First-in-Humans Study of the SSTR Antagonist ¹⁷⁷Lu-DOTA-LM3 for Peptide Receptor Radionuclide Therapy in Patients with Metastatic Neuroendocrine Neoplasms: Dosimetry, Safety, and Efficacy

Abstract

The objective of this study was to assess the safety, dosimetry, and efficacy of the 177 Lu-labeled somatostatin receptor (SSTR) antagonist DOTA-p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys) D-Tyr-NH 2 ( 177 Lu-DOTA-LM3) in patients with metastatic neuroendocrine neoplasms (NENs). Methods: Fifty-one patients (aged 27-76 y; mean, 51.6 6 13.9 y) with metastatic NENs underwent peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTA-LM3 between August 2017 and December 2019. The median administered activity per cycle was 6.1 6 0.88 GBq (range, 2.8-7.4 GBq). 68 Ga-NODAGA-LM3 PET/CT was used for patient selection and follow-up after 177 Lu-DOTA-LM3 PRRT. Morphologic and molecular responses were evaluated in accordance with RECIST 1.1 and the criteria of the European Organisation for Research and Treatment of Cancer (EORTC). Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dosimetry was performed on 11 patients and compared with the SSTR agonist 177 Lu-DOTATOC in 247 patients undergoing PRRT on the same dosimetry protocol. Results: Higher uptake and a longer effective half-life were found for 177 Lu-DOTA-LM3 than for the agonist 177 Lu-DOTATOC in the whole body and in the kidneys, spleen, and metastases, resulting in higher mean absorbed organ and tumor doses. 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 Common Terminology Criteria (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 the 47 patients monitored after 177 Lu-DOTA-LM3 PRRT, with a partial response in 17 (36.2%) and stable disease in 23 (48.9%), whereas 7 patients (14.9%) had progressive disease, and by EORTC criteria, there was complete remission in 2 patients (4.3%), partial remission in 21 (44.7%), stable disease in 18 (38.3%), and progressive disease in 6 (12.8%). Conclusion: The antagonist