Interim Results of a Phase I/II Clinical Study to Assess the Safety And Efficacy of Peptide Receptor Radionuclide Therapy with ¹⁷⁷Lu-DOTA-TATE Produced by the N.N. Blokhin National Medical Research Center of Oncology in Patients with Neuroendocrine Neoplasia

Introduction: Peptide-receptor radionuclide therapy (PRRT) is currently a well-studied treatment option for patients with neuroendocrine tumors. Based on the results of the Phase III NETTER-1 and NETTER-2 trials, ¹⁷⁷Lu-DOTA-TATE therapy has become the standard for second- and subsequent-line therapy. However, there are currently no domestic studies investigating PRRT. In our study, we evaluated the efficacy and safety of ¹⁷⁷Lu-DOTA-TATE, a radiopharmaceutical drug synthesized in the cyclotron-radiochemistry laboratory of the Department of Radionuclide Diagnostics and Therapy at the N.N. Blokhin National Medical Research Center of Oncology and having undergone preclinical trials, in patients with neuroendocrine neoplasias (NENs).

Materials and Methods: This phase I/II study enrolled patients with metastatic NENs of various locations with Ki-67 <55 %, progressing despite ≥​​ 2 prior lines of therapy. Patients received 4 cycles of PRRT with the ¹⁷⁷Lu-DOTA-TATE radiopharmaceutical every 8–10 weeks, along with extended-release somatostatin analogs. The primary endpoints were response rate (disease control) of ≥​​ 6 months and safety. Secondary endpoints were objective response rate, progression-free survival (PFS), and overall survival (OS). Patients were enrolled from June 2024 to July 2025. This study analyzes the Įrst 11 patients enrolled in the study.

Results: Eleven patients were included in this analysis. The median age was 54 years. Primary tumor localizations: gastroenteropan‑ creatic (GEP) NEN — 6 patients (54.5 %), pheochromocytomas/paragangliomas — 3 patients (27.3 %), lung NEN and NEN metastases from the esophagus — 1 patient each (9.3 %). Median Ki-67 was 10 % (5–25 %). All patients had previously received everolimus therapy, 9 patients (81.8 %) — chemotherapy. The objective response rate (ORR) was 54.5 %, all responses were partial. Disease stabilization (DS) was recorded in 36.4 %. Disease control (DC) ≥​​ 6 months was noted in 90.9 % of cases. Median PFS and OS with a median follow-up of 11.3 months were not achieved. Grade 3–4 leukopenia was recorded in 2 patients (18.2 %). No decrease in renal function was noted. One serious adverse event associated with disease progression was recorded: pleurisy, requiring thoracentesis for fluid evacuation.

Conclusion: Peptide-receptor radionuclide therapy with ¹⁷⁷Lu-DOTA-TATE, manufactured at the Blokhin National Medical Research Center of Oncology, resulted in high ORR and CFS rates in patients with NEN of various locations. Clinically signiĮcant myelosuppres‑ sion was observed in 18.2 % of cases.

1. Weber WA, Barthel H, Bengel F, et al. What Is Theranostics͍ J Nucl Med. 2023;64(5):669-70. https://doi.org/10.2967/jnumed.123.265670.

2. Taniyama Y, Suzuki T, Mikami Y, et al. Systemic distribution of somatostatin receptor subtypes in human: an immunohisto chemical study. Endocr J. 2005;52(5):605-12. https://doi.org/10.1507/endocrj.52.605.

3. Hennrich U. Kopka K. Lutathera®: The First FDA- and EMAApproved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy. Pharmaceuticals. 2019;12(3):114. https://doi.org/10.3390/ph12030114.

4. Fani M, Good S, Maecke HR. Radiometals (non-Tc, non-re) and bifunctional labeling chemistry. In: Handbook of Nuclear Chemistry. Dordrecht; Heidelberg; London; New York: Spring er (2011). p. 2143. https://doi.org/10.1007/978-1-4419-0720-2_45.

5. Strosberg J, El-Haddad G, Wolin E, et al. NETTER-1 Trial Inves tigators. Phase 3 trial of 177Lu-Dotatate for midgut neuroen docrine tumors. N Engl J Med. 2017; 376(2):125-35. https://doi.org/10.1056/NEJMoa1607427.

6. Strosberg JR, Caplin ME, Kunz PL, et al. NETTER-1 investiga tors. 177Lu-Dotatate plus long-acting octreotide versus highdose long-acting octreotide in patients with midgut neu roendocrine tumours (NETTER-1): Įnal overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(12):1752-63. https://doi.org/10.1016/S1470-2045(21)00572-6.

7. FDA Letter of Approval for LUTATHERAΠ. (accessed on 23 April 2019); Available online: https://www.accessdata.fda.gov/ drugsaƞda_docs/appletter/2018/208700Orig1s000ltr.pdf

8. Naraev BG, Ramirez RA, Kendi AT, et al. Peptide Receptor Ra dionuclide Therapy for Patients with Advanced Lung Carci noids. Lung Cancer. 2019;20(3):376-92. https://doi.org/10.1016/j.cllc.2019.02.007.

9. Evdokimova EV, Artamonova EV, Delektorskaya VV, Chemeris GYu. NET G3: a new subgroup, new approaches. Malignant Tumors. 2021;3s1:16-18. (In Russ.). https://doi.org/10.18027/2224-5057-2021-11-3s1-16-18.

10. Sorbye H, Kong G, Grozinsky-Glasberg S. PRRT in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3). Endocr Relat Cancer. 2020;27(3):67-77. https://doi.org/10.1530/ERC-19-0400.

11. Singh S, Halperin D, Myrehaug S, et al. NETTER-2 Trial Investigators. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, welldifferentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. 2024;403(10446):2807-17. https://doi.org/10.1016/S0140-6736(24)00701-3.

12. Clinical guidelines ͞Neuroendocrine tumors͟, 2025. (In Russ.). https://oncology-association.ru/wp-content/uploads/2025/04/kr-neo-_nejroendokrijnye_nps.pdf

13. Larenkov A, Mitrofanov I, Rakhimov M. Improvement of End-of-Synthesis Radiochemical Purity of 177Lu-DOTA-PS MA-Ligands with Alternative Synthesis Approaches: Conver sion Upswing and Side-Products Minimization. Pharmaceu tics. 2024;16(12),1535. https://doi.org/10.3390/pharmaceutics16121535.

14. Smirnova AV, Grigorieva EYu, Kulbachevskaya NYu, et al. Preclinical evaluation of biodistribution parameters of the domestic radiopharmaceutical 177Lu-DOTA-TATE in the gastrointestinal tract of rats in vivo and ex vivo. In: Proceedings of the 49th session of the Central Research Institute of “Gastroenterology ͞Gastroenterology: Present and Future“,͟ 2023. 2023; 25:55. (In Russ.).