%0 Journal Article %A Richard P. Baum %A Jingjing Zhang %A Christiane Schuchardt %A Dirk Mueller %A Helmut Maecke %T First-in-human study of novel SSTR antagonist 177Lu-DOTA-LM3 for peptide receptor radionuclide therapy in patients with metastatic neuroendocrine neoplasms: dosimetry, safety and efficacy %D 2021 %R 10.2967/jnumed.120.258889 %J Journal of Nuclear Medicine %P jnumed.120.258889 %X The objective of this study was to assess the safety, dosimetry, 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 metastatic neuroendocrine neoplasms (NENs). Methods: Fifty-one patients (age 27–76, mean 51.6±13.9 years) with metastatic NENs underwent peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-LM3 between August 2017 and December 2019. The median administered activity per cycle was 6.1±0.88 GBq (range 2.8–7.4 GBq). 68Ga-NODAGA-LM3 PET/CT was used for patient selection and follow-up after 177Lu-DOTA-LM3 PRRT. Morphologic and molecular responses were evaluated in accordance with RECIST 1.1 and European Organization for Research and Treatment of Cancer (EORTC) criteria. Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dosimetry was performed in 11 patients and compared with the SSTR agonist 177Lu-DOTATOC in 247 patients undergoing PRRT on the same dosimetry protocol. Results: Higher uptake and a longer effective half-life of 177Lu-DOTA-LM3 was found for whole-body as well as kidneys, spleen, and metastases, resulting in higher mean absorbed organ and tumor doses as compared to the agonist 177Lu-DOTA-TOC. All patients tolerated therapy without any serious acute adverse effects. Mild nausea without vomiting was observed in 5 (9.8%) patients; no other symptoms were reported. The most severe delayed adverse event was CTC-3 thrombocytopenia in 3 (5.9%) patients. Neither CTC-4 thrombocytopenia nor CTC-3-4 anemia or leukopenia was observed after treatment. No significant decline in renal function was observed, nor was hepatotoxicity. According to RECIST 1.1, disease control could be reached in 40 patients (disease control rate, 85.1%) of 47 patients monitored after 177Lu-DOTA-LM3 PRRT, with a partial response in 17 (36.2%) and stable disease in 23 (48.9%), whereas 7 (14.9%) patients had progressive disease, and by EORTC criteria, 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. Conclusion: “Antagonist PRRT” with 177Lu-DOTA-LM3 could be administered without severe adverse effects and was well tolerated by the majority of patients, with thrombocytopenia occurring only in a few patients. No other severe adverse effects were observed, particularly no nephrotoxicity. The SSTR antagonist 177Lu-DOTA-LM3 appears to be very promising for PRRT, provides favorable biodistribution and higher tumor radiation doses than SSTR agonists, and was very effective in treating advanced metastatic NENs, especially in patients with low or no SSTR agonist binding, even achieving complete remission in some patients. %U https://jnm.snmjournals.org/content/jnumed/early/2021/03/05/jnumed.120.258889.full.pdf