Feasibility, tolerability and response of fractionated radioligand therapies with Bi-213-FAPI46: preliminary experience in 6 patients with end-stage, progressive metastatic tumors

Introduction: FAPI-radioligand therapies (RLT) are a new therapeutic option in progressive metastatic, multiply pre-treated patients. To date, published data refer to initial experiences with the beta-emitters Y-90 and Lu-177-based RLT. However, the short tumor retention time of FAPI ligands is considered a major limitation of FAPI-RLT using these radionuclides. Therefore, fractionated FAPI-RLT with Bi-213, an alpha-emitter markedly shorter half-life of 46 minutes appears a promising FAPI-RLT therapy regimen. Aim of the present study is to gain initial experiences regarding feasibility, tolerability and response of a fractionated Bi-213-FAPI46-RLT.

Methods: 6 patients with progressive metastatic solid tumors (3 colon cancer, 1 anal cancer, 1 breast cancer, 1 prostate cancer) aged 16 - 77 years (4 f, 2 m) were included and received a mean of 1609 MBq Bi-213-FAPI46, fractionated in a total of 52 single applications over up to 107 hours. 4/6 patients received adjuvant treatment with pembrolizumab. F-18-FDG (in 4/6 patients) and Ga-68-FAPI46 PET/CTs (in 5/6 patients) were performed before and after RLT and assessed visually and by metabolic tumor volume (MTV), total lesion glycolysis (TLG) and total lesion FAPI (TLFAPI).

Results: RLT with Bi-213-FAPI46 were well tolerated with no undesirable side effects occurring. In terms of visual response assessment, there was 1 partial response (16.7%), 1 stable disease (16.7%) and 4 patients with progressive disease (66.7%) in the short term. Concordantly, MTV, TLG and TLFAPI were reduced to 86.3, n.a., and 75.7% in the responding patient, similarly (-10.6, -10.6, and -5.9%) in the patient with stable disease and increasing (average +103.6, +104.4, and +321.3%) in the 4 patients with progressive disease.

Conclusions: Fractionated FAPI-RLT with the short half-life alpha emitter Bi-213-FAPI46 is a promising therapeutic approach with better fitting to the pharmacokinetics of FAPI-46 than the Lu-177- or Y-90-labelled compounds. In this pilot project, fractionated Bi-213 FAPI-RLT showed good clinical tolerability and led to regressive or stable disease in short term in 1/3 of the end-stage patients. However, further studies with larger patient cohorts are required in order to evaluate the actual efficacy and long-term effects of this new variant of FAPI-RLT.