Safety, Biodistribution, and Dosimetry of FAP and Integrin α_vβ₃ Dual-Targeting Radioligand ¹⁷⁷Lu-DOTA-FAPI-RGD: Preclinical Validation and First-in-Human Study in Patients with Advanced Adenocarcinomas.

Abstract

Fibroblast activation protein (FAP) and integrin α_vβ₃ are attractive theranostic targets. We developed a dual-targeting radiotheranostic agent, ¹⁷⁷Lu-DOTA-FAPI-RGD (¹⁷⁷Lu-LNC1009), and conducted a first-in-human study to evaluate its safety, biodistribution, dosimetry, and preliminary efficacy in patients with advanced adenocarcinomas. <b>Methods:</b> LNC1009 was synthesized by conjugating an FAP inhibitor, an RGDfK peptide, and DOTA. Preclinical biodistribution was assessed in HT1080-FAP and U87MG xenografts. Nine patients with advanced solid tumors and positive ⁶⁸Ga-FAPI-RGD PET/CT received 2.0 ± 0.3 GBq (range, 1.6-2.4 GBq) of ¹⁷⁷Lu-LNC1009. Primary endpoints included biodistribution, dosimetry, and safety; efficacy was the secondary endpoint. <b>Results:</b> ¹⁷⁷Lu-LNC1009 showed high radiochemical purity and stability, strong dual-target binding, and sustained tumor uptake with favorable tumor-to-background ratios. In patients, treatment was well-tolerated, with no grade 4 adverse events. The whole-body effective dose was 0.08 ± 0.02 mSv/MBq. Mean absorbed doses were 0.04 ± 0.01 Gy/GBq (red marrow), 0.50 ± 0.31 Gy/GBq (liver), and 0.31 ± 0.11 Gy/GBq (kidneys). Tumor-absorbed doses reached 6.10 ± 1.42 Gy/GBq (lung metastases) and 4.20 ± 0.84 Gy/GBq (lymph nodes). Grade 3 adverse events included thrombocytopenia (<i>n</i> = 3), leukopenia (<i>n</i> = 2), and anemia (<i>n</i> = 1). Partial responses occurred in 2 patients (22.2%), stable disease in 6 (66.7%), and progressive disease in 1 (11.1%), yielding an objective response rate of 22.2% and disease control rate of 88.9%. <b>Conclusion:</b> This first-in-human, dual-targeting radiopharmaceutical therapy agent ¹⁷⁷Lu-LNC1009 demonstrated favorable dosimetry, high tumor radiation delivery, and encouraging preliminary efficacy across a variety of advanced solid tumors. Future ligand structural optimization and refined screening protocols are warranted to improve safety and further efficacy in multicycle, tumor-specific dose-escalation trials.