Methods of treating cancer

Abstract

The present disclosure relates to a method of treating highly differentiated G2 or G3 neuroendocrine neoplasms (NET) in a patient in need thereof, the method comprising administering to the patient a treatment of a radioligand therapy (RLT) agent comprising a therapeutically effective dose of a targeted somatostatin receptor (SSTR), in particular [177Lu] Lu-DOTA0-Tyr3-octoic acid, as a first-tier therapy.

Description

Technical Field

[0001] This disclosure relates to methods for treating well-differentiated G2 or G3 neuroendocrine tumors (NETs) in patients in need, including treatment with a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as a first-line therapy. Background Technology

[0002] Neuroendocrine tumors (NETs) are rare malignancies that can occur throughout the body and account for approximately 1% of all human tumors. NETs have been classified according to their embryonic origin as foregut, midgut, or hindgut NETs. The World Health Organization (WHO) staging system classifies gastrointestinal pancreatic NETs (GEP-NETs) based on the location, size, mitotic activity, invasiveness, and functional status of the primary tumor (Klöppel, 2011). Despite some common morphological and immunohistochemical features, significant heterogeneity exists in prognosis and treatment strategies based on primary site, histological differentiation (poor or high differentiation), and stage. Histological differentiation and proliferative activity are the strongest predictors of survival. In terms of site of origin, the majority (50%–70%) of NETs diagnosed in Western countries are gastrointestinal NETs (Modlin, Lye, and Kidd, 2003). Of the 270 cases of NETs originating in the midgut or hindgut, 62% (5-year survival rate (YSR), 95.2%) were grade 1, 32% (5-YSR, 82.0%) were grade 2, and 6% (5-YSR, 51.4%) were grade 3 NETs (Jann et al., 2011). It has been reported that 50%–70% of NETs of unknown origin are highly differentiated (Catena et al., 2011) and exhibit similar behavior and prognosis to midgut NETs (Kirshbom, Kherani, Onaitis, Feldman, and Tyler, 1998).

[0003] Surgical resection of both primary and metastatic lesions remains the primary treatment and the only way to achieve a cure. However, resection is often not possible because NETs are frequently detected in later stages of the tumor (Yao et al., 2008).

[0004] In patients with inoperable NETs, ​​the treatment goals are to prolong survival, improve and maintain quality of life, control tumor growth, and control secretory symptoms (if the tumor is functional). Somatostatin analogues (SSAs) such as long-acting octreotide 30 mg (Sandostatin) are effective treatments. ® LAR ® ) or lanreotide ATG 120 mg (somatine)® Depot or Somatoline ® AUTOGEL ® ( ) has become the main treatment for patients with low or intermediate GEP-NET.

[0005] In the PROMID study, the time to disease progression (TTP) in 42 patients with metastatic midgut NETs treated with long-acting octreotide 30 mg / month was more than twice that in 43 patients treated with placebo (14.3 months vs. 6.0 months; P = 0.000072). Overall, 67% of patients treated with long-acting octreotide achieved disease stability, compared to 37% of patients treated with placebo (Rinke et al., 2009). In the CLARINET study, progression-free survival (PFS) was significantly prolonged in G1-2 midgut and pancreatic NETs treated with lanreotide 120 mg / month compared to placebo (median PFS not reached vs. 18.0 months, P < 0.001; HR for progression or death with lanreotide vs. placebo, 0.47; 95% CI 0.30 to 0.73) (Caplin et al., 2014).

[0006] When approved, the dose of long-acting octreotide for the treatment of advanced midgut NET is 30 mg / month. Higher doses of octreotide, up to 120 mg / month, have been used for symptom control in patients who no longer respond adequately to standard doses. Higher doses have also been used for tumor control, although controlled studies are lacking (Broder, Beenhouwer, Strosberg, Neary, and Cherepanov, 2015). Three studies have investigated the antiproliferative efficacy of high-dose long-acting octreotide (up to 160 mg / 2 weeks) or lanreotide (up to 15 mg / day), showing stable disease in 37%–75% of patients with advanced midgut carcinoid and / or metastatic GEP-NET (Eriksson, Renstrup, Imam, and Oberg, 1997; Faiss et al., 1999; Welin et al., 2004).

[0007] Furthermore, retrospective analyses have shown that higher doses of octreotide can delay the time to tumor progression / other types of intervention (Lau, Abdel-Rahman and Cheung, 2018; Chadha et al., 2009). In small (n = 28) consecutive studies, increased frequency of somatostatin analogue administration led to delays in both the time to tumor progression and the time to biochemical progression (Ferolla et al., 2012).

[0008] In patients with disease progression, mTOR therapy (everolimus), tyrosine kinase inhibitors (sunitinib), and peptide radionuclide receptor therapy (PRRT) offer treatment options (Yao et al., 2010; Yao et al., 2011; Pavel et al., 2011; Yao et al., 2016; Kwekkeboom and Krenning, Peptide Receptor Radionuclide Therapy in the Treatment of Neuroendocrine Tumors, 2016). There is currently no widely accepted standard chemotherapy for the treatment of NET. Combinations of streptozotocin and 5-fluorouracil or doxorubicin are frequently used in patients with well-differentiated pancreatic NET (PNET) and those with inoperable progressive liver metastases, but there is no strong evidence to support the use of chemotherapy in patients with NET of other origins (Pavel et al., 2012).

[0009] Within the neuroendocrine tumor (NEN) G3 group, the distinction between NET G3 and neuroendocrine carcinoma (NEC) G3 is clinically significant. NET G3 and NEC are characterized by a significant difference in the Ki67 index (tumors with a Ki67 index between 20% and 55% are less aggressive compared to tumors with a Ki67 index greater than 55%). While platinum-based chemotherapy is effective in NEC, its value appears limited in NET G3. Treatments established for NET G2, such as temozolomide chemotherapy or PRRT, may be considered for the treatment of NET G3 (Rinke 2017).

[0010] Since 1992, tumor-targeted peptide receptor radionuclide therapy (PRRT) for tumors expressing somatostatin receptors has been in clinical evaluation. The biological basis of radionuclide receptor imaging and receptor-targeted radionuclide therapy lies in the receptor-mediated internalization and intracellular retention of radiolabeled somatostatin analogs. Because the receptor density is higher in tumor tissues than in non-tumor tissues (Reubi, Waser, Schaer, and Laissue, 2001; Reubi JC, 2003), and because the sst2 receptor is internalized into cells after ligand binding, it is an attractive target for PRRT. Therefore, upon binding to the sst2 receptor, radioactivity delivered by radiolabeled peptides is trapped in target cells (Reubi et al., 2000).

[0011] 177 Lu-DOTA 0 -Tyr3 -Octreotate ( 177 Lu-Dotatate, Lutathera ® It consists of DOTA, a somatostatin peptide analogue coupled to the metal ion chelating portion, and is used with 177 Lu radioactive labeling. 177 Lu-DOTA 0 -Tyr 3 Octreotide binds to somatostatin receptors with high affinity, and when it binds to... 177 Lu retains its binding properties and physiological functions when compounded. 177 Lu emits low to medium energy beta particles, E max It has a voltage of 0.5 MeV and a tissue penetration range of up to 2 mm. 177 The relatively short penetration range of Lu β leaves more radiation dose in the tumor and less damage to surrounding tissues.

[0012] Radiolabeled 177 Lu-DOTA 0 -Tyr 3 Octrenic acid is rapidly eliminated from circulation via urine, giving this radiopharmaceutical an advantage over other methods, such as cell-targeted radiolabeled antibodies.

[0013] because 177 Lu-DOTA 0 -Tyr 3 The mechanism of action of octreotate involves some radioactive retention in the kidneys, but the co-administration of amino acids such as lysine and arginine reduces renal uptake of radioactivity without altering tumor uptake (Kwekkeboom et al., 2001; Strosberg et al., 2017). This protective effect mediated by the co-infusion of lysine and arginine solutions occurs through a mechanism that “blocks” the renal tubular uptake of proteins or peptides (Hammond et al., 1993; Rolleman, Valkema, Jong, Kooij, and Krenning, 2003). Co-administration of a 2.5% lysine and arginine (Lys-Arg) amino acid solution resulted in approximately 33% inhibition of renal radioactive uptake over 24 hours and was better tolerated compared to commercially available amino acid solutions, particularly in terms of nausea and vomiting, due to the higher osmolarity of the more complexly formulated commercially available AA solutions (Rolleman, Valkema, Jong, Kooij and Krenning, 2003; Kwekkeboom et al., 2008).

[0014] Common side effects of Lutathera include lymphopenia, elevated GGT, AST, and / or ALT, vomiting, nausea, hyperglycemia, and hypokalemia. Serious side effects of Lutathera include myelosuppression, secondary myelodysplastic syndrome and leukemia, nephrotoxicity, hepatotoxicity, neuroendocrine hormone crisis, and infertility.

[0015] Lutathera (lutetium ( 177 Lu) oxodotreotide) was approved in Europe on September 26, 2017 for the treatment of unresectable or metastatic, progressive, well-differentiated (G1 and G2) GEP-NET, and in the United States on January 26, 2018 for the treatment of somatostatin receptor-positive GEP-NET.

[0016] The approval of Lutathera was supported by the following two studies:

[0017] The first was the phase III NETTER-1 study sponsored by Advanced Accelerator Applications. This was a multicenter, stratified, open, randomized, comparative, controlled, parallel-group study that compared, in patients with inoperable, somatostatin receptor-positive, histologically confirmed midgut carcinoid tumors that had progressed on long-acting octreotide, 177 Lu-DOTA 0 -Tyr 3 -octreotate (Lutathera, lutetium Lu 177 dotatate) plus best supportive care (30 mg long-acting octreotide) with treatment with high-dose (60 mg) long-acting octreotide (Strosberg et al., 2017; Strosberg et al., 2018). A significant improvement in the primary endpoint of PFS was confirmed. There were 21 confirmed events (disease progression or death without confirmed progression according to central RECIST 1.1 assessment) in the Lutathera group, compared with 70 events in the 60 mg long-acting octreotide group. The median PFS in the control group was 8.5 months, while the median PFS in the Lutathera group was not reached. The improvement in median PFS in the Lutathera group was statistically significant, with a hazard ratio of 0.18 (95% CI, 0.11 - 0.29), indicating a 79% reduction in the risk of progression or death events when treated with Lutathera compared with 60 mg long-acting octreotide.

[0018] The second study was based on data from 1,214 patients with somatostatin receptor-positive tumors (including GEP-NETS) who received Lutathera at Erasmus Medical Centre in the Netherlands (Kwekkeboom et al., 2008; Brabander et al., Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. [[177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors], 2017a). 39% of patients reported complete or partial tumor remission.

[0019] On June 2, 2016, NETSPOT, an advanced accelerator applications company... ™ (68Ga-Dotatate) received FDA approval, and on December 15, 2016, Lutathera's diagnostic companion product, Somakit-TOC... ™ (68Ga-Dotatoc) has received marketing authorization from the European Commission.

[0020] Neuroendocrine tumors (NETs) are rare in childhood. The incidence is low in children and adolescents under 30 years of age, at 2.8 per million. Despite the low incidence, NETs represent the most common gastrointestinal tumors in children (Howell and O'Dorisio, 2012). Currently, all treatments approved for GEP-NETs are only available for adults. Summary of the Invention

[0021] The pivotal Phase III NETTER-1 study demonstrated that Lutathera with optimal supportive care (30 mg long-acting octreotide) provided a significant increase in PFS (at enrollment) in patients with progressive midgut carcinoid tumors compared to those treated with a high dose (60 mg) of long-acting octreotide. The NETTER-1 patient cohort included 34.5% of G2 NET patients (65.5% G1), while G3 NET patients were excluded. Eligibility was limited to patients who progressed with SSA (second-line therapy); patients who had not received SSA were excluded.

[0022] The objective of the NETTER-2 study, which is relevant to this invention, is to determine whether the combination of Lutathera and long-acting octreotide as first-line therapy prolongs progression-free survival (PFS) in patients with GEP-NET tumors (G2 and G3) with high-dose (60 mg) long-acting octreotide compared to high-dose (60 mg) long-acting octreotide. Eligible patients include those who have not previously received SSA therapy and those who have previously received SSA therapy but have not experienced progression. Based on extensive experience with Lutathera and octreotide LAR in adult GEP-NET patients, and the relevance of the molecular target in adolescent GEP-NET patients, this study will be open to adolescents aged ≥ 15 years and weighing (BW) > 40 kg; younger patients are not expected to have disease meeting the severity criteria for this trial. Due to the rarity of the disease, particularly GEP-NET with severity assessed in this study, a minimum number of adolescent patients is not required. The study has been opened to adolescents to ensure that their participation is not unnecessarily excluded.

[0023] In addition, in the NETTER-2 study, any patient with progression-related disease in the high-dose long-acting octreotide group (if eligible) could choose to participate in post-progression Lutathera crossover therapy.

[0024] In addition, patients in the Lutathera group who experience disease progression after receiving and benefiting from 4 doses / cycles of initial treatment (if eligible according to the criteria below) may choose to participate in a retreatment period of Lutathera.

[0025] As disclosed in this article, the results from the NETTER-2 study demonstrate the efficacy and safety of Lutathera in patients aged ≥ 15 years with grade 2 and 3 advanced GEP-NET (Ki67 index ≥ 10% and ≤ 55%), who are considered candidates for treatment with high-dose long-acting octreotide.

[0026] Lutathera®, a radioligand therapy, has demonstrated statistically significant and clinically meaningful progression-free survival in first-line treatment of advanced gastrointestinal pancreatic neuroendocrine tumors (GEP-NET).

[0027] Compared with high-dose long-acting octreotide alone, the Phase III NETTER-2 trial of patients with grade 2 and 3 advanced gastrointestinal pancreatic neuroendocrine tumors (GEP-NET) who received Lutathera® in combination with long-acting octreotide as first-line therapy met the primary endpoint of improved progression-free survival (PFS) and the key secondary endpoint of objective response rate (ORR) [1,2].

[0028] Lutathera is the first radioligand therapy (RLT) to demonstrate clinically meaningful benefits in a first-line setting[1].

[0029] The Phase III NETTER-2 trial using Lutathera® (INN: lutetium (177Lu) octreotide / USAN: lutetium Lu 177 dotatate) met its primary endpoint. First-line treatment with Lutathera® in combination with long-acting octreotide showed a significant improvement in progression-free survival (PFS) compared to high-dose long-acting octreotide alone in patients with newly diagnosed, somatostatin receptor (SSTR)-positive, grade 2 and 3 advanced gastrointestinal pancreatic neuroendocrine neoplasms (GEP-NET) [1,2]. No new or unexpected safety findings were observed in this study, and the data were consistent with the established safety profile of Lutathera [1–4].

[0030] NETs are cancers originating from neuroendocrine cells throughout the body and are generally considered slow-growing malignancies. However, some NETs are associated with rapid progression and poor prognosis, and in many cases, they are not diagnosed until the patient's condition has progressed to an advanced stage [5-7]. Even though NETs are a rare (orphan) disease, their incidence has increased by more than 500% in the past three decades [5-8], and there is an urgent need to provide additional treatment options for newly diagnosed patients with inoperable or advanced disease.

[0031] Based on these results, NETTER-2 was Lutathera's second phase III trial to demonstrate clinically meaningful outcomes for patients [2,4]. Lutathera was initially approved based on the pivotal NETTER-1 trial, which demonstrated that in patients with SSTR-positive, unresectable midgut neuroendocrine tumors (NETs), treatment with Lutathera in combination with long-acting octreotide resulted in a significantly and clinically meaningful prolongation of progression-free survival (PFS) compared to patients treated with a high dose (60 mg) of long-acting octreotide who had progressed despite receiving standard therapy [3-4,9].

[0032] These positive results from Lutathera are remarkable and represent the potential for radioligand therapy to have a meaningful impact on newly diagnosed patients with advanced GEP-NET. Using radioligand therapy in early lines of treatment for cancer patients precisely delivers novel treatment modalities directly to cancer cells to improve patient outcomes.

[0033] NETTER-2 (NCT03972488) is an open-label, multicenter, randomized, comparative-controlled phase III trial evaluating whether Lutathera plus long-acting octreotide, as first-line therapy, could prolong progression-free survival (PFS) in patients with high-proliferative tumors (G2 and G3) compared to high-dose (60 mg) long-acting octreotide.2 . Eligible patients were diagnosed with SSTR-positive advanced GEP-NET within 6 months before enrollment [2].

[0034] Lutathera ® (INN: lutetium ( 177 Lu) oxodotreotide / USAN: lutetium Lu 177 dotatate) is a RLT of Advanced Accelerator Applications, which is approved in the United States for the treatment of SSTR-positive GEP-NET (including foregut, midgut, and hindgut neuroendocrine tumors) in adults and in Europe for the treatment of inoperable or metastatic, progressive, well-differentiated (G1 and G2) SSTR-positive GEP-NET in adults [10-11].

[0035] This disclosure relates to cancer care of advanced cancer patients using RLT. By harnessing the power of radioactive atoms and applying it to advanced cancer, RLT theoretically enables the delivery of radiation to target cells anywhere in the body [12-13].

[0036] References (for the foregoing paragraph):

[0037] 1. See the data disclosed herein.

[0038] 2. ClinicalTrials.gov. NETTER-2 (NCT03972488). Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET (NETTER-2). Accessed September 15, 2023. https: / / classic.clinicaltrials.gov / ct2 / show / NCT03972488

[0039] 3.Strosberg JR, Caplin ME, Kunz PL, et al. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients withmidgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial[published correction appears in Lancet Oncol. 2022 Feb;23(2):e59]. LancetOncol. 2021;22(12):1752-1763. doi:10.1016 / S1470-2045(21)00572-6

[0040] 4.NETTER-1 Phase III in Patients With Midgut Neuroendocrine TumorsTreated With 177Lu-DOTATATE: Efficacy and Safety Results. Clin Adv HematolOncol. 2016;14(5 Suppl 7):8-9.

[0041] 5.Man D, Wu J, Shen Z, Zhu X. Prognosis of patients withneuroendocrine tumor: a SEER database analysis. Cancer Manag Res. 2018;10:5629-5638. Published 2018 Nov 13. doi:10.2147 / CMAR.S174907Dasari

[0042] 6.A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, Shih T, Yao JC. Trendsin the Incidence, Prevalence, and Survival Outcomes in Patients WithNeuroendocrine Tumors in the United States. JAMA Oncol. 2017; doi:10.1001 / jamaoncol.2017.0589

[0043] 7.Frilling A, Åkerström G, Falconi, M, et al. Neuroendocrine tumordisease: an evolving landscape. Endoc Related Cancer 2012; 19: R163-815.

[0044] 8.Lawrence B, Gustafsson BI, et al. The Epidemiology ofGastroenteropancreatic Neuroendocrine Tumors. Endocrinol Metab Clin N Am.2011; 40:1-18

[0045] 9.Novartis. Press Release. Available online: https: / / www.novartis.com / news / media-releases / advanced-accelerator-applications-receives-fda-approval-lutathera-treatment-gastroenteropancreatic-neuroendocrine-tumors. Last accessed September 2023.

[0046] 10.Lutathera. Full Prescribing Information. 2018. Revised March 2023.https: / / www.novartis.com / us-en / sites / novartis_us / files / lutathera.pdf

[0047] 11.Lutathera. Summary of Product Characteristics (SmPC). 2018.Revised February 2023. https: / / www.ema.europa.eu / en / documents / product-information / lutathera-epar-product-information_en.pdf

[0048] 12.Jadvar H. Targeted radionuclide therapy: an evolution towardprecision cancer treatment. AJR Am J Roentagenol. 2017;209(2);277-288.

[0049] 13.Jurcic JG, Wong JYC, Knoc SJ, et al. Targeted radionuclidetherapy. In: Tepper JE, Foote RE, Michalski JM, eds. Gunderson & Tepper'sClinical Radiation Oncology. 5th ed. Elsevier, Inc. 2021;71(3):209-249

[0050] In patients with well-differentiated grade 2 and 3 advanced gastrointestinal pancreatic neuroendocrine tumors (GEP-NET), the phase III NETTER-2 trial of Lutathera® met the primary endpoint of improved progression-free survival (PFS) and the key secondary endpoint of objective response rate (ORR) [1,2].

[0051] According to the data disclosed in this article, Lutathera is the first radioligand therapy (RLT) to demonstrate statistically significant and clinically meaningful benefits in a first-line setting [1].

[0052] The phase III NETTER-2 trial is evaluating whether Lutathera plus long-acting octreotide, as first-line therapy, can prolong progression-free survival (PFS) in patients with grade 2 and 3 (defined as mitotic count > 2 and Ki67 > 3%) high-proliferative gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs) compared to high-dose (60 mg) long-acting octreotide alone. The phase III NETTER-1 trial explored the same treatment regimen in patients with midgut NETs who were progressing despite receiving standard therapy [2,6,7]. NETTER-2 is also investigating patients with more aggressive disease forms compared to those included in the NETTER-1 patient cohort.

[0053] NETTER-2 was the first clinical trial to demonstrate statistically significant benefit of radioligand therapy (RLT) in a first-line setting [1]. The results collected to date provide evidence of the benefit of RLT as a first-line treatment.

[0054] NETTER-2 met its primary endpoint of progression-free survival (PFS) and showed statistical significance in objective response rate (ORR), a key secondary endpoint [1].

[0055] No new or unexpected security findings were observed in NETTER-2, and the data are consistent with the well-established security features of Lutathera [1,8,9].

[0056] The Phase III NETTER-2 trial also confirmed for the first time the safety profile of Lutathera using a 2.5% lysine-arginine solution [1,2]. In contrast, NETTER-1 used a complex amino acid solution, which resulted in a higher frequency of adverse reactions (e.g., nausea and vomiting) due to the emetic effect of the accompanying amino acid infusion [1,8,9].

[0057] References (for the preceding paragraph)

[0058] 1. The data disclosed in this article.

