Fibroblast Activation Protein-Targeted Radiopharmaceutical Therapy Using ¹⁷⁷Lu-, ⁹⁰Y-, and ²²⁵Ac-Labeled 3BP-3940:...

Fibroblast activation protein (FAP) is an attractive target for molecular precision imaging and therapy, given its specific tumor expression across various cancer types. We report first-in-human results using a FAP-targeted cyclic peptide, 3BP-3940, labeled with ¹⁷⁷Lu, ⁹⁰Y, and ²²⁵Ac for FAP-targeted radiopharmaceutical therapy (FRT) in patients with end-stage cancer. Methods: Eighty-eight patients with 21 distinct advanced metastatic solid tumor types received 227 cycles of ¹⁷⁷Lu-, ⁹⁰Y-, ²²⁵Ac-labeled 3BP-3940, either alone or as tandem treatment, FRT between March 2021 and January 2025, after confirmation of tumor uptake by [⁶⁸Ga]Ga-3BP-3940 PET/CT. Toxicity was graded using Common Terminology Criteria for Adverse Events version 5.0. Treatment response was assessed, and survival from treatment initiation was calculated using Kaplan-Meier analysis. Results: Administrations of [¹⁷⁷Lu]Lu-, [⁹⁰Y]Y-, and [²²⁵Ac]Ac-3BP-3940 were well tolerated, and most adverse events were mild (pain 16%, pain flare 13%, nausea 13%, vomiting 7%, partial alopecia 8%, intensified fatigue 5%, diarrhea 3%, headache 2%, and transient fever 5%). No other clinically relevant adverse symptoms or pharmacologic effects were reported. Dosimetry in a patient with pancreatic cancer receiving 9.73 GBq of [¹⁷⁷Lu]Lu-3BP-3940 showed absorbed doses of 37 mGy in the brain, 168 mGy in the lungs, 86 mGy in healthy liver tissue, 142 mGy in the pancreas, 265 mGy in the kidneys, and 2200 mGy for the primary tumor. Some patients underwent additional treatments as their standard of care. After 2 cycles of FRT, tumor responses were complete remission (3.0%), partial remission (51.5%), stable disease (15.2%), and progressive disease (30.3%). The best tumor response observed after any FRT cycle was 2 of 51 (3.9%) with complete remission, 32 of 51 (62.7%) with partial remission, 7 of 51 (13.7%) with stable disease, 8 of 51 (15.7%) with progressive disease, and 2 of 51 (3.9%) with a mixed response, yielding an objective response rate of 66.7% and a disease control rate of 80.4%. For the entire cohort, median overall survival was 7.0 mo from FRT initiation. Conclusion: 3BP-3940 FRT is feasible with ¹⁷⁷Lu, ⁹⁰Y, or ²²⁵Ac alone or as tandem treatment for patients with end-stage cancer. Treatments were relatively well tolerated without serious adverse effects. 3BP-3940 FRT demonstrated favorable biodistribution (exceptionally very low renal accumulation), significant tumor uptake, and long retention with very high tumor-to-background ratios, demonstrating objective responses in advanced, aggressive, and heavily pretreated metastatic adenocarcinomas and sarcomas. The observed survival benefit appears to be highly promising. Further prospective randomized analysis in a larger cohort with longer follow-up is warranted.