
- To evaluate the feasibility and safety of 90Y-FAPI-46 for radioligand therapy in heavily pretreated patients with solid tumors.
- To assess the therapeutic potential and toxicity profile of FAP-targeted radioligand therapy.
Main Methods:
- Nine patients with metastatic sarcoma or pancreatic cancer, exhibiting high FAP expression (SUVmax ≥ 10 in >50% of lesions), received 90Y-FAPI-46 therapy.
- Post-therapy scintigraphy and PET scans assessed distribution and absorbed dose; blood-based dosimetry evaluated bone marrow dose.
- Adverse events were graded using Common Terminology Criteria for Adverse Events (version 5.0).
Main Results:
- 78% of patients showed sufficient 90Y-FAPI-46 uptake in tumor lesions.
- Low mean absorbed doses were observed in kidneys (0.52 Gy/GBq), bone marrow (0.04 Gy/GBq), lungs, and liver.
- 44% of patients experienced Grade 3 or 4 laboratory toxicities (thrombocytopenia, anemia); no acute toxicities were directly attributed to the therapy.
- Radiographic disease control was observed in 50% of patients.
Conclusions:
- 90Y-FAPI-46 radioligand therapy is well-tolerated in extensively pretreated patients with solid tumors, with a low incidence of FAP-targeted adverse events.
- Low radiation doses to organs at risk support the feasibility of administering repeat cycles.
- Preliminary signs of tumor response were noted, warranting further investigation into efficacy and toxicity in larger patient cohorts.
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