[0059] 2.ClinicalTrials.gov. NETTER-2 (NCT03972488). Study to Evaluate theEfficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3Advanced GEP-NET (NETTER-2). Accessed September 15, 2023. https: / / clinicaltrials.gov / ct2 / show / NCT03972488

[0060] 3.Lutathera. Full Prescribing Information. 2018. Revised March 2023.https: / / www.novartis.com / us-en / sites / novartis_us / files / lutathera.pdf

[0061] 4.Lutathera. Summary of Product Characteristics (SmPC). 2018. RevisedFebruary 2023. https: / / www.ema.europa.eu / en / documents / product-information / lutathera-epar-product-information_en.pdf

[0062] 5.Lutathera. Product monograph. 2019. Revised May 2021. https: / / ed2b79.p3cdn1.secureserver.net / wp-content / uploads / 2022 / 02 / Lutathera-PM-E.pdf

[0063] 6.ClinicalTrials.gov. NETTER-1 (NCT01578239). A Study ComparingTreatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients WithInoperable, Progressive, Somatostatin Receptor Positive Midgut CarcinoidTumours. Accessed September 15, 2023. https: / / clinicaltrials.gov / study / NCT01578239

[0064] 7.American Society of Clinical Oncology (ASCO). Cancer.net.Neuroendocrine Tumors: Grades. May 2022. Accessed September 22, 2023.https: / / www.cancer.net / cancer-types / neuroendocrine-tumors / grades

[0065] 8.Strosberg JR, Caplin ME, Kunz PL, et al. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients withmidgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial[published correction appears in Lancet Oncol. 2022 Feb;23(2):e59]. LancetOncol. 2021;22(12):1752-1763. doi:10.1016 / S1470-2045(21)00572-6

[0066] 9.NETTER-1 Phase III in Patients With Midgut Neuroendocrine TumorsTreated With 177Lu-DOTATATE: Efficacy and Safety Results. Clin Adv HematolOncol. 2016;14(5 Suppl 7):8-9.

[0067] 10. Novartis. Press Release. Available online: https: / / www.novartis.com / news / media-releases / advanced-accelerator-applications-receives-fda-approval-lutathera-treatment-gastroenteropancreatic-neuroendocrine-tumors. Last accessed September 2023.

[0068] This disclosure provides:

[0069] A method for treating well-differentiated G2 or G3 neuroendocrine tumors (NETs) in patients in need, comprising administering to the patient a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as a first-line therapy.

[0070] A method for delaying the time to first progression or death in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET) comprising administering the patient a radioligand therapy (RLT) containing a therapeutically effective dose of a somatostatin receptor (SSTR)-targeting agent as first-line therapy.

[0071] A method for delaying the need to initiate chemotherapy in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET), the method comprising administering to the patient a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as first-line therapy.

[0072] A method for controlling disease in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET) comprising administering treatment to the patient as a first-line therapy with a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR).

[0073] A method for alleviating well-differentiated G2 or G3 neuroendocrine tumors (NETs) in patients in need, comprising administering to the patient a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as a first-line (1L) therapy.

[0074] A method for reducing the risk of progression of well-differentiated G2 or G3 neuroendocrine tumors (NETs) in patients in need or reducing the risk of death in said patients, the method comprising administering to said patients a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as a first-line (1L) therapy. Attached Figure Description

[0075] Figure 1 The design of the clinical trial is shown.

[0076] and Figure 1 The relevant footnotes are provided below:

[0077] (1) Randomization ratio: 2:1. Stratification factors: grade (G2 vs. G3) and tumor origin (pNET vs. other origins).

[0078] (2) Long-acting octreotide 30 mg, every 8 weeks during Lutathera treatment and every 4 weeks after the last Lutathera treatment.

[0079] (3) The use of somatostatin analogs during the retreatment period shall be determined at the discretion of the investigator.

[0080] (4) If RECIST progression occurs at week 72 after the primary endpoint analysis, the decision on whether to include the patient in the crossover or retreatment period will be based on local assessment results.

[0081] (5) Patients included in the optional crossover or retreatment period will be followed up for 3 years or until EoS, whichever occurs first.

[0082] Figure 2 Kaplan-Mayer plots (full analysis set) of progression-free survival (PFS) (months) based on central review and using RECIST 1.1 criteria are shown.

[0083] Figure 3 and Figure 4 Forest plots of progression-free survival (PFS) (months) based on central review and using RECIST 1.1 criteria are shown – key subgroups of interest (full analysis set). Detailed Implementation

[0084] This disclosure is described and illustrated in more detail below.

[0085] Research Design

[0086] This is a multicenter, stratified, randomized, open-label, comparative-controlled phase III study. The study included patients aged ≥15 years who were diagnosed with somatostatin receptor-positive, well-differentiated G2 and G3, or advanced GEP NET within the first 6 months of screening.

[0087] Overall, 222 patients will be randomized (2:1 randomization ratio) to receive either Lutathera (7.4 GBq / 200 mCi × 4 doses every 8 ± 1 weeks; cumulative dose: 29.6 GBq / 800 mCi) plus long-acting octreotide (30 mg every 8 weeks during Lutathera treatment and every 4 weeks after the last Lutathera treatment) or high-dose long-acting octreotide (60 mg every 4 weeks). Randomization will be stratified according to grade (G2 vs. G3) and tumor origin (pNET vs. other origins). Figure 1 ).

[0088] The primary endpoint of this study is centrally assessed progression-free survival (PFS) (target HR = 0.5; 90% efficacy, one-sided α = 2.5%). The primary analysis will be conducted after 99 PFS events (99 evaluable and centrally confirmed disease progression or death events).

[0089] This study consists of a screening period, a treatment period, an optional treatment extension period (crossover treatment) / optional retreatment period, and a follow-up period.

[0090] Screening period

[0091] The screening period should be shortened as much as possible so that patients can be treated within 2 weeks of signing the informed consent form.

[0092] Randomization should be performed as soon as possible after all eligibility criteria have been verified. Patients who were taking long-acting octreotide prior to entering the study should have their last dose carefully planned during the screening period (in the case of randomization to the Lutathera group, a 6-week washout period from long-acting octreotide must be observed before Lutathera injection).

[0093] Since the production and shipping of Lutathera will take approximately 12 days, if a patient is randomly assigned to a Lutathera group, the first dose of Lutathera should be ordered within 24 hours of randomization.

[0094] Baseline CT / MRI scans should be performed as soon as possible on the day of or before randomization (within 1 week) to ensure they reflect the disease state prior to the start of treatment.

[0095] Treatment period

[0096] During the treatment period, patients will be followed up according to the assessment schedule. Objective tumor response will be assessed at W16 ± 1, W24 ± 1, and then every 12 ± 1 weeks from the date of randomization (central + local assessment until the first progression, then local assessment only).

[0097] Duration of treatment:

[0098] • Prior to the main PFS analysis:

[0099] The treatment period is not fixed, and patients who are randomly assigned should continue to receive study treatment until progression or death occurs (patients randomly assigned to the Lutathera group will continue to receive long-acting octreotide 30 mg injection after completing 4 cycles of Lutathera treatment until progression or death occurs; patients randomly assigned to the long-acting octreotide group will continue to receive long-acting octreotide 60 mg injection until progression or death occurs).

[0100] • Following the primary analysis of PFS:

[0101] The treatment period became fixed and will be discontinued at week 72 (patients randomly assigned to the Lutathera group will continue to receive long-acting octreotide 30 mg injection after completing 4 cycles of Lutathera treatment until week 72 or earlier (in case of progression or death); patients randomly assigned to the long-acting octreotide group will continue to receive long-acting octreotide 60 mg injection until week 72 or earlier (in case of progression or death)).

[0102] In other words, prior to the primary PFS analysis (i.e., 99 evaluable and center-confirmed disease progression or death events), patients continued treatment until progression occurred; after the primary PFS analysis, the duration of treatment was limited to 72 weeks.

[0103] At any point during the study period (before or after the primary PFS analysis), any patient with progression (based on central imaging assessment) immediately discontinued treatment and entered the follow-up period. If a patient discontinued Lutathera before centrally confirmed disease progression, the patient should be assessed for tumors according to the initial CT / MRI schedule until centrally confirmed disease progression occurred.

[0104] In addition, eligible patients randomly assigned to the control group may choose to participate in Lutathera crossover therapy after disease progression. Control group patients receiving crossover therapy after disease progression will be allowed to complete Lutathera treatment after week 72, or receive crossover therapy during the follow-up period (in the case of late progression). Furthermore, eligible patients in the Lutathera group experiencing disease progression may choose to participate in a Lutathera retreatment period.

[0105] Patients included in the optional crossover or retreatment period will be followed up for at least 6 months and up to 3 years (or until EoS, whichever comes first).

[0106] Optional treatment extension period (cross-treatment)

[0107] In the control group, any patient with RECIST progression (based on central assessment) could opt to participate in post-progression crossover therapy after signing a new informed consent form to receive up to 4 cycles of Lutathera (7.4 GBq / 200 mCi × 4 cycles; cumulative dose: 29.6 GBq / 800 mCi) plus 30 mg long-acting octreotide (every 8 weeks).

[0108] If RECIST progresses at week 72 following the primary endpoint analysis, the decision to include the patient in crossover therapy will be based on local assessment results.

[0109] The crossover treatment period will continue until four Lutathera administrations are completed, after which the patient will undergo an EOT visit (week 28) and enter the follow-up period.

[0110] After the crossover period, patients are followed up for 3 years or until EoS, whichever occurs first (at least 6 months after the last Lutathera dose is administered during the crossover period).

[0111] In this study, the time window for starting Lutathera crossover treatment was 4 years after the last patient was randomized.

[0112] Optional Retreatment Period

[0113] In the Lutathera group, patients with radiographic progression based on the RECIST criteria assessed by the central assessment were eligible to participate in progression-free retreatment after signing a new informed consent form, receiving an additional 2 to 4 cycles of 7.4 GBq / 200 mCi Lutathera. If RECIST progression occurred at week 72 following the primary endpoint analysis, patient inclusion in retreatment would be determined based on local assessment results.

[0114] Patients who have received Lutathera during the optional treatment extension period (crossover therapy) are not eligible for Lutathera retreatment.

[0115] To participate in the optional retreatment period, patients must undergo SSTR imaging and meet all requirements.

[0116] Upon entering the retreatment phase, patients will initially receive two doses of Lutathera 7.4 GBq / 200 mCi at 8-week intervals. Thereafter, investigators should determine:

[0117] • Whether the patient shows evidence of stable condition or response (i.e., no radiological progression, or as assessed by clinical benefit).

[0118] • Whether good tolerability of Lutathera retreatment has been demonstrated.

[0119] If the investigator deems the treatment option to be in the best interests of the participants, and if the participants meet these criteria and agree to continue further treatment with Lutathera, the investigator may administer up to two additional doses of Lutathera 7.4 GBq / 200 mCi at 8-week intervals. A maximum of four doses of Lutathera are permitted during the retreatment period.

[0120] All safety and efficacy assessments during the retreatment period will be conducted locally, following the timeline of the initial treatment period (expression of somatostatin receptors on all target lesions will be evaluated locally prior to retreatment; SRI images will not be evaluated centrally in real time, but images should be submitted to the central imaging center for a second review within one month).

[0121] During the retreatment period, the administration of SSA is at the investigator's discretion.

[0122] The retreatment period will continue until locally confirmed disease progression or until the end of the disease (EoS), whichever comes first. If a patient discontinues Lutathera before locally confirmed disease progression occurs during retreatment, the patient should be evaluated for tumors according to the initial CT / MRI schedule until locally confirmed disease progression occurs. After the retreatment period, patients will be followed up for 3 years or until the end of the disease (EoS), whichever comes first (at least 6 months after the last retreatment dose in the study).

[0123] In this study, the time window for initiating retreatment was within 4 years after the last patient was randomized.

[0124] For patients in the Lutathera group who are eligible for retreatment beyond this window, retreatment with Lutathera may be permitted through the Post-Study Drug Supply (PSDS) program, in accordance with local regulations.

[0125] Follow-up period

[0126] At the end of the treatment period (or, in the case of crossover treatment, an optional treatment extension period, or an optional retreatment period) or after treatment is discontinued for any reason, including disease progression, all patients will continue to be followed for at least 6 months and up to 3 years (or until EoS, whichever comes first) to continue data collection for secondary endpoints of the study, such as long-term safety and overall survival.

[0127] During the follow-up period, SAEs and adverse events of particular concern (AESIs) other than secondary hematologic malignancies, excluding causally related secondary hematologic malignancies, will be reported. In both groups, antitumor therapy administered after progression / treatment discontinuation, disease status based on local CT / MRI assessment, and overall survival (OS) data will be collected every 6 months (±1 month).

[0128] Basic principles

[0129] Basic Principles of Research Design

[0130] As demonstrated in the Lutathera group of the pivotal Phase III NETTER-1 study, the significantly longer PFS and significantly higher response rates in the midgut NETs of line 2 G1 and G2 validate the rationale for this study (Strosberg et al., 2017).

[0131] The WHO 2010 classification distinguishes G3 NET (typically ≤ 55% Ki67) from G3 NET (typically > 55%), thereby identifying the NET-specific characteristics of G3-NET (a continuum between G2 and G3 NET) (Rindi 2010, Rindi 2014).

[0132] Although the Erasmus MC Phase I-II and NETTER-1 studies demonstrated the safety and efficacy of Lutathera in well-differentiated grade 1 and 2 GEP-NETs (Kwekkeboom et al., 2008; Strosberg et al., 2017), grade 3 GEP-NETs still represent a significant unmet medical need for the following reasons:

[0133] Historically, most studies have excluded G3 NETs (which account for about 20% of all NETs);

[0134] The number of patients diagnosed with G3 NET stage continues to increase (Dasari et al., 2017).

[0135] There is currently no universally accepted standard of care for treating G3 NET. The ESMO (Oberg, Knigge, Kwekkeboom, Perren and Group, 2012), ENET (Perren et al., 2017), NANETS (Kunz et al., 2013), and NET NCCN (Kulke et al., 2015) guidelines outline chemotherapy as the primary treatment; however, physician practice may vary (first-line and second-line use of SSA and / or chemotherapy).

[0136] Based on expert considerations and the NORDIC NEC study, a Ki-67 cutoff value between 50% and 60% is recommended as the minimum level at which platinum-based chemotherapy should be considered. Therefore, similar management for patients with well-differentiated G3 and G2 NETs appears reasonable (Vélayoudom-Céphise et al., 2013; Heetfeld et al., 2015). Furthermore, the prognosis and response rate of well-differentiated G3 NET appear to be similar to those of well-differentiated G1 / 2 NET, but with poorer overall survival (Coriat, Walter, Terris, Couvelard, and Ruszniewski, 2016).

[0137] The efficacy of current first-line treatments appears to be limited, with low objective response rates (ORR) and limited evidence of benefit in progression-free survival (PFS / OS) (Coriat, Walter, Terris, Couvelard, and Ruszniewski, 2016). Furthermore, given the extremely limited amount of available data in non-pancreatic NET G-3, no chemotherapy regimen should be considered a standard of first-line care.

[0138] Therefore, the current NETTER-2 study has included patients with advanced GEP-NET in the G2 (Ki67 ≥ 10%) and G3 (Ki67 ≤ 55%) groups to evaluate potential new treatment options for these patients.

[0139] Based on the recently finalized industry guidance on considerations for including adolescent patients in adult oncology clinical trials, and the expert consensus opinion from the European multi-stakeholder platform ACCELERATE, which states that adolescents should be included in adult oncology clinical trials when the histological and biological behavior of the cancer in the study is identical to that of cancers in adult and adolescent patients, or when the molecular target of the drug is associated with cancers in adult and adolescent patients (FDA guidance), this study will include adolescents aged ≥15 years and with a body weight > 40 kg. Although the number of adolescents ≥15 years old meeting the inclusion criteria for this study is very small, the unmet medical needs of this group are high, making their inclusion reasonable. It is anticipated that adolescents under 15 years of age will not have diseases that meet the inclusion criteria for this study.

[0140] Due to the radioactivity of Lutathera and its infusion method, and because of the similarity to the NETTER-1 trial design, it was not possible to implement a fully double-blind design in this study. However, a centrally blinded, real-time IRC (Independent Review Committee) assessment was implemented to ensure independent evaluation of tumor response according to RECIST 1.1 criteria.

[0141] Randomization will be stratified according to grade (G2 vs. G3) and tumor origin (pNET vs. other origins) to prevent imbalances between treatment groups due to known prognostic factors.

[0142] For this trial, a 2:1 randomization design was chosen to give patients a greater chance of receiving the expected more effective treatment. For the same reason, and to minimize the potentially high dropout rate in the control group, patients will receive Lutathera crossover after a center-confirmed RECIST progression (or, if confirmed locally, at week 72 after the primary endpoint analysis).

[0143] Based on physician assessment of potential clinical benefit, patients randomized to the Lutathera group will also receive an optional 2–4 additional Lutathera doses / cycles of retreatment following centrally confirmed RECIST progression (or locally confirmed if at week 72 after the primary endpoint analysis). Overall, treatment options for patients experiencing progression after PRRT are very limited. Based on a meta-analysis (Strosberg et al., 2021), including 560 patients with advanced GEP-NET who received Lutathera retreatment (one to six doses during retreatment, with most patients receiving 200 mCi per dose), the clinical benefit of retreatment was supported by the following: median PFS of 12.52 months (applicable to 414 patients), median OS of 26.78 months from retreatment initiation (applicable to 194 patients), and DCR of 71% (applicable to 347 patients). The safety profile of Lutathera retreatment was similar to that of initial treatment. These data suggest that Lutathera retreatment can be considered a treatment approach that maximizes benefit without compromising safety and by carefully assessing each patient’s clinical condition.

[0144] Basic principles of dosage / regimen and duration of treatment

[0145] The dosage / regimen of Lutathera in the NETTER-2 study was the same as the established regimen used in the Erasmus MC Phase I / II study (Kwekkeboom et al., 2008) and the Phase III pivotal NETTER-1 study (Strosberg et al., 2017), in which the cumulative dose of Lutathera was 29.6 GBq (800 mCi), administered in four divided doses every 8 ± 1 weeks, plus long-acting octreotide (30 mg) every 4 weeks.

[0146] Based on the results of the pivotal Phase III NETTER-1 study and data from 1,214 patients with somatostatin receptor-positive tumors (including GEP-NETS) who received Lutathera at Erasmus Medical Center in the Netherlands, Lutathera was approved in Europe for the treatment of unresectable or metastatic, progressive, well-differentiated (G1 and G2) GEP-NETs and in the United States for the treatment of somatostatin receptor-positive GEP-NETs.

[0147] In patients with advanced midgut neuroendocrine tumors, Lutathera treatment resulted in significantly longer progression-free survival and significantly higher response rates compared to high-dose long-acting octreotide. Preliminary evidence of overall survival benefit was observed in the interim analysis; this needs to be confirmed in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the Lutathera group. Similar PFS prolongations were observed in both Ki67 strata (≤ 2% and 3%–20%), suggesting that patients with advanced G2 and 3 GEP-NET tumors included in the NETTER-2 study may benefit.

[0148] Based on recently published GEP-NET retreatment data (Strosberg et al., 2021), patients treated in the Lutathera group at disease progression will receive optional retreatment with additional doses of Lutathera. Candidates for Lutathera retreatment in this protocol are patients in the Lutathera group with centrally documented tumor progression who have completed four doses / cycles of Lutathera during the treatment period, have achieved CR / PR / SD as the best response at least 6 months after the fourth Lutathera dose (allowed for a -2 week window), and are already tolerating treatment (according to the criteria defined in this article). Patients will initially receive two doses of Lutathera during the retreatment period. Based on the physician's judgment of the clinical benefit derived from the first two doses, patients may receive up to two additional doses of Lutathera (the criteria for additional doses are listed in this article). A maximum of four doses of Lutathera are permitted during the retreatment period. The dose level assessed in the retreatment portion of this study will be the same as the approved 7.4 GBq per cycle, based on published meta-analysis data showing that most patients received this dose (Strosberg et al., 2021).

[0149] Basic principles of drug selection

[0150] The control group dose / regimen in the NETTER-2 study was the same as that used in the NETTER-1 study (long-acting octreotide (60 mg), every 4 weeks).

[0151] Octreotide has extensive clinical experience, but there is currently a lack of data on its use as a somatostatin analog in G3 GEP-NET patients.

[0152] Patients in the comparison group of this NETTER-2 study will receive 60 mg of long-acting octreotide at 4-week intervals. This dosage is supported by the findings of Broder et al. (2015), who conducted a systematic review of the literature to analyze the antiproliferative benefits of somatostatin analogs. They demonstrated that clinicians typically use doses of >30 mg of long-acting octreotide to control symptoms and tumor progression in NET patients. This dose (60 mg) was also tested in the comparison group of the pivotal phase III NETTER-1 study (Strosberg et al., 2017). In current clinical practice, it is likely that even a higher percentage of patients will receive >30 mg of octreotide LAR (Anthony and Vinik, 2011; Joseph et al., 2010; Wolin, 2012; Broder, Beenhouwer, Strosberg, Neary, and Cherepanov, 2015). A 4-week interval injection of 60 mg long-acting octreotide is a higher dose than a 4-week interval injection of 20 mg or 30 mg, the latter being the current maximum dose for Sandostatin. ® The registered dose at LAR Depot. With this treatment, most symptomatic patients showed improvement in QoL, and based on CT scans, the condition of most patients was temporarily stabilized (Faiss et al., 1999; Faiss et al., 2003; Rinke et al., 2009; Ludlam and Anthony, 2011; Anthony and Vinik, 2011; Wolin, 2012; Broder, Beenhouwer, Strosberg, Neary and Cherepanov, 2015).

[0153] Furthermore, based on the results of the Phase III NETTER-1 study, patients with metastatic midgut tumors that progressed after a standard dose (30 mg) of SSA treated with high-dose (60 mg) long-acting octreotide in the control group of this study had a median recurrence-free time of 8.4 months (Strosberg et al., 2017) without significant side effects, which confirms that the regimen has antitumor benefits and is well tolerated.

