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

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.

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