Initial clinical experience with <sup>90</sup>Y-FAPI-46 radioligand therapy for advanced stage solid tumors: a case series of nine patients
Justin Ferdinandus, Pedro Fragoso Costa, Lukas Kessler, Manuel Weber, Nader Hirmas, Karina Kostbade, Sebastian Bauer, Martin Schüler, Marit Ahrens, Hans‐Ulrich Schildhaus, Christoph Rischpler, Hong Grafe, Jens T. Siveke, Ken Herrmann, Wolfgang P. Fendler, Rainer Hamacher
Abstract
<b>Introduction:</b> 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 (<sup>68</sup>Ga-FAPI-46) for PET imaging. Here, we report our initial experience in terms of feasibility and safety of <sup>90</sup>Y-labelled FAPI-46 (<sup>90</sup>Y-FAPI-46) for radioligand therapy (RLT) of extensively pretreated patients with solid tumors. <b>Methods:</b> Patients were considered for <sup>90</sup>Y-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 SUV<sub>max</sub> ≥ 10 in more than 50% of all lesions. If tolerated, post-therapeutic <sup>90</sup>Y-FAPI-46 bremsstrahlung scintigraphy was performed to visually confirm systemic distribution and focal tumor uptake, and <sup>90</sup>Y-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. <b>Results:</b> Nine patients with either metastatic soft tissue or bone sarcoma (<i>N</i> = 6) and pancreatic cancer (<i>N</i> = 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 <sup>90</sup>Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient <sup>90</sup>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) 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 (<i>N</i> = 6; 67%), whereas other G3/G4 laboratory-based adverse events were N ≤ 2. No acute toxicities attributed to <sup>90</sup>Y-FAPI-46 were noted. Radiographic disease control was noted in three patients (33 %). <b>Conclusion:</b> FAP-targeted RLT with <sup>90</sup>Y-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 <sup>90</sup>Y-FAPI-46. We observe signs of clinical activity, but further studies are warranted to determine efficacy and toxicity profile in a larger cohort.