[0154] In a clinical study published by Astruc et al. (Astruc et al., 2005), healthy subjects were treated with 20 mg and 60 mg of octreotide LAR. PK data showed that plasma exposure was proportional to the dose and treatment was well tolerated at both doses.

[0155] Available pharmacokinetic (PK) data in children taking 40 mg octreotide LAR showed that dose-corrected plasma exposure was similar in adults and younger patients. Furthermore, 40 mg octreotide LAR was well tolerated in children. Notably, the same dose was administered to patients < 12 years of age and > 12 years of age.

[0156] Therefore, based on the available PK data and in accordance with the FDA guidance on including adolescents in adult cancer trials and the expert consensus opinion proposed by the European multi-stakeholder platform ACCELERATE, considering the population ≥ 15 years old and > 40 kg, we believe that including adolescents in the NETTER-2 study at the same dose as the fixed dose for adults is acceptable.

[0157] Based on the data of currently available high-dose somatostatin analogs, and considering the researchers’ belief that there is a large unmet medical need in populations unsuitable for chemotherapy or targeted therapy, it is reasonable to use a 60 mg dose of somatostatin analog as a comparison in this study.

[0158] Purpose and timing of mid-term analysis

[0159] When performing the primary analysis of PFS, the overall survival estimate will be calculated based on the hazard ratio (point estimate) and the 95% confidence interval.

[0160] Risks and benefits

[0161] Neuroendocrine tumors (NETs) account for a small percentage of cancers, but their incidence is increasing due to incidental diagnosis. The prognosis for grade 1 and local NETs has steadily improved, but patients with distant and / or grade 3 NETs continue to fare poorly (Sackstein, O'Neil, Neugut, Chabot, and Fojo, 2018).

[0162] Patient management is a significant challenge due to the varying clinical presentations and degrees of invasiveness.

[0163] Randomization will be stratified according to tumor origin (pNET vs. other origins) and grade (G2 vs. G3) to prevent imbalances between treatment groups due to known prognostic factors.

[0164] Researchers believe that the G2 and G3 GEP-NET patients included in the NETTER-2 study are not candidates for chemotherapy or targeted therapy. G3 GEP-NET patients with Ki67 ≤ 55 belong to a type of G3 neuroendocrine tumor (NEN), in which the tumor maintains its highly differentiated characteristics, continues to express somatostatin receptors, but has a higher proliferation rate than most GEP-NETs (Rindi et al., 2018). Aggressive G2 GEP-NET patients, with Ki67 ranging from 10% to 20%, are similar to G3 GEP-NET patients in that they are more likely to have a poor prognosis and limited treatment options. Despite advances in medical treatments for these tumors, the medical need to control tumor growth remains unmet, especially for G3 GEP-NETs (which account for approximately 10%–20% of all NETs), which have historically been excluded from most studies (Sorbye et al., 2019; Coriat, Walter, Terris, Couvelard and Ruszniewski, 2016; Dasari et al., 2017).

[0165] For GEP-NET patients considering Lutathera treatment, the most important risk mitigation factor is the ability to use receptor scintillation imaging to select those most likely to respond to PRRT and exclude those who cannot benefit from treatment because their tumors do not express sufficiently high levels of somatostatin receptors.

[0166] Based on other uses 177 Results from the PRRT study of Lu-dotatate (Strosberg 2017; Brabander 2016, 2018) indicate that the main expected benefits for patients receiving Lutathera treatment include a high probability of prolonged progression-free survival, increased overall survival, and a longer time to the onset of quality of life deterioration.

[0167] For this trial, a 2:1 randomization design was chosen to give patients a greater chance of receiving the expected more effective treatment. For the same reason, and to minimize the potentially high dropout rate in the control group, patients will receive Lutathera crossover after a center-confirmed RECIST progression (or, if confirmed locally, at week 72 after the primary endpoint analysis).

[0168] The highest risk associated with Lutathera treatment is radiotoxicity that can affect bone marrow or kidney function (Bergsma et al., 2016a; Bergsma et al., 2016b).

[0169] The risk to renal function can be largely eliminated by co-infusion of 2.5% Lys-Arg solution during Lutathera administration, which reduces the radiation dose to the kidneys by approximately 45% (Rolleman, Valkema, Jong, Kooij, and Krenning, 2003). In the NETTER-1 trial, there was no evidence of nephrotoxicity during the observation period (Strosberg et al., 2017).

[0170] Myelotoxicity can occur in two forms: 1) acute toxicity, which occurs after Lutathera administration during the treatment period; and 2) delayed toxicity, which occurs in 1.5%–2% of patients. Potential observed effects of short-term myelotoxicity include anemia, thrombocytopenia, and neutropenia, which are usually mild and transient. In the NETTER-1 trial, grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9% of patients, respectively (Strosberg et al., 2017). In cases of hematologic toxicity, a trend toward stabilization followed by improvement was observed in patients with longer follow-up periods. It is important to note that lymphocytic toxicity observed after PRRT is not a major concern in terms of infection risk, as only B lymphocytes are affected, and B lymphocytes are a subtype not directly involved in infection defense (Sierra et al., 2009).

[0171] There is evidence that... 177 Following PRRT with Lu-dotatate, men may face the risk of reduced sperm production. In a study (Teunissen et al., 2009), when using... 177 A significant decrease in mean serum inhibin B levels was observed in male patients (N = 35) treated with Lu-dotatate. Studies have shown a positive correlation between serum inhibin B levels and spermatogenesis status and sperm count (Pierik, Vreeburg, Stijnen, De Jong, and Weber, 1998). A study (Teunissen et al., 2009) also found that levels almost returned to pre-treatment levels after 24 months. The potential long-term genetic damage to spermatogenic cells has not been investigated.

[0172] Women and men may conceive six months after their last Lutathera treatment. However, due to additional exposure caused by CT scans performed during the study, women in both groups should not conceive throughout the study treatment period. Women of fertility and sexually active men must be informed that receiving study treatment may pose unknown risks to the fetus if pregnancy occurs during the study period, and agree that they must adhere to the contraceptive requirements listed in the exclusion criteria in order to participate in the study. If any participant has difficulty reliably adhering to these requirements, they should not enter or continue participating in the study.

[0173] Based on the FDA guidance on including adolescents in adult oncology trials and the expert consensus proposed by the European multi-stakeholder platform ACCELERATE, it is recommended that adolescents receive the same dosage as adults if body size does not have a relevant impact on pharmacokinetics. This applies to both Lutathera and long-acting octreotide. Based on the similar clinical presentation of the evaluated diseases in adolescents, this study selected the following inclusion criteria: ≥ 15 years of age and body weight (BW) > 40 kg (meeting the BW recommendations in the FDA guidance).

[0174] Regarding retreatment of Lutathera, results from a meta-analysis of patients with advanced GEP-NET who received retreatment of peptide receptor radionuclide therapy (PRRT) support the administration of additional Lutathera doses after progression of initial treatment. Studies have shown that the safety profile of Lutathera retreatment is similar to that of initial treatment (Strosberg et al., 2021). In this meta-analysis, the duration of additional Lutathera treatment ranged from one to six doses, with most patients receiving 200 mCi per dose. Nine percent of patients retreated with PRRT reported hematologic grade 3 / 4 adverse events. Notably, <1% of patients retreated with Lutathera developed AML and MDS, comparable to the incidence observed with initial PRRT. Lutathera retreatment provided an encouraging median progression-free survival (PFS). These data suggest that Lutathera retreatment can be offered to patients to maximize benefit without compromising safety and with careful assessment of each patient's clinical status.

[0175] Given the higher severity of GEP-NET in the NETTER-2 study compared to the approved indication, a dose-modification toxicity rule was implemented in this study. If toxicity subsides, the full dose of Lutathera (200 mCi / 7.4 GBq) is administered, which will maximize the potential therapeutic effect and maintain a positive benefit / risk ratio.

[0176] To ensure the safety of participants in this trial, this protocol includes appropriate eligibility criteria and study procedures, as well as rigorous clinical monitoring, adherence to dose-modification toxicity rules, and study oversight by a steering committee.

[0177] Given all the factors mentioned above, in the overall clinical context defined in the clinical trial, the benefit-risk balance of Lutathera appears to favor patient benefit.

[0178] group

[0179] This study will evaluate the safety and efficacy of Lutathera plus long-acting octreotide (30 mg) versus high-dose long-acting octreotide (60 mg) in patients ≥15 years of age with somatostatin receptor-positive, well-differentiated G2 (Ki67 index ≥ 10%) and G3 (Ki67 ≤ 55%) advanced GEP-NET. Patients with a documented history of RECIST progression in their current GEP-NET at any time prior to randomization are not eligible to participate in this study.

[0180] Inclusion criteria

[0181] To be eligible for inclusion in this study, participants must meet all of the following criteria:

[0182] 1. Patients must be diagnosed within the previous 6 months with metastatic or locally advanced, inoperable (for radical purposes), histologically confirmed, well-differentiated grade 2 or 3 gastrointestinal pancreatic neuroendocrine (GEP-NET) tumors.

[0183] 2. Ki67 index ≥ 10 and ≤ 55%.

[0184] 3. During screening, patients must be ≥ 15 years old and weigh > 40 kg.

[0185] 4. Within 3 months prior to randomization, the expression of somatostatin receptors on all target lesions was recorded by CT / MRI scans and assessed using any of the following somatostatin receptor imaging (SRI) modalities: [68Ga]-DOTA-TOC (e.g., Somakit-TOC). ® PET / CT (or target lesion-based MRI, if applicable) imaging, [68Ga]-DOTA-TATE PET / CT (or target lesion-based MRI, if applicable) imaging (e.g., NETSPOT) ® ), using [111In]-spray peptide for somatostatin receptor scintillation imaging (SRS) (Octreoscan) ®SPECT / CT, SRS using [99mTc]-Tektrotyd, [64Cu]-DOTA-TATEPET / CT (or target lesion-based MRI, if applicable) imaging.

[0186] 5. Tumor uptake observed in the target lesion must be greater than that observed in the normal liver.

[0187] 6. Karnofsky Performance Score (KPS) ≥ 60.

[0188] 7. There is at least one measurable disease site.

[0189] 8. The patient has signed an informed consent form to participate in this study, which was obtained prior to the commencement of any protocol-related activities.

[0190] Exclusion criteria

[0191] Subjects who meet any of the following criteria are not eligible for inclusion in this study.

[0192] 1. Creatinine clearance calculated using the Cockroft-Gault method was < 40 mL / min.

[0193] 2. Hb concentration < 5.0 mmol / L (< 8.0 g / dL); WBC < 2 × 10⁻⁶ 9 / L (2000 / mm) 3 ); platelets < 75×10 9 / L (75 × 10 3 / mm 3 ).

[0194] 3. Total bilirubin > 3 × ULN.

[0195] 4. Serum albumin < 3.0 g / dL, unless prothrombin time is within the normal range.

[0196] 5. Pregnant or breastfeeding.

[0197] A) Women of childbearing potential (defined as all women who are physiologically capable of conceiving) are not eligible to participate in this study unless they use highly effective contraception throughout the entire study treatment period (including crossover and retreatment, if applicable) and for 7 months after discontinuation of the study medication. Highly effective contraception includes:

[0198] • Complete abstinence (when this aligns with the patient's preferred and daily lifestyle). Regular abstinence (e.g., calendar method, ovulation method, cervical mucus symptom basal body temperature method, post-ovulation method), abstinence for the duration of IMP exposure, and withdrawal as an unacceptable method of contraception.

[0199] • Male and female sterilization

[0200] • Any combination of any two of the following (a+b, a+c, or b+c):

[0201] a. Use oral, injectable, or implantable hormonal contraceptive methods. If using oral contraceptives, women should maintain a stable supply of the same medication for at least 3 months before receiving study treatment.

[0202] b. Insertion of an intrauterine device (IUD) or intrauterine system (IUS).

[0203] c. Barrier contraception: Condoms or occluders (septum or cervical / vault) with spermicidal foam / gel / film / cream / vaginal suppositories. Postmenopausal women are eligible to participate in this study. Women are considered postmenopausal and infertile if they have 12 months of spontaneous amenorrhea and an appropriate clinical profile (e.g., appropriate age, history of vasomotor symptoms), or have undergone bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to screening. In the case of oophorectomy alone, a woman is considered infertile only if her reproductive status has been confirmed by subsequent hormone level assessment.

[0204] B) Sexually active male patients are required to abstain from sexual intercourse (avoiding heterosexual intercourse) during treatment (including crossover and retreatment, if applicable) and for 4 months after discontinuation of the study drug, unless they agree to use condoms and highly effective contraceptive methods with a fertile or pregnant female partner. Furthermore, male patients must avoid sperm donation during the same period.

[0205] 6. Anyone who received peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in this study.

[0206] 7. There is a documented history of current GEP-NET progression to RECIST during previous treatment at any time prior to randomization.

[0207] 8. Based on the patient and disease characteristics, the researchers believed that other treatment options (such as chemotherapy and targeted therapy) were more suitable for the patient than the treatment presented in this study.

[0208] 9. Any prior interferon, everolimus (mTOR inhibitor), chemotherapy, or other GEP-NET systemic therapy administered within 1 month or 12 weeks prior to randomization in this study.

[0209] 10. Has previously undergone any radioembolization, chemoembolization, or radiofrequency ablation for GEP-NET.

[0210] 11. Had any surgery within 12 weeks prior to randomization in this study.

[0211] 12. Known brain metastases, unless these metastases have been treated and stable for at least 24 weeks prior to study screening. Patients with a history of brain metastases must undergo a head CT or MRI scan prior to randomization in this study to document disease stability.

[0212] 13. Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with a history of congestive heart failure but who do not meet this exclusion criterion will have their cardiac ejection fraction evaluated by echocardiography prior to randomization. If no clinical deterioration is observed, the investigator may, at their discretion, use previous assessments (no more than 30 days prior to randomization) instead of this evaluation. These patients must have a measured cardiac ejection fraction ≥ 40% prior to randomization.

[0213] 14. Women with a QTcF > 470 msec, men with a QTcF > 450, or those with congenital long QT syndrome.

[0214] 15. Uncontrolled diabetes mellitus, as defined by a hemoglobin A1c value >7.5%.

[0215] 16. Hyperkalemia > 6.0 mmol / L (CTCAE grade 3) that was not corrected before study enrollment.

[0216] 17. Any patient receiving short-acting octreotide treatment must not interrupt the treatment for 24 hours before and after Lutathera administration; or any patient receiving SSA (e.g., long-acting octreotide) treatment must not interrupt the treatment for at least 6 weeks before Lutathera administration.

[0217] 18. Patients with any other serious medical, psychiatric, or surgical condition that is currently uncontrolled and may interfere with the completion of the study.

[0218] 19. More than 25% of the bone marrow had previously undergone external beam radiotherapy.

[0219] 20. Currently suffering from spontaneous urinary incontinence.

[0220] 21. Other known coexisting malignancies besides melanoma, skin cancer, and cervical carcinoma in situ, unless clearly treated and proven to be free of recurrence within 5 years.

[0221] 22. Patients known to be incompatible with IV contrast-enhanced CT scans due to allergic reactions or renal insufficiency. If MRI imaging is available for such patients, they cannot be excluded.

[0222] 23. Hypersensitive to any somatostatin analogue, IMP-active substance, or any excipient.

[0223] 24. Patients who have participated in any therapeutic clinical study or received any investigational medication within the past 30 days.

[0224] Eligibility criteria for optional treatment extension (crossover therapy)

[0225] Any patient with advanced RECIST confirmed by the center may choose to participate in post-progression crossover therapy and receive up to 4 cycles of Lutathera (7.4 GBq / 200 mCi × 4 cycles; cumulative dose: 29.6 GBq / 800 mCi) plus long-acting octreotide (30 mg, every 8 weeks), provided that the following criteria are met:

[0226] The patient has signed an informed consent form to participate in the extended treatment phase of this study, which was obtained before any relevant surgery begins.

[0227] Within the first 3 months of Lutathera treatment, expression of somatostatin receptors on all target lesions (assessed based on a new baseline after progression) was recorded by CT / MRI scans (Note: Cross-treatment eligibility CT / MRI scans performed within the first 12 weeks do not need to be repeated), and assessed using any of the following somatostatin receptor imaging (SRI) modalities: [68Ga]-DOTA-TOC (e.g., Somakit-TOC). ® PET / CT imaging (or target lesion-based MRI, if applicable), [68Ga]-DOTA-TATEPET / CT (or target lesion-based MRI, if applicable) imaging (e.g., NETSPOT) ® ), using [111In]-spray peptide for somatostatin receptor scintillation imaging (SRS) (Octreoscan) ® SPECT / CT, SRS using [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET / CT imaging (or target lesion-based MRI, if applicable).

[0228] All inclusion / exclusion criteria were met.

[0229] The time window for initiating crossover therapy was 4 years after the last patient was randomized.

[0230] Note: A 6-week washout period from the last long-acting octreotide administration must be applied before each Lutathera administration.

[0231] If RECIST progresses at week 72 following the primary endpoint analysis, the decision to include the patient in crossover therapy will be based on local assessment results.

[0232] Images (cross-treatment eligibility SRI and CT or MRI scans) will also be submitted to the Central Imaging Center for a second review: cross-treatment eligibility SRI ingestion will not be subject to a central "real-time" assessment; however, images should be submitted to the Central Imaging Center within one month. Images do not need to be submitted for patients who fail the screening.

[0233] Eligibility criteria for optional retreatment

[0234] In the Lutathera group, patients with radiographic progression based on the RECIST criteria of central assessment could opt to participate in post-progression retraining after signing a new informed consent form to receive an additional 2 to 4 cycles of 7.4 GBq / 200 mCi Lutathera.

[0235] To participate in an optional retreatment period, patients must meet all of the following requirements:

[0236] Patients were randomly assigned to the Lutathera group and received four doses of Lutathera in their initial treatment, achieving stable disease (SD) or objective response (PR / CR) at least six months after the fourth Lutathera dose (confirmed by the center). If a patient's response changed from PR / CR to SD within six months after the fourth Lutathera dose, the patient was still eligible for retreatment, provided there were no documented progressions within that six-month period. The confirmation window for SD / PR / CR response at six months was -2 weeks.

[0237] Lutathera was generally well tolerated; no Lutathera-related SAEs were recorded that were not resolved before the next Lutathera dose and led to treatment interruption.

[0238] Following SD / PR / CR response, radiological RECIST progression occurred (confirmed by the center). If RECIST progression occurs at week 72 after the primary endpoint analysis, the patient's inclusion in retreatment will be determined based on local assessment results.

[0239] After the progression of the disease, the patient did not receive any other systemic treatment with GEP-NET (the use of somatostatin analogues was permitted).

[0240] Researchers agree that retreatment is in the best interests of patients.

[0241] The patient has signed an informed consent form to participate in the retreatment period, which was obtained before any relevant surgery begins.

[0242] The time window for initiating re-treatment: 4 years after the last patient was randomized.

[0243] Within 3 months prior to Lutathera retreatment, expression of somatostatin receptors on all target lesions (assessed based on a new baseline after progression) was recorded by CT / MRI scans (Note: if the retreatment eligibility CT / MRI scan was performed within the first 12 weeks, it does not need to be repeated), and assessed using any of the following somatostatin receptor imaging (SRI) modalities: [68Ga]-DOTA-TOC (e.g., Somakit-TOC). ® PET / CT imaging (or target lesion-based MRI, if applicable), [68Ga]-DOTA-TATEPET / CT (or target lesion-based MRI, if applicable) imaging (e.g., NETSPOT) ® ), using [111In]-spray peptide for somatostatin receptor scintillation imaging (SRS) (Octreoscan) ® SPECT / CT, SRS using [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET / CT imaging (or target lesion-based MRI, if applicable).

[0244] Images (retreatment eligibility SRI and CT or MRI scans) will also be submitted to the Central Imaging Center for a second review: no central "real-time" assessment of the treatment eligibility SRI ingestion will be conducted, but images should be submitted to the Central Imaging Center within one month. Images do not need to be submitted for patients who fail the screening.

[0245] treat

[0246] In this study, approximately 222 patients with advanced G2-3 GEP-NET will be randomized (2:1 randomization ratio) to receive Lutathera (7.4 GBq or 200 mCi × 4 doses every 8 ± 1 weeks; cumulative dose: 29.6 GBq or 800 mCi) plus a standard dose of long-acting octreotide (30 mg every 8 weeks during Lutathera treatment and every 4 weeks after the last Lutathera treatment) or a high dose of long-acting octreotide (60 mg every 4 weeks).

[0247] Lutathera, the investigational drug ® ( 177 Lu-DOTA 0 -Tyr 3 Octreotide will be provided by the sponsor. The sponsor will also provide 2.5% Lys-Arg sterile amino acid solution for infusion (if it cannot be prepared at a hospital pharmacy), and long-acting octreotide (Sandostatin).® LAR Depot) will be used for the entire treatment period of the study (and optional treatment extensions). For optional retreatment, the sponsor will provide Lutathera and a 2.5% Lys-Arg sterile amino acid solution; long-acting octreotide administration is not mandatory and is at the investigator's discretion. Patients will switch to prescription medication during the follow-up period.

[0248] The sponsor will not provide antiemetics, SRI imaging agents, short-acting octreotide, or any other supportive care medications.

[0249] Research on treatment

[0250] investigational drug and control drug

[0251] The investigational drugs and control drugs provided by the sponsor are shown in the table below.

[0252] Study drug and control drug

[0253]

[0254] The sponsor will provide a 2.5% Lys-Arg sterile amino acid solution for infusion (if it cannot be prepared at the hospital pharmacy).

[0255] Lutathera Group

[0256] Research drug: Lutathera ® ( 177 Lu-Dotatate)

[0257] Lutathera is a sterile radiopharmaceutical supplied as a ready-to-use infusion solution, containing... 177 Lu-DOTA 0 -Tyr 3 -Octrenic acid as the active pharmaceutical ingredient has a volumetric activity of 370 MBq / mL at the reference date and time (calibration time (tc)).

