177Lu-LNC1004 Radioligand Therapy in Patients with End-Stage Metastatic Cancers: A Single-Center, Single-Arm, Phase II Study

Purpose: Fibroblast activation protein (FAP) is highly expressed in cancer-associated fibroblasts and certain tumor cells, making it a promising therapeutic target for various malignancies. This study evaluated the efficacy and safety of 177Lu-Evans blue-FAP inhibitor (177Lu-EB-FAPI; 177Lu-LNC1004) radioligand therapy (RLT) for treating end-stage metastatic tumors. Patients and Methods: This single-arm, single-center, phase II trial included 28 patients with progressive metastatic malignancies (11 types) and high FAP expression (defined as a maximum standardized uptake value [SUVmax] ≥10 in >50% of tumors) who had exhausted all approved therapies, screened between June 2022 and April 2024. Patients were scheduled to receive four 177Lu-LNC1004 RLT cycles at 3.33 GBq/cycle every 6 weeks. The primary endpoint was post-RLT radiological response. The secondary endpoints were progression-free survival (PFS), overall survival (OS), dosimetry, and safety. Results: Eastern Cooperative Oncology Group scores >2 were observed in 68% of patients. Overall, 63 177Lu-LNC1004 RLT cycles were performed, with 19 (68%) patients undergoing ≥2 cycles. Disease control was achieved in 13 patients [13/28, 46%], with 4 and 9 demonstrating partial response and stable disease, respectively, and associated with improved PFS and OS (P<0.001). The mean absorbed dose in tumors was 4.69±3.83 Gy/GBq (1.18–25.03 Gy/GBq). Treatment-related grade 3/4 hematotoxicity was observed in six patients (21%), with thrombocytopenia, leukopenia, and neutropenia most prevalent. No grade 3/4 hepatotoxicity or nephrotoxicity was observed. Conclusions: FAP-directed RLT using 177Lu-LNC1004 at 3.33 GBq/cycle was well tolerated with an acceptable toxicity profile. Nearly half of patients achieved disease control, which was associated with prolonged PFS and OS.