Initial clinical experience with 90Y-FAPI-46 radioligand therapy for advanced stage solid tumors: a case series of nine patients.

Introduction: 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 in terms of feasibility and safety of 90Y-labelled FAPI-46 (90Y-FAPI-46) for radioligand therapy (RLT) of extensively pretreated patients with solid tumors. Methods: Patients were considered for 90Y-FAPI-46 therapy in case of (a) exhaustion of all approved therapies based on multidisciplinary tumor board decision and (b) high FAP expression, defined as SUVmax ≥ 10 in more than 50% of all lesions. If tolerated, post-therapeutic 90Y-FAPI-46 bremsstrahlung scintigraphy was performed to visually confirm systemic distribution and focal tumor uptake, and 90Y-FAPI-46 PET scans at multiple time-points were performed to determine absorbed dose. Blood-based dosimetry was used to determine bone-marrow absorbed dose. Adverse Events were graded using CTCAE v.5.0. Results: Nine patients with either metastatic soft tissue or bone sarcoma (N = 6) and pancreatic cancer (N = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 (IQR 3.25-5.40) GBq for the first cycle and three patients received subsequent cycles with a median of 7.4 (IQR 7.3-7-5) GBq. Post-therapy 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) in kidney, 0.04 Gy/GBq (IQR 0.03-0.06) in bone marrow and below 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median 1.28 Gy/GBq). Hematologic G3/G4 toxicities were noted in four patients (44%), of which thrombocytopenia was most prevalent (N = 6; 67%), whereas other G3/G4 laboratory-based adverse events were N ≤ 2. No acute toxicities attributed to 90Y-FAPI-46 were noted. Radiographic disease control was noted in three patients (33 %). Conclusion: FAP-targeted RLT with 90Y-FAPI-46 was well tolerated with a low rate of attributable adverse events. Low radiation doses to organs at risk suggest feasibility of repeat cycles of 90Y-FAPI-46. We observe signs of clinical activity, but further studies are warranted to determine efficacy and toxicity profile in a larger cohort.