[0258] On the day of Lutathera treatment, an intravenous bolus of antiemetic was administered. To protect the kidneys, a sterile amino acid solution was infused 30 minutes before starting Lutathera and continued for a total of 4 hours.

[0259] Lutathera is a radiopharmaceutical solution for infusion, supplied as a ready-to-use product. The only quality control (QC) tests that must be performed at the clinical trial facility are: 1) verifying the product certificate is correct; 2) determining the total radioactivity; and 3) verifying the visual appearance. Because Lutathera is manufactured in a centralized GMP facility, most of the required QC tests are performed before product shipment. A batch release certificate for the product is sent to the research center. This batch release certificate is provided by the Quality Authorized Person (QP) at the manufacturing site to ensure that the product is suitable for administration and conforms to the specifications stated in the product instructions.

[0260] The manufacturing facility prepared single doses calibrated within the range of 7.4 GBq ± 10% (200 mCi) between t0+6 hours and t0+52 hours after production. The release certificate reported the exact activity provided and the time to achieve this activity. At the date and time of infusion, the total radioactivity of each single-dose vial was 7,400 MBq. Given a fixed volumetric activity of 370 MBq / ml at the calibration date and time, the solution volume was adjusted between 20.5 ml and 25.0 ml to provide the amount of radioactivity required at the infusion date and time.

[0261] The composition of the medicine is listed in the table below.

[0262] Lutathera ® Composition of the medicine (per vial)

[0263]

[0264] Tc = Calibration Time = EOP: End of Production = t0 = Activity Measurement of the First Vial

[0265] RSE: Radiostability Enhancer

[0266] 1 The synthesis and formulation of active pharmaceutical ingredients (APIs) into finished products is a continuous process; therefore, APIs are not isolated processes.

[0267] 2 176+177 Lu-DOTA 0 -Tyr 3 -Octrenic acid represents the fraction of peptides labeled as lutetium (radioactive and non-radioactive lutetium) and corresponds to 176 Lu-DOTA 0 -Tyr 3 -Octellanic acid and 177 Lu-DOTA 0 -Tyr 3 - Total octreotic acid

[0268] Based on 740 GBq / mL (20 Ci / mg) at labeling time 177 The indicated values ​​calculated at calibration time are: Lu ratio activity, average synthetic yield of 80%, and radiochemical purity of ≥97%.

[0269] This amount also includes water for injection that was filled into bulk solution bottles (0.5 ± 0.1 mL) and primary packaging (0.20 ± 0.02 mL) during the sterilization process, as the amount added is considered negligible.

[0270] Concomitant therapy: 2.5% Lys-Arg sterile amino acid solution

[0271] In this study, patients randomly assigned to the Lutathera group will also receive 2.5% Lys-Arg solution to protect the kidneys (see table below). For renal protection purposes, the 2.5% Lys-Arg solution must be administered intravenously over 4 hours (infusion rate: 250 ml / h); the infusion should begin 30 minutes before the start of the Lutathera infusion and continue during the Lutathera infusion and for at least 3 hours after the infusion.

[0272] If hyperkalemia is > 6.0 mmol / L (CTCAE grade 3), it must be corrected before 2.5% Lys-Arg infusion.

[0273] If the 2.5% Lys-Arg solution cannot be prepared at the hospital pharmacy, it will be provided by the sponsor. The composition of the 2.5% Lys-Arg solution is shown below.

[0274] Composition of 2.5% Lys-Arg sterile solution

[0275]

[0276] The recommended pH range for 2.5% Lys-Arg sterile solution is 5.0-7.0, and the osmotic pressure is 420-480 mOsm / kg.

[0277] In addition to prophylactic antiemetics, researchers are advised to use antiemetics commonly used in their facility to treat chemotherapy-induced nausea in cases of persistent nausea or vomiting during amino acid administration. Among these antiemetics, aprepitant (Emend) should be considered. ® Haloperidol may be considered if the suggested antiemetic regimen is ineffective and the patient continues to vomit. ®) and Laurazepam (Ativan) ® ) as adjunctive therapy (iv or oral).

[0278] If previous treatment for nausea and vomiting has been insufficient, a single dose of corticosteroid may be used, provided it is not administered before the start of the Lutathera infusion or within one hour after the end of the Lutathera infusion.

[0279] Concomitant therapy: 30 mg long-acting octreotide (Sandostatin) ® LAR Depot)

[0280] Sandostatin ® LAR Depot (Long-Acting Octreotide) is a drug supplied as a single-use kit containing a 6 mL vial (10 mg, 20 mg, or 30 mg for intramuscular injection), a syringe containing 2.5 mL of diluent, two sterile 1½" 19 gauge needles, and two alcohol wipes. For long-term storage, Sandostatin... ® LARDepot should be stored at a refrigerated temperature between 2°C and 8°C (36°F–46°F) and protected from light until use. Each kit also includes instructions for preparing the injectable drug suspension.

[0281] Long-acting octreotide 30 mg (Sandostatin) ® LAR Depot (Long-acting octreotide) is preferably administered the day after each Lutathera infusion and no earlier than 4 hours after the completion of the Lutathera infusion. Due to the 6-week washout period before each Lutathera injection, additional long-acting octreotide administration between Lutathera treatments is not recommended. Once Lutathera treatment is completed, and if Lutathera infusions have been paused (e.g., due to dose-modification toxicity), the patient will continue to receive 30 mg of long-acting octreotide at 4-week intervals until the completion of treatment.

[0282] control group

[0283] 60 mg long-acting octreotide (Sandostatin) ® LAR Depot)

[0284] Sandostatin ®LAR Depot (Long-Acting Octreotide) is a drug supplied as a single-use kit containing a 6 mL vial (10 mg, 20 mg, or 30 mg for intramuscular injection), a syringe containing 2.5 mL of diluent, two sterile 1½" 19 gauge needles, and two alcohol wipes. For long-term storage, Sandostatin... ® LARDepot should be stored at a refrigerated temperature between 2°C and 8°C (36°F–46°F) and protected from light until use. Each kit also includes instructions for preparing the injectable drug suspension.

[0285] In the control group, patients received long-acting octreotide 60 mg (Sandostatin) at 4-week intervals (+ / - 3 days) unless they experienced disease progression or death. ® Sandostatin was administered via LAR Depot until the end of the treatment period (i.e., two injections of Sandostatin per treatment session). ® LAR 30 mg).

[0286] Patients who have not used SSA prior to enrollment in this study should receive a first planned dose of 30 mg and a second (and subsequent) planned dose of 60 mg (full dose).

[0287] One or more other treatments

[0288] rescue drugs

[0289] Short-acting octreotide

[0290] According to the manufacturer's prescribing information, subcutaneous short-acting octreotide injection can be used to control symptoms (i.e., diarrhea and hot flashes) in patients in both study groups. The short-acting octreotide used for symptom control is administered to patients (at home) at the investigator's discretion.

[0291] Other anti-cancer treatments

[0292] During the study treatment period, patients may not receive any other systemic therapy (chemotherapy, biologic, or any investigational agent) for GEP-NET other than Lutathera and / or short-acting octreotide and / or long-acting octreotide. Additional local treatments, such as surgery or external beam radiation, may be administered to additional sites without compromising the assessment of treatment response; surgery must not be performed within 12 weeks prior to Lutathera administration.

[0293] The final administration of long-acting SSA before the start of treatment can be performed during the screening period prior to randomization, but should be carefully planned to allow for a 6-week washout period before administration of Lutathera.

[0294] New anticancer therapies administered after progression or during follow-up must be registered in the eCRF.

[0295] Banned drugs

[0296] Somatostatin and its analogues bind competitively to the somatostatin receptor. Therefore, long-acting somatostatin analogues should be avoided for up to 6 weeks prior to Lutathera administration. If necessary, patients may be treated with short-acting somatostatin analogues from 6 weeks to 24 hours prior to Lutathera administration.

[0297] There is some evidence that corticosteroids can induce downregulation of the SST2 receptor. Therefore, as a precaution, repeated administration of high doses of glucocorticoids should be avoided during Lutathera treatment. Patients with a history of long-term glucocorticoid use should be carefully evaluated for adequate somatostatin receptor expression. It is unclear whether intermittent use of glucocorticoids to prevent nausea and vomiting during Lutathera administration will cause interactions. Therefore, glucocorticoids should be avoided as prophylactic antiemetic therapy. In cases where prior treatment for nausea and vomiting has been inadequate, a single dose of corticosteroid may be used, provided it is not administered before the start of the Lutathera infusion or within one hour after the end of the Lutathera infusion.

[0298] In preclinical studies, human CYP450 enzymes were not inhibited or significantly induced, and there were no specific interactions with P-glycoproteins (efflux transporters) or OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3 and BCRP transporters, suggesting that Lutathera is unlikely to induce clinically relevant metabolic or transporter-mediated interactions.

[0299] The following precautions regarding potential drug-drug interactions (DDIs) with octreotide must be observed (according to the octreotide label):

[0300] - When administered concurrently, dosage adjustments may be required for pharmaceutical products such as beta-blockers, calcium channel blockers, or agents that control fluid and electrolyte balance.

[0301] - When administered concurrently, dosage adjustments for insulin and antidiabetic medications may be necessary.

[0302] - Octreotide has been found to reduce the intestinal absorption of cyclosporine and delay the intestinal absorption of cimetidine.

[0303] - The co-administration of octreotide and bromocriptine increases the bioavailability of bromocriptine.

[0304] - Caution should be exercised when using drugs that are primarily metabolized by CYP3A4 and have a low therapeutic index (e.g., quinidine, terfenadine).

[0305] Octreotide can alter the absorption of dietary fat in some patients.

[0306] Decreased vitamin B12 levels and abnormal Shilling tests have been observed in some patients receiving octreotide therapy. Monitoring vitamin B12 levels is recommended during octreotide LAR therapy.

[0307] Subject numbering, treatment allocation, and randomization

[0308] Subject number

[0309] For all patients who have signed up for the ICF, screening numbers will be assigned chronologically, starting with the lowest number available at the trial facility. Patients will be identified by a unique patient identification number (Patient ID), which consists of a center number and a screening number.

[0310] Treatment allocation, randomization

[0311] Following the screening period, eligible patients will be randomly assigned (2:1 ratio) to one of two study groups to receive either Lutathera plus long-acting octreotide (30 mg) or high-dose long-acting octreotide (60 mg). A unique randomization number will be assigned to each patient to connect them to the treatment group. Randomization will be stratified according to a stratified replacement block scheme, based on tumor grade (G2 vs. G3) and tumor origin (pNET vs. other origins).

[0312] The procedure for obtaining patient randomization numbers will be described in the investigator's manual.

[0313] Treatment for blindness

[0314] Due to the radioactivity of Lutathera and its infusion method, a blinded design could not be implemented in this study.

[0315] Dosage adherence, modification and discontinuation

[0316] Dosage compliance

[0317] For each single dose of Lutathera, a deviation of ±10% from the predetermined dose is allowed.

[0318] Dosage modification

[0319] Both groups will be subject to modified toxicity (DMT). Patients who discontinue or permanently discontinue treatment due to toxicity meeting the DMT criteria must be followed up regularly (at least weekly) until the event subsides or stabilizes, whichever occurs first.

[0320] If necessary, consult an appropriate clinical specialist, such as a cardiologist, endocrinologist, hepatologist, or nephrologist.

[0321] Dose-modified toxicity (DMT) of Lutathera

[0322] For patients who do not tolerate the prescribed dosing schedule, dose adjustments are permitted to allow them to continue receiving study treatment.

[0323] This article outlines the criteria for Lutathera dosage modifications due to toxicity.

[0324] If a patient requires a delay of >16 weeks from the date of last dose to receive Lutathera, study treatment should be discontinued. In exceptional circumstances, if a patient clearly benefits from study treatment (i.e., stable condition, partial response, or complete response) and the investigator believes there are no safety concerns, the patient may continue study treatment after discussion with the sponsor's medical monitor.

[0325] For each patient, a maximum of one dose reduction will be allowed, after which the patient will discontinue the study.

[0326] These dose changes must be recorded on the appropriate electronic case report form (eCRF).

[0327] Lutathera dosage modification due to adverse events

[0328]

[0329] also,

[0330] • If a hypersensitivity reaction is observed due to the active substance of Lutathera or any excipient, Lutathera treatment should be permanently discontinued.

[0331] • Temporarily suspend Lutathera treatment until the condition subsides or returns to pre-treatment stability.

[0332] - The development of complications (such as urinary tract infection);

[0333] - Major surgery: Wait 12 weeks after the surgery, then restart Lutathera treatment.

[0334] Following resolution of the DMT, patients may receive subsequent planned treatment at the full dose (if resolution occurs within 9 weeks of the previous dose) or 50% of the standard treatment dose (if resolution occurs within 9–16 weeks of the previous dose), provided this is safe for the patient or the risk-benefit assessment is favorable. If the same DMT recurs after treatment with a reduced dose of Lutathera, the patient will remain in the study and continue to undergo scheduled clinical / tumor evaluations until tumor progression, but will no longer receive Lutathera treatment. Long-acting octreotide 30 mg will continue to be taken monthly. If the DMT event does not recur, the next treatment will be at the full dose, provided this is deemed safe for the patient or the risk-benefit assessment is favorable.

[0335] If a patient experiences DMT during Lutathera therapy, subsequent Lutathera treatment is permitted, provided the DMT resolves within 16 weeks of the intolerant administration. In any case, the patient will continue to receive 30 mg of long-acting octreotide.

[0336] Because Lutathera will be supplied as a single-dose "ready-to-use product" to avoid any operations outside the manufacturing facility, the possibility of overdose is extremely low. Furthermore, the infusion system method does not permit the simultaneous use of two separate Lutathera solution vials (see Pharmacy Handbook). The administered radiation dose must not be doubled, either in absolute terms or by shortening the time interval between treatments. Treatment (radiation dose and administration time) will be monitored during the study period, and any unauthorized treatment modifications will be considered a serious breach of protocol.

[0337] Dose-modified toxicity (DMT) of octreotide LAR

[0338] Control group (octreotide LAR 60 mg)

[0339] In the long-acting octreotide treatment group, dose adjustments will be made if grade 3 or 4 toxicity occurs, especially with severe abdominal symptoms and hypoglycemia / hyperglycemia that may be related to long-acting octreotide. Dose adjustments will also be made if such adverse events are observed that are unlikely to be related to the study drug but are related to other possible or concomitant causes, and full administration of long-acting octreotide would pose a safety risk to the patient.

[0340] If a patient experiences DMT during long-acting octreotide treatment, the subsequent treatment dose will be reduced from 60 mg to the previously well-tolerated dose (or even temporarily paused), and then at the next treatment, the dose will be increased to the initial 60 mg dose of long-acting octreotide, provided that this is safe for the patient or that the risk-benefit assessment is favorable.

[0341] In any case (including when the long-acting octreotide treatment dose is paused), the patient remains in the study and continues to undergo scheduled clinical / tumor assessments until tumor progression, unless the patient inevitably withdraws from the study.

[0342] Lutathera group (octreotide LAR 30 mg)

[0343] All DMT recommendations in the control group (octreotide LAR 60 mg) also apply to the Lutathera group, where octreotide LAR is administered at the standard approved dose (30 mg). Overall, the exact dose reduction level, pause duration, and criteria for restarting and resuming the dose in the control group will be defined by the attending physician based on clinical judgment and the product label.

[0344] Dosage discontinuation

[0345] Discontinuation of either study treatment (Lutathera or long-acting octreotide) will not be a reason for a patient to withdraw from clinical / oncology evaluation until tumor progression or early termination of the study. However, in the event of a patient withdrawing from clinical / oncology evaluation or early termination of the study (based on the patient's or investigator's decision), the patient will undergo all necessary examinations for the End of Treatment (EOT) visit.

[0346] If treatment is discontinued due to laboratory abnormalities or any evidence of toxicity, investigators will collect additional samples at appropriate intervals for repeat or additional analysis. Patients will be closely monitored until sufficient information is available to determine the cause or magnitude of the decline. Appropriate remedial measures should be taken, and the response recorded in the eCRF.

[0347] Preparation and distribution of Lutathera

[0348] Patients do not need to fast before treatment.

[0349] Lutathera treatment will consist of a cumulative radiation dose of 29.6 GBq (800 mCi), administered in four divided doses at intervals of 8 ± 1 weeks or up to 16 weeks to allow for the resolution of acute toxicity. Each dose will be infused over 30 minutes.

[0350] In addition to Lutathera treatment, the patient will receive 30 mg of long-acting octreotide until the treatment period is completed.

[0351] Before each Lutathera treatment:

[0352] 1. Unless clinically impossible, long-acting octreotide should not be administered within 6 weeks of the next Lutathera treatment. In other words, only one 30 mg long-acting octreotide injection may be administered between two Lutathera injections at regular intervals (8 weeks) (possibly one day after Lutathera administration or at least 4 hours after the completion of the Lutathera infusion). If long-acting octreotide is not used, the patient must receive an equivalent dose of short-acting octreotide for sc treatment. “Clinically impossible” means that the patient’s actual clinical condition does not allow for treatment cessation due to a carcinoid syndrome that cannot be treated by other means. Long-acting octreotide injections should be planned upon enrollment to allow adequate washout time before the first Lutathera treatment. If the time interval between Lutathera treatments is prolonged for any reason, long-acting octreotide should continue to be administered every 4 weeks, but should not be administered within 6 weeks of the next Lutathera treatment.

[0353] 2. Short-acting octreotide should not be used within 24 hours prior to the Lutathera treatment date unless the patient's actual clinical condition precludes treatment interruption due to symptoms of carcinoid syndrome that cannot be treated by other means. Short-acting octreotide may only be continued if tumor uptake on SRI imaging is greater than hepatic uptake during continuous somatostatin analogue treatment (see Exclusion Criteria).

[0354] 3. Treatment with 30 mg long-acting octreotide can be resumed after administration of Lutathera. Specifically, the recommended time before resuming long-acting octreotide (or short-acting octreotide sc) is one day, but the minimum interval between receiving long-acting octreotide (or short-acting octreotide sc) after Lutathera is 4 hours, unless not permitted as described above.

[0355] The total amount of radioactivity applied was determined by measuring the radioactivity in the Lutathera vials before and after application.

[0356] The supportive care regimen for 30 mg long-acting octreotide is shown in the table below.

[0357] Lutathera group: Dosage schedule of Lutathera, 30 mg long-acting octreotide, and short-acting octreotide sc. 1 .

[0358]

[0359] Symbol 1: (X) Lutathera treatment, (Y) Long-acting octreotide treatment, (Z, Z→) Daily octreotide injections (•) No treatment

[0360] 2. The interval between Lutathera treatments can be increased to 16 weeks to allow acute toxicity to subside.

[0361] 3. If Lutathera treatment is delayed due to DMT, long-acting octreotide can be continued at 4-week intervals, but should not be administered within 6 weeks prior to the next Lutathera treatment; patients should use octreotide sc during the washout period.

[0362] 4. After patients received all 4 doses of Lutathera at intervals of 8 ± 1 weeks, or after discontinuing Lutathera treatment due to toxicity, patients continued to receive 30 mg long-acting octreotide (1 im injection every 4 weeks) until the end of the treatment period, unless progression occurred.

[0363] On the day of Lutathera treatment, and before starting the infusion of 2.5% Lys-Arg solution, administer an intravenous bolus of an antiemetic (suggested options: granisetron (3 mg), ondansetron (8 mg), or tropisetron (5 mg)). Prednisone must be avoided as a prophylactic antiemetic because somatostatin receptors may be downregulated.

[0364] If hyperkalemia is > 6.0 mmol / L (CTCAE grade 3), it must be corrected before 2.5% Lys-Arg infusion.

[0365] If the patient still experiences nausea or vomiting after using this medication, the doctor may decide to treat the patient with other antiemetic medications as appropriate.

[0366] Sterile amino acid solution and Lutathera are administered concurrently via peripheral intravenous infusion at a constant infusion rate using a pump or any other infusion system. The amino acid infusion begins 30 minutes before the start of the Lutathera infusion and continues for a total of 4 hours (extended to up to 6 hours if adverse reactions necessitate interruption or slowing of the infusion rate). Patients are permitted to urinate during the amino acid infusion.

[0367] The infusion rates are listed in the table below.

[0368] Administration procedure for antiemetics, sterile amino acid solution, and Lutathera.

[0369]

[0370] Following administration of Lutathera, the patient should remain in the clinical trial facility for an additional 4 to 5 hours in an area with appropriate radiation shielding to prevent unnecessary exposure to others. Upon discharge, the patient should be provided with a written instruction outlining the precautions they must take to minimize radiation exposure to those around them.

[0371] Post-treatment, a crisis may occur due to the excessive release of hormones or bioactive substances; therefore, overnight hospitalization for observation should be considered. Recommended treatment for patients with hormonal crisis includes: intravenous high-dose somatostatin analogues, intravenous fluids, corticosteroids, and correction of electrolyte imbalances in patients with diarrhea and vomiting.

[0372] Treatment of research therapy and additional treatment

[0373] Lutathera, amino acids, and long-acting octreotide must be administered in research facilities. Short-acting octreotide is administered by the patient themselves.

[0374] Research drugs must be stored, handled, and administered by qualified / authorized personnel, and must be prepared in accordance with Lutathera's pharmaceutical quality requirements and radiation safety regulations.

[0375] The inventory and accountability records for investigational drugs, rescue drugs, and patient-returned drugs will be maintained by the investigator / pharmacist and must be documented throughout the study. Returned supplies must not be redistributed, or even given to the same patient. The investigator may not provide investigational drugs to anyone other than patients in this study.

[0376] Unused long-acting octreotide and amino acids must be stored at the testing facility and provided prior to monitoring visits so that the CRA can monitor drug accountability.

[0377] Based on the decision and approval of the IPM / sponsor, used / unused drugs (except for Lutathera, which will be disposed of locally in accordance with all requirements for the disposal of radioactive materials) will be returned to the appropriate local warehouse for destruction upon completion of the study or upon expiration of the study.

