First-in-human study of a novel SSTR antagonist177Lu-DOTA-LM3 for peptide receptor radionuclide therapy in patients with advanced metastatic NENs and low SSTR agonist binging

414 Objectives: The objective of this study was to assess the safety and efficacy of the 177Lu-labeled somatostatin receptor (SSTR) antagonist DOTA-p-Cl-Phe-cyclo (D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2 (177Lu-DOTA-LM3) in patients with advanced metastatic neuroendocrine neoplasms (NENs). Methods: Fifty-one patients (age 27-76 y, mean age 51.6 ± 13.9 y) with advanced metastatic NENs underwent peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-LM3 between August 2017 and November 2019. The median administered activity per cycle was 6.1±0.88 GBq (range 2.8-7.4 GBq). 68Ga-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-LM3 (68Ga-NODAGA-LM3) PET/CT was used for patient selection and follow-up after 177Lu-DOTA-LM3 PRRT. Treatment response was evaluated according to RECIST 1.1 as well as by molecular imaging criteria (EORTC). Hematologic status, renal function and liver function were documented before and after therapy. Treatment-related adverse events (AEs) were graded according to the CTCAE v.5.0. Dosimetry was performed in 11 patients.Results: 177Lu-DOTA-LM3 demonstrated high absorbed tumor doses (e.g., liver lesions 15-81 Gy/GBq) as compared to dose levels in normal organs, like kidneys 2.3±0.9 Gy/GBq (0.5-3.6 Gy/GBq) and liver 0.39±0.05 Gy/GBq (0.35-0.44Gy/GBq). All patients tolerated the therapy without any serious acute adverse effects. Mild nausea without vomiting was observed in 5 patients (9.8%), no other symptoms were noticed or reported. The most severe delayed adverse event was CTC-3 thrombocytopenia in 3 (5.9%) patients. No CTC-4 thrombocytopenia and no CTC 3-4 anemia or leukopenia was observed after treatment. There was a statistically significant reduction in leukocyte counts (7.04±2.18 vs 5.81 ± 2.21 Gpt/l, p=0.0066) and platelet counts (232±104 vs 192±70 Gpt/l, p=0.0299), whereas no statistically significant reduction occurred in hemoglobin level (7.74±0.99 vs 7.46±1.00 mmol/l, p=0.1778). No significant decline in renal function was observed (88.17±37.2 vs 87.11±37.91, p=0.8899). No hepatotoxicity was observed. Of 47 patients monitored after 1-2 cycles of 177Lu-DOTA-LM3 PRRT, a molecular response evaluation based on EORTC criteria revealed complete remission in 2 (4.3%), partial remission in 21 (44.7%), stable disease in 18 (38.3%), and progressive disease in 6 (12.8%) patients, and by RECIST, partial remission in 17 (36.2%), stable disease in 23 (48.9%), and progressive disease in 7 (14.9%) patients. In 37 patients there was no or low SSTR2 agonist binging on baseline 68Ga-DOTATOC or DATATATE PET/CT, i.e. insufficient for agonist PRRT with DOTATOC or DOTATATE. Conclusion:The SSTR antagonist 177Lu-DOTA-LM3 appears very promising for PRRT, especially in patients with low or no SSTR agonist binging, achieving even complete remission in some patients. “Antagonist PRRT” could be performed without severe adverse effects, was well tolerated by the majority of patients with thrombocytopenia occurring only in few patients, and was very effective in advanced metastatic NENs. No other adverse effects were observed, especially no renal toxicity.