Feasibility, Biodistribution, and Preliminary Dosimetry in Peptide-Targeted Radionuclide Therapy of Diverse Adenocarcinomas Using ¹⁷⁷Lu-FAP-2286: First-in-Humans Results

Abstract

Fibroblast activation protein (FAP) is a promising target for diagnosis and therapy of numerous malignant tumors. FAP-2286 is the conjugate of a FAP-binding peptide, which can be labeled with radionuclides for theranostic applications. We present the first-in-human results using 177 Lu-FAP-2286 for peptide-targeted radionuclide therapy (PTRT). Methods: PTRT using 177 Lu-FAP-2286 was performed in 11 patients with advanced adenocarcinomas of pancreas, breast, rectum and ovary after prior confirmation of uptake on 68 Ga-FAP-2286/-FAPI-04-PET/CT.Results: Administration of 177 Lu-FAP-2286 (5.8 ± 2.0 GBq; range, 2.4-9.9 GBq) was well tolerated, with no adverse symptoms or clinically detectable pharmacologic effects being noticed or reported in any of the patients. The whole-body effective doses were 0.07 ± 0.02 Gy/GBq (range 0.04 -0.1). The mean absorbed doses for kidneys and red marrow were 1.0 ± 0.6 Gy/GBq (range 0.4 -2.0) and 0.05 ± 0.02 Gy/GBq (range 0.03 -0.09), respectively. Significant uptake and long tumor retention of 177 Lu-FAP-2286 resulted in high absorbed tumor doses, e.g., 3.0 ± 2.7 Gy/GBq (range 0.5 -10.6) in bone metastases. No grade (G) 4 adverse events were observed. G3 events occurred in 3 patients -1 pancytopenia, 1 leukocytopenia and 1 pain flareup; 3 patients reported pain-response. Conclusions: 177 Lu-FAP-2286 PTRT, applied in a broad spectrum of cancers, was relatively well-tolerated with acceptable side effects and demonstrated long retention of the radiopeptide. Prospective clinical studies are warranted.

Potential Targets Other Than PSMA for Prostate Cancer Theranostics: A Systematic Review

“…They are believed to be sufficiently overexpressed in CRPC to perform RLT [ 68 ]. RLT with FAPis have recently been tested in humans but not in PCa [ 71 ]. Further specific studies reporting radiolabeled FAPis interest in PCa for diagnosis or therapy are needed.…”

Fibroblast-Activated Protein Inhibitor PET/CT: Cancer Diagnosis and Management

“…Therefore, further research is necessary to optimize the therapeutic efficacy and determine the safety of high-dose radionuclide treatments. Baum et al (29) reported comparable estimated radiation dose to critical organs using 177 Lu-labeled FAP-2286; however, a higher radiation dose to tumoral lesions was achieved, justifying further investigation.…”

“…Baum et al. ( 29 ) reported comparable estimated radiation dose to critical organs using 177 Lu-labeled FAP-2286; however, a higher radiation dose to tumoral lesions was achieved, justifying further investigation.…”

“…Baum et al. ( 29 ) studied FAP-2286 and administered 177 Lu-labeled FAP-2286 to 10 patients with pancreas, breast, ovarian, and rectal cancers. Although a treatment response was not achieved, the authors concluded the reasonable toxicity profile with well-tolerated adverse effects.…”

Radioligands Targeting Fibroblast Activation Protein (FAP)

“…Additionally, G3 hematological side effects were reported, although 177 Lu-dosimetry data showed low red marrow exposure, while the doses delivered to the kidneys were comparable to 177 Lu-PSMA-617. After 6–8 weeks after the first therapy cycle, two out of 11 patients showed stable disease, of which one progressed 8 weeks after the third treatment cycle [ 45 ].…”