[0378] The investigator / pharmacist agrees to continuously inventory the supply of investigational drugs and record the results in the investigational drug accountability log. It must be possible to reconcile delivery records with records of used and unused drugs. Any discrepancies must be explained and clarified. Appropriate delivery and return forms must be signed and dated by the head of the clinical trial facility and kept on file. All returns or disposals of investigational drugs will be documented appropriately.

[0379] Visit schedule and assessment

[0380] Once all screening / baseline assessments are completed, randomization must be performed.

[0381] Baseline CT / MRI scans should be performed as soon as possible, on or before randomization (within one week), to ensure they reflect the disease state prior to the start of treatment. Baseline CT / MRI results must be assessed by the investigator prior to randomization.

[0382] The screening period must be shortened as much as possible so that patients can be treated shortly after signing the informed consent form.

[0383] Randomization should be conducted as soon as possible after all screening assessments and eligibility confirmation are completed. Since the production and shipment of Lutathera will take approximately 12 days, if a patient is randomized to the Lutathera group, the first dose of Lutathera must be ordered immediately after randomization.

[0384] During the study, patient safety and tolerability will be evaluated according to the visit schedules of the Lutathera group and the long-acting octreotide group (the visit schedules are allowed to vary by ±1 week).

[0385] All visits / assessments should be conducted on the assessment schedule or as close as possible to the designated date / time. Missed or rescheduled visits should not result in automatic termination. Subjects who prematurely discontinue study treatment for any reason should be scheduled for a visit as soon as possible, at which time all assessments listed in the EOT / Early Termination Visit will be performed. At the EOT / Early Termination Visit, all allocated study products should be verified, and adverse events and concomitant medications should be recorded on the eCRF.

[0386] Because the randomization date and the first treatment date may not be consistent, a misalignment should be observed between tumor imaging examinations (CT / MRI scans) scheduled from the randomization date and other clinical and laboratory evaluations scheduled from the first treatment date.

[0387] The assessments listed in the table below will be conducted centrally. The centralized evaluation procedures will be described in detail in the laboratory manual provided to each participating institution.

[0388] The assessment schedule lists all assessments and their execution times. All data obtained from these assessments must be supported by the subject's source documentation.

[0389] The assessment was conducted by the central government.

[0390]

[0391] Demographic and baseline characteristics

[0392] Each patient's date of birth, sex, race, weight, height, and relevant baseline characteristics will be recorded in the e-CRF.

[0393] Diagnosis and severity of cancer

[0394] Patients' medical history will be collected, including the initial diagnosis of documented gastrointestinal-pancreatic cancer, the date of diagnosis (for metastatic or locally advanced disease, the diagnosis date must not be earlier than 6 months prior to screening), and the disease status at the time of entry into the study. This includes the date of initial diagnosis and the presence or absence of metastases (specifying the metastatic sites). TNM criteria will be used to determine the disease stage at the time of initial diagnosis.

[0395] Ki67

[0396] All patients require a documented local assessment of the Ki67 proliferation index based on surgical / biopsy specimens of the primary tumor or liver or soft tissue metastases, and evaluation by microscopy and immunohistochemical staining.

[0397] For eligible patients, Ki67 must be ≥ 10% and ≤ 55%.

[0398] Previous anti-tumor drugs / radiotherapy / surgery

[0399] Information related to any previous chemotherapy, hormone therapy, immunotherapy, radiation, or surgery received by the patient will be recorded. If applicable, previous somatostatin analogue treatments will also be recorded.

[0400] SRI tumor uptake in documented lesions

[0401] All patients are required to undergo [68Ga]-DOTA-TOC (e.g., Somakit-TOC) within 3 months prior to the study's expected randomization date. ® PET / CT (or target lesion-based MRI, if applicable) imaging or [68Ga]-DOTA-TATE PET / CT (or target lesion-based MRI, if applicable) imaging (e.g., NETSPOT) ® ), or somatostatin receptor scintillation imaging (SRS) using [111In]-spray peptide (Octreoscan) ® SPECT / CT, or SRS or PET / CT using [99mTc]-Tektrotyd or [64Cu]-DOTA-TATE (or target lesion-based MRI, if applicable) imaging (repeat examinations available for more than 3 months are required to evaluate patient eligibility).

[0402] If the patient participates in the optional treatment extension period, SRI imaging must be repeated before crossover treatment (after progression in the control group) and before optional retreatment (after progression in the Lutathera group).

[0403] Prior to randomization, crossover, and retreatment, a local assessment of the recorded SRI tumor uptake in the target lesions will be performed to evaluate patient eligibility. Tumor uptake in all target lesions must be greater than hepatic uptake.

[0404] Images will also be submitted to the Central Imaging Center for a second review: SRI images will not undergo a central "real-time" evaluation, but should be submitted to the Central Imaging Center within one month. Patients who fail the screening do not need to submit SRI images.

[0405] If the soft tissue components otherwise meet the definition of measurability according to RECIST 1.1, then osteolytic lesions with identifiable soft tissue components as evaluated by CT or MRI can be considered measurable lesions (in any case, fragmented osteopathies are not measurable). Therefore, if a bone lesion has the above characteristics and the SRI is positive, the patient can be enrolled.

[0406] If the primary tumor has been removed, the metastatic tumors will be evaluated using tumor assessment methods including SRI.

[0407] The imaging manual and imaging regulations specify the operational details and quality certificates.

[0408] Previous / companion medications

[0409] All medications taken from the start of screening until the end of the treatment period / optional treatment extension period / optional retreatment period or early termination should be recorded. This includes prescription and over-the-counter medications taken within this timeframe.

[0410] During the follow-up period, concomitant medications must be collected only if administered for related SAE / AESI and / or secondary hematologic malignancies. Furthermore, any further antitumor treatment administered after progression must be reported until the end of the follow-up period.

[0411] If any additional medications or procedures were administered during the study period for the treatment of suspected or confirmed COVID-19, request the trial facility to enter this as a concomitant medication or procedure (e.g., intubation) and state / select the “Reason” to match the reported relevant adverse event (if applicable).

[0412] Tests performed to diagnose COVID-19 symptoms should be reported only as adverse events and should not be repeated in accompanying medications / surgeries and medical procedures or equivalent CRFs.

[0413] Efficacy evaluation

[0414] 1. Progression-free survival

[0415] The primary efficacy endpoint is progression-free survival (PFS) as measured by objective tumor response, determined according to RECIST criteria version 1.1 (Eisenhauer et al., 2009). Tumor response will be assessed locally and at the center.

[0416] Compared to MRI, three-stage CT imaging is the preferred mode for determining objective tumor response. Combined PET / CT, including the use of IV contrast agents, should only be used when the diagnostic quality of CT is similar to that of CT without PET.

[0417] Baseline CT / MRI scans should be performed as soon as possible, on or before randomization (within one week), to ensure they reflect the disease state prior to the start of treatment. Baseline CT / MRI results must be assessed by the investigator prior to randomization.

[0418] The tumor diameter of the indicative lesion used for response assessment should be measured at the location closest to the baseline CT or MRI assessment.

[0419] Starting from the randomization date, restaging will be scheduled at regular intervals in both treatment groups (week 16 ± 1, week 24 ± 1, and then every 12 ± 1 weeks). Every effort should be made to avoid discrepancies in these timings between the two treatment groups. If delays occur, the reasons for the delays must be documented, and a CT / MRI evaluation should be performed as soon as possible.

[0420] If a CT / MRI scan is performed on the same day as Lutathera administration (e.g., in cases of treatment delay due to DMT or scheduling issues), the scan should be performed before drug administration. When a CT / MRI assessment is performed more than 6 weeks earlier or later than planned, the timing of the next reassessment must be discussed with the study's medical monitor and adjusted to gradually return to the original schedule.

[0421] It is recommended that each patient use the same acquisition and reconstruction protocol at all time points. A central, blinded, real-time IRC (Independent Review Committee) assessment will be performed to identify progressive disease. Changes since randomization will be assessed at week 16 ± 1, week 24 ± 1, and then every 12 ± 1 weeks until the primary endpoint of PFS is reached, and then until week 72 post-randomization, unless the patient experiences progression or death.

[0422] Once 99 PFS incidents occur, the sponsor will notify all centers and their ethics committees.

[0423] Additional PFS / PFS2 data will be collected up to 3 years from the end of the last patient's treatment period (during the follow-up period, RECIST 1.1 assessments will be performed only once every 6 months (±1 month) locally).

[0424] As necessary, additional imaging assessments may be performed at any time during the study period to support efficacy evaluations of participants, at the investigator's discretion. Clinically suspected disease progression at any time requires prompt physical examination and imaging assessment, rather than waiting for the next scheduled imaging assessment. These additional scans should be provided to the IRC for central evaluation. If an imaging assessment deviates from the schedule due to suspected progression, subsequent imaging assessments should be performed according to the original imaging schedule.

[0425] During the post-progression and follow-up period, researchers must make every effort to collect additional information on further anti-tumor therapies and scan assessment results (RECIST 1.1 local evaluation) to evaluate the second progression-free survival (PFS2) for both study groups.

[0426] For patients with advanced disease who are eligible for crossover or retreatment, CT / MRI scans performed after eligibility for crossover or retreatment will follow a visit schedule that starts counting from the first dose of Lutathera.

[0427] For patients who received Lutathera retreatment, a separate PFS analysis will be performed during the retreatment period using the same definition, but the baseline will be based on an assessment of tumor progression, thus allowing for Lutathera retreatment. The PFS analysis during the retreatment period will be descriptive only.

[0428] The imaging manual and imaging regulations specify the operational details and quality certificates.

[0429] Objective response rate (ORR), duration of response (DOR), and time to second progress (PFS2)

[0430] The objective response rate (ORR) will be calculated as the percentage of patients with the best overall response, either a partial response (PR) or a complete response (CR). The duration of response will be calculated from the initial response until documented tumor progression.

[0431] Duration of response (DOR) is defined as the time from initial satisfaction of response criteria (CR or PR) to the onset of RECIST progression or death due to underlying disease. DOR for each group will be reported descriptively without inter-group comparisons.

[0432] As an additional secondary exploratory endpoint (local RECIST assessment), time to second progression (PFS2) will be evaluated in both study groups. PFS2 is defined as the time from randomization to disease progression or death due to any cause (on any treatment) following the first onset of disease progression.

[0433] For patients who received Lutathera retreatment, separate ORR, DoR, and PFS2 analyses will be performed during the retreatment period using the same definitions as ORR and DoR, but the new baseline will be based on tumor assessment showing progression, thus allowing for Lutathera retreatment. The definition of PFS2 remains the same. ORR, DoR, and PFS2 analyses during the retreatment period will be descriptive only.

[0434] We recognize that limitations, including crossover therapy and lower scan frequency during follow-up, reduce the likelihood of drawing definitive conclusions about PFS2.

[0435] After the center confirms the first progression and the local confirms the second progression (i.e., after the PFS2 event), trial facilities that have not performed the 6-month routine CT / MRI follow-up scan for patients with advanced GEP-NET may omit this examination in subsequent patient follow-ups (without protocol deviation).

[0436] Overall survival

[0437] Overall survival (OS) will be calculated from the date of randomization until the date of death from any cause; if the patient receives other anti-cancer treatments after receiving the study drug, OS will not be censored.

[0438] For patients who received Lutathera retreatment, their overall survival (OS) will be estimated separately. The definition of OS remains the same, and this analysis of retreatment patients will be descriptive only.

[0439] Survival data will be analyzed when the primary endpoint (PFS) is analyzed and will continue to be evaluated up to 4 years from the last patient’s randomization or 6 months after the last crossover treatment / retreatment dose in the study, whichever occurs later.

[0440] Quality of life

[0441] The impact of treatment on health-related QoL will be assessed using the EORTC QLQ-GINET21, EORTC QLQ-C30, and EQ-5D-L5 questionnaires, which patients will complete before receiving their CT / MRI results. Baseline changes will be assessed every 12 ± 1 weeks from the date of initial treatment until the end of treatment.

[0442] Applicants will provide a form in the country-specific language.

[0443] Safety and tolerability

[0444] Adverse events

[0445] All adverse events (AEs), whether or not they are reported voluntarily by the patient, will be recorded from the date of signing the ICF until the end of the treatment period / optional treatment extension period.

[0446] During the follow-up period, only relevant SAEs and related AESIs, excluding secondary hematologic malignancies, will be recorded. AESIs related to secondary hematologic malignancies will be recorded throughout the study period, regardless of causation. An independent steering committee will evaluate patient safety throughout the study. During the follow-up period, concomitant medications must be collected in the eCRF only if administered due to relevant SAEs / AESIs and / or secondary hematologic malignancies.

[0447] Laboratory assessment

[0448] The laboratory assessment requires the collection of blood samples for hematology and blood chemistry and urine samples for urine analysis. The laboratory assessment will be conducted at the research facility.

[0449] During screening All patients will undergo screening laboratory assessments, including hematology and blood chemistry, within 3 weeks prior to the expected date of their first treatment (preferably within 2 weeks in the Lutathera group).

[0450] During the treatment period (including crossover treatment and retreatment):

[0451] • In Lutathera group : Within 2 weeks before and 4 ± 1 weeks after each Lutathera treatment. Additionally, for the second, third, and fourth Lutathera treatments, further laboratory assessments will be performed on the same day or the day before Lutathera administration. Any blood tests performed 4 weeks after treatment cannot be used as baseline values ​​for the next treatment. After the completion of Lutathera treatment, laboratory assessments will be performed every 12 ± 1 weeks.

[0452] • In the 60 mg long-acting octreotide group: Throughout the study, laboratory assessments will be performed from 4 weeks (±3 days) after the first treatment to week 28, and every 12±1 weeks starting from week 36.

[0453] If a significant laboratory abnormality occurs, or if there is evidence of clinical or laboratory toxicity, the investigator will collect additional samples at appropriate intervals for repeat or additional analysis. The patient will be closely monitored until sufficient information is obtained to determine the cause or magnitude of the decline. Appropriate remedial measures should be taken and responses recorded.

[0454] All safety laboratory results must be evaluated by the investigator before administration of the study drug.

[0455] Any clinically relevant changes from baseline will be recorded on the adverse events page of the e-CRF. In some cases, a single diagnosis may cover all changes that could support that single diagnosis.

[0456] During the COVID-19 pandemic, researchers should consider whether it is possible to arrange for patients who are unable to arrive at clinical trial facilities on time to undergo laboratory testing at local laboratories. Researchers should collect all local laboratory reports and file them in the patient's medical record or form.

[0457] Laboratory assessment 1 .

[0458]

[0459] 1 Laboratory assessments performed on the day of or the day before administration of the second, third, and fourth doses of Lutathera must include at least:

[0460] • Serum urea or blood urea nitrogen and creatinine (including creatinine clearance calculation)

[0461] • Serum potassium, serum total bilirubin, aspartate aminotransferase, alanine aminotransferase

[0462] • Hemoglobin, platelet count, total white blood cell count, and absolute neutrophil count.

[0463] 2 Before each dose of Lutathera, patients must meet the inclusion criteria for Hb, WBC, and platelets at baseline and before each subsequent treatment. If a patient is no longer treatable due to hematological abnormalities, the evaluation must be repeated at least weekly until treatment is resumed.

[0464] 3 Prior to each dose of Lutathera, patients must meet the eligibility criteria for creatinine clearance and total bilirubin at baseline and before each refresh treatment. As an entry criterion, the patient's creatinine clearance, calculated using the Cockcroft-Gault method, must not be < 40 mL / min. During the study period, if the serum creatinine level in the Lutathera group increases by 40% from baseline, or if the creatinine clearance calculated from serum creatinine concentration decreases by more than 40% according to the Cockcroft-Gault formula, the DMT rule must be applied, and the patient must also undergo creatinine clearance (or GFR) measurement. Creatinine clearance should be measured by collecting 24-hour urine. Total urinary protein should also be measured in this collection. If the measured urinary creatinine clearance shows a decrease of ≤ 40% from baseline, treatment can continue.

[0465] The Cockcroft-Gault formula allows this estimate to be made based on the occurrence of hypercreatinine and correlates the patient’s muscle mass (and the resulting creatinine) with weight, sex, and age:

[0466] Estimated creatinine clearance = [[140 - age (years)]] Weight (kg)] / [72 Serum Cr (mg / dL)

[0467] (Multiply by 0.85 for women)

[0468] or

[0469] Estimated creatinine clearance rate = [[140 - age (years)]] Weight (kg)] / [0.814 Serum Cr (umol / L)

[0470] (Multiply by 0.85 for women)

[0471] 4 In South Korea alone, the CgA assessment was suspended in Q3 2022 due to a shortage of laboratory test kits.

[0472] 5 In the UK, a serum pregnancy test is required at baseline.

[0473] During the follow-up period, both research groups will undergo laboratory assessments (hematology and blood chemistry) every 6 months (±1 month).

[0474] Safety monitoring and reporting

[0475] Adverse event definition and reporting requirements

[0476] Adverse events

[0477] An adverse event (AE) is any unfortunate medical event (e.g., any adverse or unexpected sign [including abnormal laboratory findings], symptom, or illness) that occurs in a subject or clinical study participant after written informed consent has been given to participate in the study. Therefore, an AE may or may not be temporally or causally related to the use of the drug (investigation) product.

[0478] Researchers have a responsibility to manage the safety of individual participants and identify adverse events.

[0479] Abnormal laboratory values ​​or test results that occur after informed consent are considered adverse events only if they induce clinical signs or symptoms, are deemed clinically significant, require treatment (e.g., hematological abnormalities requiring blood transfusion or blood stem cell support), or require a change of investigational drug.

[0480] Researchers have a responsibility to manage the safety of individual participants and identify adverse events.

[0481] Adverse events that begin or worsen after informed consent must be recorded in the adverse event eCRF. Conditions present at the time of informed consent must be recorded in the subject's medical history page in the eCRF. Adverse event surveillance must continue for at least 30 days (or 5 half-lives, whichever is longer) after the last dose of study treatment. Adverse events (including laboratory abnormalities constituting AEs) must be described using diagnoses rather than individual underlying signs and symptoms whenever possible. When a definitive diagnosis cannot be identified, each sign or symptom must be reported as a separate adverse event.

[0482] During each visit during the study period, adverse events must be sought through non-directive questioning of the participants. Adverse events may also be detected when they are discovered during a visit, between visits, or voluntarily reported by the participants through physical examination, laboratory testing, or other assessments.

[0483] Adverse events must be recorded under the relevant signs, symptoms, or diagnoses, with the following information (if possible):

[0484] 1. Severity level or Common Toxicity Standard (CTC) AE level.

[0485] a. If you select "Severity Level", the following will be included:

[0486] i. Mild: Usually brief and does not interfere with normal activities.

[0487] ii. Moderate: Discomfort level sufficient to interfere with normal activities

[0488] iii. Severe: Impairs normal activities

[0489] b. If you select "CTCAE Level", the following will be included:

[0490] i. Adverse events will be assessed and classified into levels 1 to 5.

[0491] 2. Its relationship to the investigational treatment. If the event is due to lack of efficacy or progression of the underlying disease (i.e., progression of the investigational indication), the assessment of causality will generally be “not questionable.” The basic principle of this guideline is that the symptoms of lack of efficacy or progression of the underlying disease are not caused by the investigational drug, although they occur at the time of administration of the investigational drug, and / or both lack of efficacy and progression of the underlying disease can only be meaningfully evaluated on an analytical cohort basis (rather than on an individual patient basis).

[0492] 3. Its duration (start and end dates) or, if the event is ongoing, results that have not been recovered / regressed must be reported.

[0493] 4. Whether it constitutes an SAE and which severity criteria have been met.

[0494] 5. Actions taken in response to research and treatment

[0495] 6. All adverse events must be treated appropriately. Treatment may include one or more of the following:

[0496] • No change in dosage

[0497] • Dosage reduction

[0498] • Discontinuation of medication / discontinuation of medication

[0499] 7. The outcome, i.e., the state of recovery or whether it is fatal.

[0500] If an event worsens, it should be reported a second time in the eCRF, noting the start date of the toxicity deterioration. Only for Level 3 and 4 adverse events, if improvement to a lower level is determined, a new entry for the event should be reported in the eCRF, noting the start date of the improvement from Level 3 or 4.

[0501] Pre-existing conditions should be recorded in the patient's medical history at the time of informed consent.

[0502] Adverse events (including laboratory abnormalities that constitute AEs) should be described using diagnoses rather than individual underlying signs and symptoms whenever possible.

[0503] Once an adverse event is detected, it must be followed up until it subsides or is determined to be permanent (e.g., continuing at the end of the study), and any changes in severity, the suspected relationship to the intervention required to treat it, and the outcome must be assessed at each visit (or more frequently if necessary).

[0504] Information about adverse drug reactions of investigational drugs can be found in the Investigator's Handbook (IB).

[0505] An abnormal laboratory value or test result can constitute an adverse event only if it meets at least one of the following criteria:

[0506] • They induce clinical signs or symptoms

[0507] • They are considered clinically significant

[0508] •They need treatment

[0509] Clinically significant abnormal laboratory values ​​or test results must be identified by reviewing values ​​that are outside the normal / clinically noteworthy range, significant changes from baseline or the previous visit, or values ​​that are considered atypical for patients with underlying diseases.

[0510] If the progression of GEP-NET (including fatal outcomes) is documented using appropriate methods, it should not be reported as a serious adverse event unless the investigator believes that the progression of the malignancy is related to the investigational treatment.

[0511] If a patient in the study is infected with SARS-CoV-2 (COVID-19) and / or has been tested for SARS-CoV-2 (COVID-19), the trial facility should obtain relevant patient details from the patient's medical record / source data, i.e., the start and end dates of suspected infection, any dates of testing, the name / method of testing and the result (positive / negative), and treatment interruption or discontinuation for each affected patient included in the trial, where information is available.

[0512] If symptoms suggest a suspected COVID-19 infection, the testing facility is required to enter an AE (Adverse Event), termed "suspected COVID-19" or "confirmed COVID-19," if confirmed by testing (e.g., antigen / radiology).

