RT Journal Article SR Electronic T1 Development of 177Lu‑LNC1010 for Peptide Receptor Radionuclide Therapy in Patients with Metastatic Neuroendocrine Tumors: from preclinical research to First-in-Human, Dose-escalation Study JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 241932 OP 241932 VO 65 IS supplement 2 A1 Guo, Wei A1 Wen, Xuejun A1 Zhao, Tianzhi A1 Fu, Hao A1 Xu, Weizhi A1 Pang, Yizhen A1 Zhao, Liang A1 Xu, Pengfei A1 Guo, Zhide A1 miao, Weibing A1 Zhang, Jingjing A1 Chen, Xiaoyuan A1 Chen, Haojun YR 2024 UL http://jnm.snmjournals.org/content/65/supplement_2/241932.abstract AB 241932 Introduction: Radiolabeled somatostatin analog (SSA) therapy is established for unresectable or metastatic neuroendocrine tumors (NETs). However, A potential disadvantage of 177Lu-DOTATATE is its rapid blood clearance, resulting in relatively short tumor retention. So, through combining Evans blue (EB, albumin binder) and altering the linker we developed an optimized EB-modified radiolabeled SSA, 177Lu-LNC1010. Following preclinical in vitro and in vivo biological evaluation, advanced/metastatic SSTR2-positive NETs.Radiolabeled somatostatin analog (SSA) therapy is established for unresectable or metastatic neuroendocrine tumors (NETs). However, A potential disadvantage of 177Lu-DOTATATE is its rapid blood clearance, resulting in relatively short tumor retention. So, through combining Evans blue (EB, albumin binder) and altering the linker we developed an optimized EB-modified radiolabeled SSA, 177Lu-LNC1010. Following preclinical in vitro and in vivo biological evaluation, advanced/metastatic SSTR2-positive NETs.Methods: LNC1010 was synthesized based on SSTR2-targeting agent and radiolabeled with 177Lu for radioligand therapy. Binding affinity and SSTR2 targeting specificity were verified through cell assays. SPECT imaging and biodistribution studies of 177Lu-LNC1010 was performed to visualize the radioligand distribution in vivo and absolute tumor uptake. This was an open-label, non-randomized, first-in-human, dose-escalation, and investigator-initiated trial (IIT) involving patients with advanced/metastatic SSTR2-positive NETs. Using a 3+3 design, patients underwent a 8-week treatment cycles with 177Lu-LNC1010. Treatment began with 2.22 GBq of 177Lu-LNC1010, with subsequent cohorts receiving an incremental 50% dose increase, which was continued until dose-limiting toxicity (DLT) was observed. The primary objectives were to determine the safety, tolerability, and maximum tolerated dose of 177Lu-LNC1010.Results: High binding affinity of LNC1010 (IC50 = 20.39 nM) for SSTR2 was confirmed in vitro. SPECT imaging and biodistribution studies of 177Lu-LNC1010 demonstrated significantly improved tumor uptake and retention than those of FDA approved 177Lu-DOTATATE. Administration of 177Lu-LNC1010 was well tolerated, with no adverse or life-threatening events in any patients. None of the 3 patients experienced DLT in Group A (low dose, 2.22 GBq/cycle). Grade 4 thrombocytopenia was recorded in one patient in Group B (median dose, 3.33 GBq/cycle); hence, another three patients were enrolled in Group B, and none experienced DLT. Grade 4 hematotoxicities were recorded in two patients in Group C (high dose, 4.99 GBq/cycle). G3 thrombocytopenia was recorded in one patient in Group D (EB-TATE, 3.33 GBq/cycle). G3 hepatotoxicity was observed in two patients from Groups C and D.No nephrotoxicity was observed. The whole-body effective dose (mean ± SD) was 0.17 ± 0.04 mSv/MBq. The study identified 3.3 GBq/cycle as the optimal therapeutic dose for future trials.Although no significant difference in whole-body mean effective dose was observed between 177Lu-LNC1010 and 177Lu-EB-TATE (0.23±0.06 vs. 0.23±0.08 mSv/MBq, P=1.00),177Lu-LNC1010 exhibited higher uptake, prolonged effective half-life, and residence time than that of 177Lu-EB-TATE in most tumor lesions, resulting in 2.7-, 4.0-, and 3.0-fold higher radiation doses in the metastatic lymph nodes, liver, and other metastases than those of 177Lu-EB-TATE, respectively. According to the RECIST criteria, 12 patients treated with 177Lu-LNC1010, partial response, stable disease, and progressive disease were observed in 5 (42%), 5 (42%), and 2 patients (17%), respectively. The objective response rate (ORR) and disease control rate (DCR) were 25% and 83%, respectively.Conclusions: The first-in-human trial with 177Lu-LNC1010 is well tolerated in patients with advanced NETs, with high radiation doses delivered to the tumor lesions. Further investigations through multicenter, prospective, and randomized controlled trials are needed.