Abstract
PURPOSE: This phase I, first-in-human study evaluated the safety, dosimetry, and preliminary efficacy of (177)Lu-FAPI-XT, a novel fibroblast activation protein (FAP)-targeted radioligand, in patients with advanced solid tumors refractory to standard therapies. METHODS: This open-label, non-randomized, dose-escalation, investigator-initiated trial had a "accelerated titration" and "3 + 3" design involved a 6-week (177)Lu-FAPI-XT treatment cycle in patients with advanced-stage solid tumors at 3.7GBq initially, with subsequent cohorts receiving an incremental 1.85GBq dose increase until dose limiting toxicity (DLT) was observed. RESULTS: (177)Lu-FAPI-XT was well tolerated and no DLT or grade ≥ 3 treatment-related adverse events (TRAE) were observed. The whole-body effective dose was 0.039 ± 0.013 Sv/GBq. The mean effective half-lives for the whole-body and tumor lesions were 52.13 ± 12.33 h and 31.78 ± 15.03 h, respectively. According to RECIST stable disease (SD) were observed in 5 (5/14, 35.7%) patients, with the highest benefit observed in fibroblastic sarcoma subtypes with SD presented in 4 (4/8, 50%) patients. The median progression-free survival (PFS) was 4.63 m (95%CI: 1.25, NE). Metabolic reductions on PET/CT were observed in 2 sarcoma cases. (URL: hclinicaltrials.gov . Trial registration: NCT06211647, NCT06197139. Registered 4 January 2024.) CONCLUSION: (177)Lu-FAPI-XT demonstrated a favorable safety profile, with preliminary signs of tumor response observed. Complete/partial response deficiency in (177)Lu-FAPI-XT therapy necessitate optimized strategies for efficacy improvement.