[0513] • For suspected cases, if a test is conducted and COVID-19 is confirmed, the testing facility is required to update the suspected COVID-19 AE record, with the AE terminology being "Confirmed COVID-19," but the start date remains unchanged.

[0514] • For suspected cases, if testing was conducted and COVID-19 was not confirmed, the testing facility is required to follow the normal adverse event reporting process and record the AE term as a diagnosis, or as a symptom if no diagnosis is found. If COVID-19 is still suspected (e.g., a false negative), the AE term may remain "suspected COVID-19" at the investigator's discretion.

[0515] Under normal circumstances, COVID-19 “tests” would not be reported as adverse events. However, in order to fully understand the impact of COVID-19 on trial patients, these tests are needed to understand the patients’ health status and the sequence of events for testing to diagnose COVID-19 symptoms.

[0516] - If a test was conducted, the testing facility is required to enter an additional AE, using appropriate AE terminology based on the test type and result, such as "SARS-CoV-2 test negative" or "SARS-CoV-2 test positive".

[0517] - Start and end dates should be entered as test dates.

[0518] - All other fields on the adverse event CRF should be left blank. The data management department will disable any queries resulting from this.

[0519] - Tests performed after a patient's death should not be reported as adverse events.

[0520] An infection is considered a serious infection and will be reported as a serious adverse event only if it meets the protocol definition of a serious adverse event (SAE).

[0521] Serious adverse events

[0522] SAE is defined as any adverse event [occurrence (or worsening of any pre-existing condition)] that meets any of the following criteria for an undesirable sign, symptom, or medical condition:

[0523] •fatal

[0524] • Life-threatening

[0525] • In the context of SAE, life-threatening refers to a reaction in which the subject is at risk of death at the time of the reaction; it does not mention a reaction that, if more severe (see ICH-E2D guidelines), could lead to death.

[0526] • Leading to persistent or obvious disability / incapacity

[0527] • Constitutes congenital abnormalities / birth defects

[0528] • Hospitalization or extension of the existing hospital stay is required, unless the hospitalization is for:

[0529] The indications for routine treatment or monitoring studies are not related to any worsening of the condition.

[0530] Selective or pre-planned treatment for a pre-existing condition that is unrelated to the indication in the study and has not worsened since the informed consent was signed.

[0531] In the absence of any deterioration in the general condition of the subjects, social causes and temporary care

[0532] For events that do not meet any of the above SAE definitions and do not result in hospitalization, treatment should be provided in addition to emergency outpatient care.

[0533] • Medically significant events, such as those defined as events that endanger the subject or may require medical or surgical intervention to prevent one of the outcomes listed above.

[0534] In determining whether other situations should be considered serious reactions, such as major medical events that may not be immediately life-threatening or result in death or hospitalization but may endanger the subject or may require intervention to prevent one of the other outcomes listed above, medical and scientific judgment should be made. Such events should be considered “medically significant.” Examples of such events are intensive treatment in the emergency room or at home for anaphylactic bronchospasm, blood dysregulation, or seizures that do not lead to hospitalization or the development of drug dependence or abuse (see ICH-E2D guidelines).

[0535] If other severity criteria are not met, and the malignancy is not a disease progression for the research indication, all malignancies will be assessed as serious “medically significant”.

[0536] Any suspected transmission of infectious agent drugs is also considered a serious adverse reaction.

[0537] In the event of a clinical event, all reports of intentional misuse and abuse of the product are also considered serious adverse events.

[0538] A COVID-19 infection is considered a serious infection and reported as a serious adverse event only if it meets the protocol definition of a serious adverse event (SAE). All SAE data should be entered according to the study-level CRF completion guidelines; for example, if a patient dies from COVID-19, the outcome should be reported as "fatal."

[0539] In cases where a patient dies from COVID-19, the cause of death must be clearly stated in the eCRF as either potential COVID-19 or another cause. Therefore, the “Primary Cause / Cause of Death” should state “Suspected COVID-19” or “Confirmed COVID-19”. If testing was conducted after the patient's death and the assessment indicates that the death was due to COVID-19 infection, the “Primary Cause / Cause of Death” should be retrospectively changed from “Suspected COVID-19” to “Confirmed COVID-19”.

[0540] Adverse drug reactions (ADRs)

[0541] An adverse response (ADR) is any dose-related adverse and unintended response to IMP that has at least a reasonably probable causal relationship with IMP. In short, an ADR is an adverse event (AE) that the investigator or research sponsor suspects may be related to IMP.

[0542] Suspected unexpected serious adverse reaction (SUSAR)

[0543] If the nature, severity, or frequency of an event is inconsistent with the applicable product information available in the IMP, the ADR will be assessed as “unexpected.” If it is listed in the Investigator’s Manual, the ADR will be assessed as “expected.”

[0544] SUSAR is considered a serious adverse event that is at least potentially causally related to the drug and whose nature, severity, or frequency is inconsistent with the applicable information in the reference documents available in the IMP.

[0545] In the case of octreotide, "anticipation" will be assessed based on the octreotide reference safety information (RSI) reported in the prescribing information.

[0546] Adverse events of particular concern

[0547] An AESI is defined as an event (serious or non-serious) that has scientific and medical significance for the sponsor's product or program, and for which investigators should continuously monitor and promptly communicate with the sponsor. Such events require further investigation to characterize and understand them.

[0548] The definition of AESI is based on the AESI list established by the NETTER-1 study, as well as on ongoing review of safety data collected from Lutathera's clinical programs and post-marketing.

[0549] These potential risks, even if they do not meet any severity criteria, warrant special attention. AESIs occurring in both enrolled patient groups should be reported to the sponsor in accordance with SAE reporting procedures and timelines for safety analysis. During the treatment period, all AESIs must be reported to the sponsor, regardless of their causal relationship. During the follow-up period, AESIs only need to be reported if they are considered relevant to the study treatment, except for all secondary hematologic malignancies, which must be reported as AESIs regardless of their causal relationship.

[0550] The table below lists the following AESI categories representing the major risks of Lutathera and amino acid therapy.

[0551] Adverse events of particular concern

[0552]

[0553] Blood toxicity:The primary critical organ for Lutathera treatment is the bone marrow. Significant hematologic toxicity (defined as grade 2 or higher thrombocytopenia or grade 3 or 4 anemia, leukopenia / neutropenia) is considered dose-modified toxicity in studies and must be reported as an AESI when it does not strictly meet the criteria for a serious adverse event. Hematologic toxicity must be reported as an AESI if it is accompanied by clinical consequences, such as infection with leukopenia / neutropenia / lymphopenia, bleeding / purpuric lesions under thrombocytopenia (unexplained by other coagulation disorders), or dyspnea / fatigue with anemia (unexplained by underlying carcinoid syndrome or other comorbidities), regardless of its severity.

[0554] Secondary hematologic malignancies Regardless of causation, any secondary hematologic malignancy, including MDS and acute myeloid leukemia, should be reported as AESI / SAE.

[0555] Nephrotoxicity: Because Lutathera is cleared and reabsorbed by the kidneys, the kidneys have always been considered a “critical organ.” Infusion of sterile amino acids can inhibit the reabsorption of Lutathera by the renal tubules, thereby protecting the kidneys. Based on these risk minimization efforts, and in addition to dose-modified toxicity criteria and inclusion criteria (at baseline and before subsequent treatment) related to renal function measurements, renal and urinary tract toxicities are considered as AESIs. Investigators must report renal toxicities as AESIs, including renal failure (from a significant decrease in measured or estimated creatinine clearance to clinically evident renal failure, but excluding obvious non-IMP-induced renal failure), any type of suspected radiation nephropathy such as radiation-induced thrombotic microangiopathy (manifested as, for example, proteinuria, hypertension, edema, anemia, decreased serum haptoglobin), or general symptoms and signs of acute radiation toxicity (e.g., urinary frequency, urgency, nocturia, dysuria, bladder spasms, bladder obstruction, urogenital ulcers or necrosis).

[0556] Cardiovascular and electrolyte imbalances: Based on the investigator's judgment, any clinically significant changes in blood pressure, heart rate, and electrocardiogram parameters within a reasonable timeframe following administration of Lutathera and / or amino acids must be reported as AESI. Similarly, clinical manifestations and / or consequences of hypotension / hypertension, arrhythmias, cardiac conduction disturbances, and other cardiological pathologies demonstrated by objective findings / changes on electrocardiogram or echocardiography should also be considered for AESI reporting. Furthermore, any clinically significant events of hyperkalemia or hypokalemia must be reported as AESI.

[0557] Data analysis and statistical methods

[0558] The primary efficacy and safety analysis will be conducted after approximately 99 PFS events are observed in each central assessment. The primary CSR will be generated after the primary PFS analysis. The primary secondary endpoints will be stratified during the primary PFS analysis. Any additional data from participants who continued treatment after this period and, where protocol allows, continued efficacy follow-up (PFS, OS) and quality-of-life follow-up will be further summarized during the final analysis. A final report supporting the final analysis is planned after the study ends (EOS).

[0559] Advanced accelerator application companies and / or designated contract research organizations (CROs) will perform all analyses.

[0560] Any data analysis conducted independently by researchers should be submitted to Advanced Accelerator Applications before being made public or published.

[0561] Analysis set

[0562] The full analysis set (FAS) includes all subjects randomly assigned to the study treatment. Subjects will be analyzed based on their intention-to-treat principle, according to the treatment assigned and stratified during the randomization process.

[0563] The safety set includes all subjects who have received at least one dose of the study treatment. Patients will be analyzed based on the study treatment they received, where treatment is defined as: randomized treatment if a subject has received at least one dose of the treatment; or first treatment if they have never received randomized / assigned treatment.

[0564] The pharmacokinetic analysis set (PAS) consists of all randomized patients who have received at least one dose of the study drug and have at least one post-dose evaluable PK assessment.

[0565] The crossover treatment group included all patients who were randomly assigned to the Sandostatin LAR Depot (long-acting octreotide) group, who received at least one dose of Lutathera after crossover treatment, and whose disease progression was confirmed by central, blinded, real-time image readings during the randomization period.

[0566] The retreatment group included all patients who were randomly assigned to the Lutathera group and who received at least one dose of Lutathera during the retreatment period after disease progression was confirmed by central, blinded, real-time image readings during the randomization period.

[0567] Subject demographics and other baseline characteristics

[0568] Demographic and other baseline data (including disease characteristics) will be listed for FAS and safety sets by treatment group and a descriptive summary will be provided.

[0569] Categorical data will be presented as frequency and percentage. For continuous data, the mean, standard deviation, median, minimum, and maximum will be presented. For the selected parameter, the 25th and 75th percentiles will also be presented.

[0570] Relevant medical history and current medical conditions at baseline will be summarized separately by system organ classification and preferred terminology (by treatment group).

[0571] treat

[0572] The security dataset will be used for the following analysis. Categorical data will be summarized as frequency and percentage. For continuous data, the mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum values ​​will be presented.

[0573] The duration (in months) of exposure to Lutathera plus standard dose long-acting octreotide (30 mg) and high dose long-acting octreotide (60 mg), as well as the dose intensity (calculated as the ratio of the actual cumulative dose received to the actual duration of exposure) and relative dose intensity (calculated as the ratio of the dose intensity to the planned dose intensity) will be summarized using the safety set through descriptive statistics.

[0574] The accompanying medications and significant non-pharmacological therapies before and after the start of the study will be listed and summarized according to the Anatomical Therapeutic Chemistry (ATC) classification system (by treatment group).

[0575] The number of subjects with dose adjustments (reduction, interruption, or permanent discontinuation) and the reasons will be summarized by treatment group, and all dosing data will be listed.

[0576] Analysis of primary endpoints

[0577] The primary objective of this study was to demonstrate the extension of progression-free survival (PFS) (central assessment according to RECIST 1.1).

[0578] Definition of primary endpoint

[0579] The primary endpoint of this study is progression-free survival (PFS), defined as the time from the date of randomization to the first documented progression or death from any cause. PFS will be assessed via central review in accordance with RECIST 1.1.

[0580] Statistical models, assumptions, and analytical methods

[0581] Assuming PFS uses a proportional hazards model, the null hypothesis will be tested at a one-sided significance level of 2.5%.

[0582] H 01 (Null hypothesis): Θ1 ≥ 0 compared to Ha1 (Alternative assumption): Θ1 < 0

[0583] Where Θ1 is the logarithmic hazard ratio of PFS in the Lutathera plus standard dose long-acting octreotide (30 mg) (experimental) group compared to the high dose long-acting octreotide (60 mg) (control) group.

[0584] The analysis to test this hypothesis and compare the primary efficacy of the two treatment groups will consist of a stratified log-rank test, which favors the Lutathera plus standard-dose long-acting octreotide (30 mg) group at an overall one-sided significance level of 2.5%. Stratification will be based on the following randomization factors (rank: G2 vs. G3; and tumor origin: pNET vs. other origins).

[0585] The analysis will be performed based on the FAS population, according to the randomized treatment group and the stratum assigned to the randomization group. The PFS distribution will be estimated using the Kaplan-Mayer method, and Kaplan-Mayer curves, medians, and associated 95% confidence intervals will be provided for each treatment group. The hazard ratio of PFS and its 95% confidence interval will be calculated from the stratified Cox model using the same stratification factor as the log-rank test.

[0586] If fewer events occur in certain strata, the primary analysis will be changed to a non-stratified analysis (the precise handling of strata will be described in SAP). Both stratified and non-stratified analyses will be presented.

[0587] Analysis of secondary endpoints

[0588] A key secondary objective of this study was to compare the two treatment groups in the following ways:

[0589] ORR: The percentage of patients with the best overall response, either partial response (PR) or complete response (CR) (central assessment according to RECIST 1.1).

[0590] The time to deterioration was defined as the first 10-point deterioration (TTD) for the EORTC QLQ-C30 and EORTC QLQ-GINET21 overall health scales, diarrhea, fatigue, and pain.

[0591] Other secondary objectives of this study were to compare the two treatment groups in the following ways:

[0592] DOR: Duration of Response, defined as the time from a complete or partial response to progression or death from underlying cancer.

[0593] Incidence of adverse events and laboratory toxicity (scored according to CTCAE).

[0594] OS: The time from the randomly grouped date to the date of death due to any cause.

[0595] Key secondary objectives

[0596] If the primary endpoint is significant, key secondary endpoints, overall response rate (ORR) and QoL, will be tested in a stratified manner to protect against Type I error rates. The hypothesis testing order should be ORR, followed by the QoL General Health Scale (TTD, see below), then QoL diarrhea (TTD), (TTD)-fatigue, and (TTD)-pain (TTD). Primary secondary endpoints will be tested during the primary analysis. Only descriptive analyses will be performed during the final analysis.

[0597] According to the central review and RECIST 1.1, the overall response rate (ORR) is defined as the proportion of subjects with a best overall response (BOR) of either a complete response (CR) or a partial response (PR).

[0598] ORR will be calculated based on FAS and according to the ITT principle. ORR and its 95% confidence interval will be presented by treatment group. The Cochran-Mantel-Haenszel chi-square test (stratified by randomization factor) will be used to compare ORR between two treatment groups at a significance level of 2.5% one-sided. As a supporting analysis, locally reviewed ORR and 95% confidence interval will be presented by treatment group.

[0599] Time to deterioration (TTD) was defined as the time from randomization to the first 10-point deterioration in domain scores of the EORTC QLQ-C30 General Health Scale, Diarrhea, Fatigue, and Pain Assessments compared to baseline. The Kaplan-Mayer method was used to estimate the TTD distribution, and Kaplan-Mayer curves, medians, and 95% confidence intervals for the median were provided for each treatment group. Treatment efficacy was tested using a stratified log-rank test. A stratified Cox model was used, with stratified randomization factors, to calculate the hazard ratios and 95% confidence intervals for TTD. Patients without baseline and / or without follow-up were censored at randomization. Diarrhea, fatigue, and pain were considered clinically relevant (Strosberg et al., 2018), identified as primary symptoms in the patient survey (Singh et al., 2018), and TTDs associated with these symptom domains were significant in the post-hoc analysis of NETTER-1.

[0600] Further details regarding the planned sensitivity analysis and supplemental analysis of key secondary endpoints will be provided in SAP.

[0601] Other efficacy endpoints

[0602] Disease control rate (DCR) is defined as the percentage of patients with the best overall response (partial response, complete response, or stable disease, as assessed centrally according to RECIST 1.1). More precisely, it counts the presence of at least one confirmed CR or confirmed PR or SD. DCR will be calculated based on FAS according to ITT principles. DCR and its 95% confidence interval will be presented by treatment group. The Cochrane-Mantel-Haenszel chi-square test (stratified by randomization factor) will be used to compare DCR between two treatment groups at a significance level of 2.5% one-sided. The p-value generated using the Cochrane-Mantel-Haenszel chi-square test is considered a nominal value and cannot be considered a confirmatory value as it is not part of the testing strategy. SAP will suggest how to proceed in cases where few events occur in any stratum.

[0603] Duration of Response (DOR) applies only to subjects who, according to RECIST 1.1, have a best overall response of complete response (CR) or partial response (PR) based on locally reviewed tumor response data. The start date is the date of first documented CR or PR response (i.e., the date the response began, not the date of confirmed response), and the end date is defined as the date of first documented progression or death from underlying cancer, according to local review. Subjects who continue treatment without progression or death from underlying cancer will be censored on the date of their last adequate tumor evaluation. The DOR for all subjects with confirmed BOR of CR or PR in the FAS will be listed and summarized by treatment group.

[0604] OS is defined as the period from the date of randomization to the date of death from any cause. If it is unknown that a subject is dead, the OS is censored at the latest date (the cutoff date or earlier) when it is known that the subject is still alive.

[0605] OS analysis will be performed in the FAS population based on the stratification assigned at the time of randomization to the treatment group. During the primary analysis of PFS, the OS distribution will be estimated using the Kaplan-Mayer method, and Kaplan-Mayer curves, medians, and 95% confidence intervals for the medians will be provided for each treatment group. Hazard ratios and their 95% confidence intervals for OS will be calculated using a stratified Cox model.

[0606] In the final analysis, supportive analyses will adjust for crossover treatment from control to Lutathera. This will be achieved by correcting for confounding effects introduced by treatment changes using the rank-preserving structured time-of-failure method (RPSFT). The RPSFT method estimates the survival time of anyone receiving Lutathera (i.e., randomly assigned to Lutathera or switched from control to Lutathera after crossover treatment). The RPSFT model is based on the accelerated time-of-failure model and uses the structural assumption of time proportions, rather than the proportional hazard assumption used in the Cox model. The widely used Cox model measures drug effect using a hazard ratio scale, while the accelerated time-of-failure model measures drug effect using a survival time ratio scale.

[0607] In addition, during the final analysis, an OS support analysis based on inverse probabilistic censoring weighting will be performed. Further details regarding these analyses will be provided in SAP documentation.

[0608] Safety endpoint

[0609] All safety analyses will use safety sets. All lists and tables will be presented by treatment group.

[0610] The frequency of adverse events and laboratory toxicities will be presented (scored according to CTCAE Level 5.0 or the current version).

[0611] All adverse events (AEs), whether or not they are reported voluntarily by the patient, will be recorded from the time the ICF is signed until the end of the treatment period.

[0612] Safety summaries (tables, graphs) include only data from the treatment period, excluding baseline data, which will also be summarized where appropriate (e.g., a summary of changes relative to baseline). Furthermore, a separate summary will be provided for deaths, including those occurring during and after treatment. Specifically, the summary table for adverse events (AEs) will only summarize events occurring during treatment with an onset date within the treatment period (AEs occurring during treatment).

[0613] The treatment period lasts from the date of the first administration of the study therapy to 30 days after the date of the last actual administration of any study therapy.

[0614] The entire observation period will be divided into three mutually exclusive parts:

[0615] • Pre-treatment period: from the day the subject gives informed consent to the day before the first dose of the study drug.

[0616] • Treatment period: From the day of the first dose of the study drug to 30 days after the last dose of the study drug.

[0617] • Post-treatment period: Begins 30+1 days after the last dose of the study drug.

[0618] • For patients undergoing cross-treatment, their safety profile will be presented in detail.

[0619] Adverse events

[0620] All information obtained regarding adverse events will be presented by treatment group and subject.

[0621] The number (and percentage) of subjects who experienced treatment-emergent adverse events (events that began after the first dose of the study drug or events that occurred before the start of double-blind treatment but with increased severity (based on preferred terminology)) will be summarized as follows:

[0622] 1. By treatment, major system organ category, and preferred terminology.

[0623] 2. By treatment, major system organ category, preferred terminology, and maximum severity.

[0624] 3. By treatment, Standardized MedDRA query (SMQ), and preferred terms

[0625] A separate summary will be provided for investigational drug-related adverse events, deaths, serious adverse events, other major adverse events leading to drug discontinuation, and adverse events leading to dose adjustments.

[0626] The number (and proportion) of subjects who experienced AESI associated with identified and potential risks will be summarized by treatment.

[0627] Subjects who experience multiple adverse events within a major organ system category are counted only once in the total number for that major organ system category.

[0628] vital signs

[0629] All vital signs data will be listed by treatment group, subject, and visit / time, and abnormalities (and related changes in posture) will be marked if ranges are available. Summary statistics will be provided by treatment and visit / time.

[0630] 12-lead ECG

[0631] PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs of each subject during the study period. ECG data will be read and interpreted (center / local).

[0632] All ECG data will be listed by treatment group, subject, and visit / time, and abnormalities will be marked. Summary statistics will be provided by treatment and visit / time.

[0633] Clinical laboratory evaluation

[0634] All laboratory data will be listed by treatment group, subject, and visit / time, and abnormalities will be marked if normal ranges are available. Summary statistics will be provided by treatment and visit / time. Baseline values ​​will be compared to the worst-case treatment values ​​using a low / normal / high / (low and high) categorization.

[0635] Laboratory values ​​will be graded in a programmed manner according to the NCI Common Terminology Standard for Adverse Events (CTCAE) version 5.0 or the current version. CTCAE grades are calculated based solely on observed laboratory values ​​and will not consider clinical assessments.

[0636] All non-missing values ​​that are not graded as 1 or higher are assigned CTCAE grade 0. Grade 5 will not be used.

[0637] For laboratory tests for which CTCAE levels are not defined, the results will be categorized as low / normal / high based on the laboratory's normal range.

[0638] The following summaries were generated for hematological and biochemical tests respectively:

[0639] 1. List all laboratory data and label the values ​​to show the corresponding CTCAE level (if applicable) and the classification relative to the laboratory's normal range.

[0640] 2. For laboratory tests that meet the standards defined by CTCAE,

[0641] 3. Most severe post-baseline CTCAE grade (regardless of baseline status). The most severe grade observed after baseline will be counted only once for each subject.

[0642] 4. Compare the baseline with the worst treatment period value using a shift table based on CTCAE grading.

[0643] 5. For laboratory tests that pass an undefined level by CTCAE,

[0644] 6. Use a shift table with low / normal / high / (low and high) categories to compare the baseline with the value in the worst treatment.

[0645] Due to a shortage of laboratory reagent kits, South Korea suspended the CgA assessment in Q3 2022 (assessments conducted before the suspension will be included in the analysis).

[0646] Exploratory endpoint analysis

[0647] PFS2

[0648] PFS2 is defined as the time from the randomization date to the first recorded local progression or death from any cause during the next first-line treatment (whichever comes first). The first recorded progression during the next first-line treatment is based on the investigator's assessment of PD (i.e., recorded on the antitumor treatment eCRF page after treatment discontinuation); for the purposes of PFS2, it is not necessary to continue collecting tumor assessment data for subsequent antitumor treatments.

[0649] • Next-line therapy is defined as the first new (systemic) anti-tumor therapy initiated after investigational treatment has been discontinued (regardless of the cause of EoT). Drugs administered as part of the same regimen should be considered as first-line (i.e., part of next-line therapy).

[0650] • New anti-tumor therapies following EoT will be collected in the post-treatment discontinuation anti-tumor therapy eCRF page, including start / end dates, reason for discontinuation, date, and progression type («clinical» vs. «radiation»).

[0651] • If no PFS2 event (progression or death) is observed during the next-line therapy period prior to the analysis cutoff date, PFS2 will be censored; the censoring date will be the last contact date.

[0652] • However, if a second new anti-tumor therapy is introduced in the absence of a previous PFS2 event, the PFS2 will be censored at the end date of the first new anti-tumor therapy (i.e., the next first-line therapy).

[0653] • Any death prior to the initiation of the next line of therapy will be considered a PFS2 event. Any death occurring after the completion of the next line of therapy will be considered an event unless a second new anti-cancer therapy is introduced.

[0654] • If the subject does not experience an event (i.e., progression) before the start of the next first-line therapy, the PFS and PFS2 may be the same, and adequate tumor assessment should continue after the start of the next first-line therapy until disease progression recorded in RECIST 1.1 occurs.

[0655] PFS2 analysis will be performed in the FAS population based on the randomized treatment groups and the stratification assigned at the time of randomization. The PFS2 distribution will be estimated using the Kaplan-Mayer method, and Kaplan-Mayer curves, medians, and 95% confidence intervals for the medians will be provided for each treatment group. The hazard ratios and their 95% confidence intervals for PFS2 will be calculated using a stratified Cox model.

[0656] The time to second progression (PFS2) in both treatment groups will be evaluated as a secondary endpoint. This endpoint is defined as the time from the first progression to the second progression or death (in months). The dates of the first and second progressions will be determined procedurally according to RECIST criteria.

[0657] We recognize that the likelihood of drawing definitive conclusions is limited due to cross-treatment, the low scanning frequency after PEP (once every six months), and the relatively short follow-up period.

[0658] Patient-reported outcomes were not related to key secondary endpoints.

[0659] The time-to-to-death (TTD) of items / scales in the EORTC QLQ-GINET21 and EORTC QLQ-30 not included in the key secondary endpoints will be analyzed as exploratory endpoints. The distribution of TTD will be estimated using the Kaplan-Mayer method, and Kaplan-Mayer curves, medians, and 95% confidence intervals for the median will be provided for each treatment group. Hazard ratios and their 95% confidence intervals for TTD will be calculated using a stratified Cox model.

[0660] Quality of life will also be assessed using a mixed-model repeated measures (MMRM) approach, based on changes in EORTC QLQ-GINET21, EORTC QLQ-C30, and EQ-5D-5L relative to baseline. This MMRM handles missing values ​​in a model-based manner and implicitly estimates missing data based on the random missing values ​​hypothesis. The model will include explanatory variables: treatment, baseline, number of weeks, and the interaction between treatment and number of weeks. Treatment effectiveness will be tested weekly and overall.

[0661] Pharmacokinetics

[0662] Patients in the control group (all countries except China) will have PK data obtained from pre-dose blood samples. These data will be correlated with long-acting octreotide IM injection at treatment cycles 2, 4, 5, and 7 (i.e., weeks 4, 12, 16, and 24, respectively) to determine plasma trough levels. For exploratory purposes, population-based models will be used to process the data. Further details regarding results presentation will be provided in SAP.

[0663] In addition, descriptive statistics and graphs of octreotide plasma concentrations during treatment will be presented by dose group. Exploratory analyses will be conducted to assess dose-exposure relationships. Further details regarding the presentation of results will be provided in SAP.

[0664] Lutathera Retreatment

[0665] For participants who received Lutathera retreatment during the retreatment period, the safety profile will be presented in a similar manner. The retreatment period begins from the date of the first administration of Lutathera and continues until progression or death occurs during the retreatment period.

[0666] All information obtained about adverse events will be presented to the subjects.

[0667] All vital signs data will be listed by subject and visit / time, and abnormalities (and related changes in posture) will be marked if ranges are available. Summary statistics will be provided by visit / time.

[0668] All ECG data (based on local assessment) will be listed by subject and visit / time, and anomalies will be marked. Summary statistics will be provided by visit / time.

[0669] All laboratory data will be listed by subject and visit / time, and abnormalities will be marked if normal ranges are available. Summary statistics will be provided by visit / time. A shift table using low / normal / high / (low and high) classification will be used to compare the most recent assessment before retreatment with the worst retreatment value.

[0670] All efficacy analyses for ORR, DoR, PFS, PFS2, and OS will be descriptive. The definitions of ORR, DoR, and PFS (based on local assessment) are the same, except that baseline will be based on assessment of tumor progression, thus allowing for retreatment with Lutathera. The definitions of OS and PFS2 are the same as described herein.

[0671] Mid-term analysis

[0672] Interim analysis of overall survival (OS) will be conducted during the final analysis of progression-free survival (PFS). At this time, only treatment efficacy will be assessed (hazard ratio and its 95% confidence interval).

[0673] Sample size calculation

[0674] Primary endpoint

[0675] Sample size calculations were based on the primary variable, PFS. Assuming a median PFS of approximately 15 months in the control group (high-dose long-acting octreotide (60 mg)), it was assumed that adding Lutathera to standard-dose long-acting octreotide would result in a 50% reduction in hazard ratio (corresponding to an increase in median PFS from 15 months to 30 months).

[0676] To ensure 90% power in testing the null hypothesis (PFS hazard ratio = 1) and compared to the specific alternative hypothesis (PFS hazard ratio = 0.50), a total of 99 PFS events needed to be observed was calculated. This calculation was analyzed using a one-sided log-rank test at an overall significance level of 2.5%, with patients randomly assigned to the two treatment groups at a 2:1 ratio. Assuming enrollment would continue at a rate of 10 patients per month for approximately 22.2 months, and a dropout rate of 15% by the final PFS analysis, a total of 222 patients (148 in the Lutathera group and 74 in the control group) would need to be randomized to observe the target 99 PFS events approximately 12.8 months after the randomization date of the last patient (i.e., 35 months after the randomization date of the first patient). If the final analysis is performed when the target 99 PFS events are observed, the observed hazard ratio must be <0.658, corresponding to a median PFS difference of 7.8 months, to declare statistical significance.

[0677] These calculations were performed using the software package East 6.4.

[0678] Randomization will be stratified according to grade (G2 vs. G3) and tumor origin (pNET vs. other origins).

[0679] Detailed Implementation Examples

[0680] The treatment method disclosed herein is specifically provided in the following embodiments:

[0681] A method for treating well-differentiated G2 or G3 neuroendocrine tumors (NETs) in patients in need, comprising administering to the patient a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as a first-line therapy.

[0682] A method for delaying the time to first progression or death in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET) comprising administering the patient a radioligand therapy (RLT) containing a therapeutically effective dose of a somatostatin receptor (SSTR)-targeting agent as first-line therapy.

[0683] A method for delaying the need to initiate chemotherapy in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET), the method comprising administering to the patient a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as first-line therapy.

[0684] A method for controlling disease in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET) comprising administering treatment to the patient as a first-line therapy with a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR).

[0685] A method for alleviating well-differentiated G2 or G3 neuroendocrine tumors (NETs) in patients in need, comprising administering to the patient a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as a first-line (1L) therapy.

[0686] A method for reducing the risk of progression of well-differentiated G2 or G3 neuroendocrine tumors (NETs) in patients in need or reducing the risk of death in said patients, the method comprising administering to said patients a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as a first-line (1L) therapy.

[0687] In some embodiments, the RLT agent comprises a radionuclide selected from the group consisting of 47Sc, 67Cu, 153Sm, 161Tb, 169Er, and 177Lu.

[0688] In some embodiments, the RLT agent comprises a radionuclide selected from the group consisting of 161Tb and 177Lu.

[0689] In some embodiments, the RLT agent comprises a radionuclide selected from the group consisting of 161Tb and 177Lu.

[0690] In some embodiments, the RLT agent contains the radionuclide 177Lu.

[0691] In some embodiments, 177Lu is carrier-free (nca)177Lu or carrier-added (ca)177Lu.

[0692] In some embodiments, 177Lu is nca177Lu (also known as NCA 177Lu).

[0693] In some embodiments, 177Lu is carrier-added (ca)177Lu (also known as CA 177Lu).

[0694] In some embodiments, the RLT agent comprises a ligand selected from the group consisting of: dotatate, edotreotide (DOTATOC), and titan-sartoretide.

[0695] In some embodiments, the RLT agent comprises a ligand selected from the group consisting of: dotatate and dotatoc.

[0696] In some embodiments, the RLT agent comprises the ligand dotatate.

[0697] In some embodiments, the RLT agent is selected from the group consisting of: lutetium (177Lu) oxodotriptide, lutetium (177Lu) edotoriptide, lutetium (177Lu) titan-sartoreptide, terbium (161Tb) oxodotriptide, terbium (161Tb) edotoriptide and terbium (161Tb) titan-sartoreptide.

[0698] In some embodiments, the RLT agent is selected from the group consisting of: lutetium (177Lu) oxodotriptide, lutetium (177Lu) edotoriptide, terbium (161Tb) oxodotriptide and terbium (161Tb) edotoriptide.

[0699] In some embodiments, the RLT agent is selected from the group consisting of lutetium (177Lu) oxodotriptide and lutetium (177Lu) edotoriptide.

[0700] In some embodiments, the RLT agent is lutetium ( 177 Lu) Ossodutritide (also known as 177 Lu[Lu]-DOTA-(Tyr 3 )-Octrenic acid or 177 Lu[Lu]-DOTA-0-Tyr3-octreotic acid).

[0701] In some embodiments, the dose of the RLT agent is 5 to 10 GBq, 6 to 9 GBq, 6.5 to 8.5 GBq, 7.4 ± 10% GBq, or 7.5 ± 0.7 GBq.

[0702] In some embodiments, the dose is administered once every 40 to 100 days, once every 49 to 90 days, once every 90 days, or once every 8 ± 1 weeks.

[0703] In some embodiments, the dose is administered up to four times (four cycles).

[0704] In some embodiments, the RLT agent is administered at a dose of 7.4 ± 10% GBq every 8 ± 1 weeks for up to 4 times (4 cycles).

[0705] In some embodiments, after the initial first cycle up to four cycles, the patient receives two additional cycles of retreatment, and optionally two more cycles (2 + opt. 2).

[0706] In some embodiments, the treatment further includes supportive care.

[0707] In some embodiments, supportive care is 30 mg of long-acting octreotide (e.g., octreotide LAR) once a month (obtained under the pharmaceutical name Sandostatin LAR).

[0708] In some embodiments, supportive care is 30 mg of long-acting octreotide (e.g., octreotide LAR, for example, obtained under the pharmaceutical name Sandostatin LAR) every 4 weeks.

[0709] In some embodiments, supportive care is 30 mg of long-acting octreotide (e.g., octreotide LAR, for example, obtained under the pharmaceutical name Sandostatin LAR) every 8 weeks.

[0710] In some embodiments, supportive care is provided as 30 mg of long-acting octreotide (e.g., octreotide LAR, available for example under the pharmaceutical name Sandostatin LAR) every eight weeks during RLT treatment. In some embodiments, long-acting octreotide (e.g., octreotide LAR) is administered every four weeks after the last RLT treatment.

[0711] In some embodiments, the RLT agent is 177Lu-DOTA-TATE, administered at a dose of 7.4 ± 10% GBq every 8 ± 1 weeks for up to 4 times (4 cycles), and treatment further includes treatment with 30 mg octreotide LAR every 8 weeks during treatment with 177Lu-DOTA-TATE. In one embodiment, octreotide LAR is administered every 4 weeks after completion of 4 cycles of 177Lu-DOTA-TATE treatment.

[0712] In some embodiments, the RLT agent is 177Lu-DOTA-TATE, administered at a dose of 7.4 ± 10% GBq every 8 ± 1 weeks for up to 4 times (4 cycles), and treatment further includes treatment with 30 mg octreotide LAR 4 to 24 hours after each 177Lu-DOTA-TATE administration. In one embodiment, octreotide LAR is administered every 4 weeks after completing 4 cycles of 177Lu-DOTA-TATE treatment.

[0713] In some embodiments, the treatment further includes intravenous (IV) administration of a 2.5% lysine-arginine solution.

[0714] In some embodiments, the treatment is characterized by a centrally assessed progression-free survival (PFS) of at least 18, 20, or 22 months. In some embodiments, the treatment is characterized by a centrally assessed PFS of at least 18, 19, 20, 21, or 22 months. In some embodiments, the treatment is characterized by a centrally assessed PFS of at least 18, 19, 20, 21, 22, 23, 24, or 25 months. In some embodiments, the treatment is characterized by a centrally assessed PFS of at least 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 months. In some embodiments, the treatment is characterized by a centrally assessed PFS of at least 18, 24, 30, 36, 42, or 48 months.

[0715] In some embodiments, progress is based on centrally assessed radiological progress according to RECIST (v.1.1).

[0716] In some embodiments, the treatment is characterized by a disease control rate (DCR, i.e., complete response (CR) rate + partial response (PR) rate + stable disease (SD) rate) of at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, or 90%.

[0717] In some embodiments, the treatment is characterized by an objective response rate (ORR, i.e., complete response (CR) rate + partial response (PR) rate) of at least 25%, 30%, 35%, 40%, 41%, 42%, or 43%.

[0718] In some embodiments, treatment reduces the risk of progression or death by at least 50%, 60%, 65%, 70%, or 72% compared to comparable treatments without the use of an RLT agent.

[0719] In some embodiments, the treatment reduces the risk of progression or death by at least 50%, 60%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, or 75% compared to comparable treatments without the use of an RLT agent.

[0720] In some embodiments, when calculating risk relative to patients receiving comparable treatment without RLT agents, the reduced risk of progression or death corresponds to a hazard ratio (HR) of less than 0.5, 0.4, 0.35, 0.3, or 0.28 (95% CI).

[0721] In some embodiments, when calculating risk relative to patients receiving comparable treatment without RLT agents, the reduced risk of progression or death corresponds to hazard ratios (HRs) of less than 0.5, 0.4, 0.35, 0.34, 0.33, 0.32, 0.32, 0.30, 0.29, 0.28, 0.27, 0.26, and 0.25.

[0722] In some embodiments, comparable treatments without the use of an RLT agent include administration of a drug selected from the group consisting of: octreotide, such as high-dose long-acting octreotide (e.g., 60 mg long-acting octreotide (octreotide LAR)), lanreotide, everolimus, interferon-α (IFN-α), sunitinib, surufatinib, lenvatinib, streptozotocin (STZ), etoposide, irinotecan, and chemotherapy (e.g., including capecitabine, temozolomide, dacarbazine, leucovorin, 5-fluorouracil (5FU), and platinum-based chemotherapy (e.g., oxaliplatin, cisplatin)) or combinations thereof (e.g., STZ-5FU, CAPTEM, CAP-5FU, FOLFOX, FOLFIRI); preferably: 60 mg long-acting octreotide (octreotide LAR), CAPTEM (capecitabine and temozolomide), everolimus and FOLFOX (leucovorin, fluorouracil and oxaliplatin); more preferably: high-dose long-acting octreotide (e.g. 60 mg long-acting octreotide (octreotide LAR)).

[0723] In some embodiments, a comparable treatment without the use of an RLT agent is 60 mg of long-acting octreotide (octreotide LAR, for example, obtained as Sandostatin LAR).

[0724] In some embodiments, the treatment is characterized in that the number of treatment-related grade 3 adverse events (AEs) does not exceed 30%, 25%, 20%, 18%, or 16%.

[0725] In some embodiments, the treatment is characterized in that the number of treatment-related grade ≥ 3 serious adverse events (SAEs) does not exceed 10%, 9%, 8%, 7%, 6%, or 5%.

[0726] In some embodiments, the patient is ≥ 15 years old.

[0727] In some embodiments, the patient is newly diagnosed with advanced G2 or G3 GEP-NET.

[0728] In some embodiments, the patient is newly diagnosed with advanced G2 GEP-NET.

[0729] In some embodiments, the patient is newly diagnosed with advanced G3 GEP-NET.

[0730] In some embodiments, a patient is newly diagnosed with advanced G2 GEP-NET and the reduced risk of progression / death corresponds to an HR of 0.31 or less.

[0731] In some embodiments, a patient is newly diagnosed with advanced G3 GEP-NET and the reduced risk of progression / death corresponds to an HR of 0.27 or less.

[0732] In some embodiments, the median time for a 10-point deterioration in overall health status on the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire) is at least 9 months, at least 10 months, at least 11 months, at least 12 months, or at least 13 months.

[0733] In one embodiment, the overall response rate is at least 10%. In one embodiment, the overall response rate is at least 15%. In one embodiment, the overall response rate is at least 20%. In one embodiment, the overall response rate is at least 25%. In one embodiment, the overall response rate is at least 30%. In one embodiment, the overall response rate is at least 35%. In one embodiment, the overall response rate is at least 40%.

[0734] In one embodiment, NET has been moved to bone.

[0735] In one embodiment, NET has metastasized to the liver.

[0736] In one embodiment, NET has migrated to the lymph nodes.

[0737] In one embodiment, NET has been transferred to the peritoneum.

[0738] In one embodiment, chromogranin A (CgA) > 2 prior to treatment with a radioligand therapeutic agent (RLT) targeting the somatostatin receptor (SSTR). In an alternative embodiment, CgA ≤ 2 prior to treatment with a radioligand therapeutic agent (RLT) targeting the somatostatin receptor (SSTR).

[0739] According to one aspect of the invention, a method for reducing the incidence of cardiovascular or electrolyte disturbances in patients with well-differentiated G2 or G3 neuroendocrine tumors (NETs) is provided (e.g., compared to treatment with 60 mg octreotide LAR every 4 weeks), the method comprising administering 177Lu-DOTA-TATE as a first-line therapy in combination with octreotide LAR to said patients.

[0740] In one embodiment, the RLT agent is 177Lu-DOTA-TATE, and 177Lu-DOTA-TATE is administered every 8 ± 1 weeks at a dose providing 7.4 GBq / 200 mCi ± 10%. In one embodiment, a total of 4 doses of 177Lu-DOTA-TATE are administered. In one embodiment, octreotide LAR is administered at a dose of 30 mg every 8 weeks during treatment with 177Lu-DOTA-TATE, and then at a dose of 30 mg every 4 weeks after the last treatment with 177Lu-DOTA-TATE.

[0741] According to one aspect of the invention, a method is provided that, compared with treatment with 60 mg octreotide LAR every 4 weeks, i) reduces the incidence of cardiovascular or electrolyte disturbances in patients with well-differentiated G2 or G3 neuroendocrine tumors (NETs) and ii) a) increases median PFS and / or b) overall response rate, the method comprising administering to said patient in combination with 177Lu-DOTA-TATE as first-line therapy and 30 mg octreotide LAR. In one embodiment, the dose of 177Lu-DOTA-TATE is 7.4 GBq / 200 mCi ± 10% every 8 ± 1 weeks. In one embodiment, a total of 4 doses of 177Lu-DOTA-TATE are administered. In one embodiment, octreotide LAR is administered at 30 mg every 8 weeks during treatment with 177Lu-DOTA-TATE and at 30 mg every 4 weeks after the last treatment with 177Lu-DOTA-TATE.

[0742] In some embodiments, the 1L therapy is characterized by the fact that no prior treatment with interferon, mTOR inhibitors, or chemotherapy agents has been used.

[0743] In some embodiments, the 1L therapy is characterized by the patient not having previously been treated with a sandostatin analogue (no SSA), or having not experienced progression under the SSA therapy in cases of previous SSA treatment.

[0744] In some embodiments, NET is Gastrointestinal-pancreatic NET (GEP-NET).

[0745] In some embodiments, NET is pancreatic NET (pNET, meaning the tumor originates in the pancreas).

[0746] In some embodiments, NET is pancreatic NET (pNET) and the reduced risk of progression / death corresponds to an HR of 0.34 or less.

[0747] In some embodiments, NET is small intestinal NET (i.e., the primary site of cancer is in the small intestine).

[0748] In some embodiments, NET is small intestinal NET and the reduced risk of progression / death corresponds to an HR of 0.30 or less.

[0749] In some embodiments, NET is a late NET.

[0750] In some embodiments, NET is metastatic or locally advanced and unresectable.

[0751] In some embodiments, NET is SSTR positive (SSTR+).

[0752] In some embodiments, NET’s SSTR positivity is determined by CT or MRI scans using a radioligand imaging (RLI) agent.

[0753] In some embodiments, NET SSR positivity is determined by performing PET / CT, SPECT / CT, or SRS (somatostatin receptor scintillation imaging) with a radioligand imaging (RLI) agent.

[0754] In some embodiments, the RLI agent is selected from the group consisting of: 68Ga-oxodotritide, 68Ga-edottritide, 68Ga-tritan-sartoretide, 64Cu-oxodotritide, 64Cu-edottritide, 64Cu-tritan-sartoretide, 111In-penetride and 99mTc-tektrotyd.

[0755] The drug [177Lu]Lu-DOTATATE, INN: lutetium (177Lu) octotreotide, is available as a pharmaceutical product under the name LUTATHERA. The drug [177Lu]Lu-DOTATOC, INN: lutetium (177Lu) octotreotide, [177Lu-DOTA(0),Tyr(3)]-octotreotide (DOTATOC, where DOTA = tetraazacyclododecanetetraacetic acid and TOC = D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)), can be manufactured as a pharmaceutical product according to WO 2022 / 111800 A1 and / or WO 2022 / 112323 A1, and may be used under the pharmaceutical names SOLUCIN or ITM-11. The drug lutetium (177Lu) titan-sartoretide can be manufactured into a drug in a manner similar to Lutathera or Solucin.

[0756] In some embodiments, the RLT agent may also comprise other somatostatin analogs that act as SSTR binders, such as octreotide, octreotide, sartoretide, lanreotide, vaporetide, and palciretide. It will form corresponding ligands with the DOTA chelating agent, such as DOTA-OC, DOTA-TOC (edotretide), DOTA-NOC, DOTA-TATE (octreotide), Titan-sartoretide, DOTA-LAN, and DOTA-VAP.

[0757] In some embodiments, the RLT agent may comprise a chelating agent selected from the group consisting of: DOTA (Titan), Tritan, DOTAGA, DTPA, NTA, EDTA, DO3A, TETA, Nota, NotaGA, NodaGA, NodaPA, PCTA, and AAZTA (e.g., AAZTA5).

[0758] In some embodiments, the RLT agent may contain an albumin binder, such as Evans blue (EB), for example [177Lu]Lu-DOTA-EB-TATE.

[0759] Medical use form

[0760] The above embodiments are formulated as treatment method claims. They can also be formulated as other forms of second medical use, such as those shown below, where the drug is an RLT agent (alone or in combination with other agents), the indication is NET as specified in the above embodiments, and the features are those characterizing features mentioned in the above embodiments:

[0761] The present invention provides a [medicine] or any pharmaceutically acceptable salt thereof for treating [the indication], characterized by [features].

[0762] Alternatively, the present invention provides a method for treating a patient requiring treatment for an indication, the method comprising administering an effective amount of the drug or any pharmaceutically acceptable salt thereof, wherein the treatment is characterized by the following features.

[0763] As a further alternative, the present invention provides the use of [the drug] or any pharmaceutically acceptable salt thereof in the preparation of a drug for treating [the indication], characterized by [features].

[0764] As a further alternative, the present invention provides the use of [the drug] or any pharmaceutically acceptable salt thereof for the treatment of [the indication], characterized by [features].

[0765] As a further alternative, the present invention provides a medicament for treating [the indication], comprising [the drug] or any pharmaceutically acceptable salt thereof, characterized by [the following features].

[0766] Other definitions

[0767] In terms of value, “about” means ±25%, preferably ±20%, more preferably ±15%, even more preferably ±10%, even more preferably ±5%.

[0768] In terms of weeks or periods, “approximately” means ±2, preferably ±1.

[0769] Unless otherwise indicated herein or clearly contradicted by the context, the use of the articles “a” and “the” in the specification and claims shall be construed as including both the singular and plural. Unless otherwise stated, the terms “comprising,” “having,” “having” (as in complexes, for example, “a radionuclide and a cell receptor-binding organic portion linked to a chelating agent,” “including,” and “containing” shall be construed as open-ended terms (i.e., meaning “including but not limited to”). Furthermore, whenever “comprising” or another open-ended term is used in an embodiment, it should be understood that the same embodiment may be claimed more narrowly using the intermediate term “consistently composed of” or the closed term “composed of”.

[0770] The term “about” or “approximately” in this document means that the following values ​​may vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, even more preferably ±1%.

[0771] In terms of value, “about” means ±25%, preferably ±20%, more preferably ±15%, even more preferably ±10%, even more preferably ±5%.

[0772] In terms of weeks or periods, “approximately” means ±2, preferably ±1.

[0773] The phrase "treatment of" and "treating" encompasses the prevention, improvement, or cessation of a disease, disorder, or its symptoms. Specifically, regarding the treatment of cancer, the term "treatment" can refer to the inhibition of tumor growth or the reduction of tumor size.

[0774] Consistent with the International System of Units (SI), "MBq" is an abbreviation for "megabecquerel," the unit of radioactivity.

[0775] Consistent with the International System of Units (SI), "GBq" is an abbreviation for "gigabecquerel," the unit of radioactivity.

[0776] The terms radionuclides and radioisotopes are used interchangeably in this disclosure and its embodiments. Where technically meaningful, the terms radiometals and radiohalogens may also be used as substitutes.

[0777] Not for example 177 The forms Lu, Lu-177, or lutetium-177 indicate radionuclides, with the form 177Lu used as a substitute herein. Therefore, regardless of the mass number, e.g., 177, there is no superscript (e.g., 177Lu) throughout the disclosure; however, it is intended to refer to the superscripted version. 177 Lu.

[0778] As used in this article, "PET" stands for positron emission tomography.

[0779] As used in this article, "SPECT" stands for Single Photon Emission Computed Tomography.

[0780] As used in this article, "MRI" stands for magnetic resonance imaging.

[0781] As used in this article, "CT" stands for computed tomography.

[0782] As used herein, the term “effective amount” or “therapeutic effective amount” of a compound refers to the amount of a compound that will elicit a biological or medical response in a subject (e.g., improve symptoms, alleviate symptoms, slow or delay disease progression, or prevent disease).

[0783] The terms “patient” and “subject” are used interchangeably to refer to humans, including subjects with cancer, for example.

[0784] As used herein, the term "radiopharmaceutical" refers to a pharmaceutical compound labeled with a radioactive nuclide element (typically metallic). Radiopharmaceutical compounds can be used in peptide receptor radionuclide therapy (PRRT).

[0785] As used herein, the term "PRRT" or "peptide receptor radionuclide therapy" refers to the systemic administration of radiolabeled peptides (such as...) 177 Molecularly targeted radiotherapy using Lu-dotatate, a radiolabeled peptide designed to target overexpressed receptors on tumors (such as somatostatin receptor subtype 2) with high affinity and specificity.

[0786] DOTA-OC: [DOTA] 0 ,D-Phe 1 Octreotide,

[0787] DOTA-TOC: [DOTA] 0 ,D-Phe 1 Tyr 3 Octreotide, Edotritide (INN).

[0788] It can be expressed by the following formula:

[0789]

[0790]

[0791] DOTA-NOC: [DOTA] 0 , D-Phe 1 ,1-Nal 3 Octreotide,

[0792] DOTA-TATE: [DOTA] 0 ,D-Phe 1 Tyr 3 Octrenic acid, DOTA-Tyr 3 -Octrenic acid, DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (ring 2,7), and octodextrin (INN) are represented by the following formula:

[0793]

[0794] DOTA-LAN: [DOTA] 0 ,D-β-Nal 1 Lanrui peptide,

[0795] DOTA-VAP: [DOTA] 0 ,D-Phe 1 Tyr 3 [Vaporpeptide]

[0796] Tratan-Sartorepeptide

[0797]

[0798] Titan-Sartorepeptide

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[0890] The disclosure will be described in more detail and with more specific examples below, but these examples are not intended to limit the disclosure.

[0891] Example 1a: Clinical trial protocol

[0892] A phase III, multicenter, randomized, open-label study was conducted to evaluate the efficacy and safety of Lutathera in patients with grade 2 and 3 advanced GEP-NETs.

[0893]

[0894] Example 1b: First Interpretable Result (FIR), PFS Main Analysis

[0895] Results Summary

[0896]

[0897] • This study is a randomized, open-label, activity-comparative, multicenter, phase III trial involving newly diagnosed grade 2 and 3 advanced GEP-NET participants who received Lutathera plus long-acting repeatable (LAR) octreotide (hereinafter referred to as Lutathera) or high-dose octreotide LAR (hereinafter referred to as high-dose octreotide). Randomization was stratified according to tumor grade (grade 2 or 3) and tumor origin (pNET or other).

[0898] This document describes the first interpretable (FIR) results of the primary analysis of PFS when 99 PFS events were documented according to central review. The data cutoff date for this analysis was July 20, 2023, and the study is ongoing. The median (minimum, maximum) follow-up time lasted 23.2 months (9.2–41.9) (from randomization to the data cutoff date). No clinical interpretation was given for the key efficacy and safety results presented.

[0899] • Between January 22, 2020 and October 13, 2022, a total of 226 participants (full analysis set) were randomized in a 2:1 ratio to receive either Lutathera treatment (n = 151) or high-dose octreotide treatment (n = 75). The safety set included 220 participants, with 147 in the Lutathera group and 73 in the high-dose octreotide group.

[0900] • Analyze the primary PFS endpoint and key secondary endpoints in a stratified manner to protect against Type I error rate. The hypothesis testing order is PFS, then ORR.

[0901] • According to reports, during the randomization period, 48.3% of participants in the Lutathera group discontinued treatment, compared to 80.0% in the high-dose octreotide group. The most frequently reported reason for discontinuation was progressive disease (27.8% in the Lutathera group and 58.7% in the high-dose octreotide group). The proportion of discontinuation due to adverse events was 5.3% in the Lutathera group and 1.3% in the high-dose octreotide group.

[0902] • 29 participants (38.7%) who were randomized to the high-dose octreotide group received Lutathera crossover therapy after disease progression. 8 participants (5.3%) who were randomized to the Lutathera group received a second course of Lutathera therapy (re-treatment) after disease progression.

[0903] • During randomization, the median duration of exposure to Lutathera was 32 weeks. 87.8% of participants received the full course of 4 doses of Lutathera. The median duration of exposure to octreotide was 71.0 weeks in the Lutathera group and 40.3 weeks in the high-dose octreotide group.

[0904] • The study met its primary objectives. The primary endpoint, progression-free survival (PFS) based on central radiology review, showed a statistically significant difference between the treatment groups (stratified log-rank test, p < 0.0001, one-sided), with a 72% reduction in risk estimate in the Lutathera group compared to the high-dose octreotide group (hazard ratio: 0.276, 95% CI: (0.182, 0.418)). The median PFS time (95% CI) was 22.8 months (19.4, NE) and 8.5 months (7.7, 13.8), respectively.

[0905] • The first key secondary endpoint tested in a stratified manner was ORR. The stratified odds ratio was 7.81, and the stratified one-sided p-value was < 0.0001, which was statistically significant. The ORR based on central assessment was 43.0% (95% CI: 35.0, 51.3) in the Lutathera group and 9.3% (95% CI: 3.8, 18.3) in the high-dose octreotide group.

[0906] • During the randomization period, the following adverse events (AEs) were reported in the Lutathera group and the high-dose octreotide group, respectively:

[0907]

[0908] • According to preferred terminology, the most common adverse events during the randomized treatment period (>20% in either group) were nausea (27.2% vs. 17.8%), diarrhea (25.9% vs. 34.2%), and abdominal pain (17.7% vs. 27.4%) in the Lutathera group and the high-dose octreotide group, respectively.

[0909] • According to preferred terminology, the most common grade 3 / 4 adverse events (≥ 3% in either group) during the randomized treatment period were decreased lymphocyte count (5.4% vs. 0%), increased GGT (4.8% vs. 2.7%), small bowel obstruction (3.4% vs. 0%), and abdominal pain (2.7% vs. 4.1%) in the Lutathera group and the high-dose octreotide group.

[0910] • During the study period, 32 (21.8%) subjects in the Lutathera group and 14 (19.2%) subjects in the high-dose octreotide group died, and 2 (1.4%) and 4 (5.5%) subjects died within 30 days after the last dose during the randomization period, respectively. The primary causes of death during the study period in the Lutathera group and the high-dose octreotide group were study-related diseases (20.4% vs. 17.8%) and adverse events (1.4% vs. 1.4%), respectively. All deaths during the randomization period were attributed to study-related diseases.

[0911] • The most common grade 3 / 4 hematologic laboratory abnormalities during the randomization period (>10% in either group) were lymphopenia in the Lutathera group and the high-dose octreotide group (38.1% vs. 2.7%). Less than 5% of subjects showed grade 3 / 4 laboratory abnormalities in any other hematologic parameter.

[0912] • The most common grade 3 / 4 biochemical laboratory abnormalities during the randomized treatment period (>5% in both groups) were elevated GGT (25.9% vs. 28.8%), elevated aspartate aminotransferase (2.7% vs. 6.8%), and elevated bilirubin (2.7% vs. 5.5%) in the Lutathera group and the high-dose octreotide group, respectively.

[0913] Additional information

[0914] The following are the treatment group labels used in the report:

[0915]

[0916] Study subjects

[0917] Subject handling

[0918] Subject treatment (complete analysis set)

[0919]

[0920] Analysis set

[0921] Analytical set (complete analytical set)

[0922]

[0923] Stratification factors for randomized grouping (complete analysis set)

[0924]

[0925] Demographic and other baseline characteristics

[0926] Demographic and baseline characteristics (complete analysis set)

[0927]

[0928] Medical history

[0929] Medical history (complete analysis set)

[0930]

[0931] Subject exposure

[0932] Lutathera exposure in the treatment group (safety set)

[0933]

[0934] Octreotide exposure during treatment (safety set)

[0935]

[0936] Efficacy Results

[0937] Main efficacy results

[0938] Kaplan-Mayer estimates of progression-free survival (PFS) (in months) based on central assessment using RECIST 1.1 criteria (full analysis set)

[0939]

[0940] Kaplan-Mayer plots of progression-free survival (PFS) (in months) based on central review and using RECIST 1.1 criteria (full analysis set): see Figure 2 .

[0941] Forest plot based on central review and using RECIST 1.1 criteria for progression-free survival (PFS) (months) - key subgroups of interest (full analysis set): see Figure 3 and 4 .

[0942] Key secondary efficacy results

[0943] Objective response rate

[0944] Best overall response based on central review using RECIST 1.1 criteria (complete analysis set)

[0945]

[0946] Security Results

[0947] Adverse events

[0948] Overview of adverse events during the randomized treatment period (safety set)

[0949]

[0950] Adverse events listed in preferred terms during the randomized treatment period (occurrence rate of at least 10% in any group) (safety set)

[0951]

[0952] Serious adverse events (incidence >1% in any group) listed in preferred terms during the randomized treatment period (safety set)

[0953]

[0954] die

[0955] All deaths (safety set)

[0956]

[0957] Serious adverse events with fatal outcomes during the randomized treatment period (safety set)

[0958]

[0959] Laboratory data

[0960] Most severe post-baseline biochemical abnormalities based on CTC grading during the randomized treatment period (safety set)

[0961]

[0962] Most severe post-baseline hematologic abnormalities based on CTC grading during the randomized treatment period (safety set)

[0963] . Claims (as amended under Article 19 of the Treaty) 1. A method for treating a patient with Ki67 ≤ 55% well-differentiated G3 neuroendocrine tumors (NETs), the method comprising administering to the patient a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as first-line therapy, wherein the first-line therapy is characterized by the patient not having previously received treatment with a sandostatin analogue (SSA), or, in cases of prior SSA treatment, the patient not experiencing progression under said SSA therapy, wherein said treatment is characterized by a centrally assessed progression-free survival (PFS) of at least 20 months. 2. The method of any one of claims 1, wherein the RLT agent comprises a radionuclide selected from the group consisting of: 47Sc, 67Cu, 153Sm, 161Tb, 169Er and 177Lu. 3. The method of claim 2, wherein the RLT agent comprises a radionuclide selected from the group consisting of 161Tb and 177Lu. 4. The method of claim 3, wherein the RLT agent comprises the radionuclide 177Lu. 5. The method of claim 4, wherein the 177Lu is carrier-free (nca)177Lu or carrier-added (ca)177Lu. 6. The method of claim 5, wherein the 177Lu is nca177Lu (also known as NCA 177Lu). 7. The method of claim 5, wherein the 177Lu is carrier-added (ca)177Lu (also known as CA177Lu). 8. The method of any of the preceding claims, wherein the RLT agent comprises a ligand selected from the group consisting of: dotatate, dototoc, and titan-sartoretide. 9. The method of claim 8, wherein the RLT agent comprises a ligand selected from the group consisting of: dotatate and dotatoc. 10. The method of claim 9, wherein the RLT agent comprises the ligand dotatate. 11. The method of claim 1, wherein the RLT agent is selected from the group consisting of: lutetium (177Lu) oxodotriptide, lutetium (177Lu) edotoriptide, lutetium (177Lu) titan-sartoreptide, terbium (161Tb) oxodotriptide, terbium (161Tb) edotoriptide and terbium (161Tb) titan-sartoreptide. 12. The method of claim 11, wherein the RLT agent is selected from the group consisting of: lutetium (177Lu) oxodotriptide, lutetium (177Lu) edotoriptide, terbium (161Tb) oxodotriptide and terbium (161Tb) edotoriptide. 13. The method of claim 12, wherein the RLT agent is selected from the group consisting of lutetium (177Lu) oxodotriptide and lutetium (177Lu) edotoriptide. 14. The method as claimed in any of the preceding claims, wherein the dose of the RLT agent is 5 to 10 GBq, 6 to 9 GBq, 6.5 to 8.5 GBq, 7.4 ± 10% GBq, or 7.5 ± 0.7 GBq. 15. The method of claim 14, wherein the dose is administered once every 40 to 100 days, once every 49 to 90 days, once every 90 days, or once every 8 ± 1 weeks. 16. The method of claim 15, wherein the dose is administered up to four times (four cycles). 17. The method of any of the preceding claims, wherein the RLT agent is administered at a dose of 7.4 ± 10% GBq every 8 ± 1 weeks for up to 4 times (4 cycles). 18. The method as claimed in any of the preceding claims, wherein after the initial first cycle up to four cycles, the patient receives two additional cycles of retreatment, optionally two more cycles (2 + opt. 2). 19. The method as described in any of the preceding claims, wherein the treatment further comprises supportive care. 20. The method of claim 19, wherein the RLT agent is administered at a dose of 7.4 ± 10% GBq every 8 ± 1 weeks for up to 4 times (4 cycles), and the supportive care is 30 mg of long-acting octreotide (e.g., octreotide LAR, obtained for example under the pharmaceutical name Sandostatin LAR) every 8 weeks during treatment with the 177Lu-DOTA-TATE (e.g., the 30 mg of long-acting octreotide is administered 4 to 24 hours after each dose of the RLT agent), and the octreotide LAR is administered every 4 weeks after completion of 4 cycles of 177Lu-DOTA-TATE treatment. 21. The method of any of the preceding claims, wherein the treatment further comprises intravenous (IV) administration of a 2.5% lysine-arginine solution. 22. The method as described in any of the preceding claims, wherein said progress is radiological progress based on central assessment according to RECIST (v.1.1). 23. The method of any of the preceding claims, wherein the treatment is characterized in that the disease control rate (DCR, i.e., complete response (CR) rate + partial response (PR) rate + stable disease (SD) rate) is at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89% or 90%. 24. The method of any of the preceding claims, wherein the treatment is characterized in that the objective response rate (ORR, i.e., complete response (CR) rate + partial response (PR) rate) is at least 25%, 30%, 35%, 40%, 41%, 42% or 43%. 25. The method as claimed in any of the preceding claims, wherein the treatment reduces the risk of progression or death by at least 50%, 60%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, or 75% compared to comparable treatments without the use of the RLT agent. 26. The method as claimed in any of the preceding claims, wherein when calculating risk relative to comparable treatments without the RLT agent, the reduced risk of progression or death associated with the treatment corresponds to a hazard ratio (HR) of less than 0.5, 0.4, 0.35, 0.34, 0.33, 0.32, 0.32, 0.30, 0.29, 0.28, 0.27, 0.26, or 0.25 (95% CI). 27. The method of claim 25 or claim 26, wherein the comparable treatment without the use of the RLT agent comprises administration of a drug selected from the group consisting of: octreotide, such as high-dose long-acting octreotide (e.g., 60 mg long-acting octreotide (octreotide LAR)), lanreotide, everolimus, interferon-α (IFN-α), sunitinib, surufatinib, lenvatinib, streptozotocin (STZ), etoposide, irinotecan, and chemotherapy (e.g., including capecitabine, temozolomide, dacarbazine, leucovorin, 5-fluorouracil (5FU), and platinum-based chemotherapy (e.g., oxaliplatin, cisplatin)) or combinations thereof (e.g., STZ-5FU, CAPTEM, CAP-5FU, FOLFOX, FOLFIRI). 28. The method of any one of claims 26 to 27, wherein the comparable treatment without the use of the RLT agent is 60 mg long-acting octreotide (octreotide LAR, for example, obtained as Sandostatin LAR). 29. The method as claimed in any of the preceding claims, wherein the treatment is characterized in that treatment-related grade ≥ 3 adverse events (AEs) do not exceed 30%, 25%, 20%, 18% or 16%. 30. The method as described in any of the preceding claims, wherein the treatment is characterized in that the number of treatment-related grade ≥ 3 serious adverse events (SAEs) does not exceed 10%, 9%, 8%, 7%, 6% or 5%. 31. The method as described in any of the preceding claims, wherein the patient is ≥ 15 years old. 32. The method as claimed in any of the preceding claims, wherein the patient is newly diagnosed with advanced G3 GEP-NET. 33. The method as described in any of the preceding claims, wherein the NET is a gastrointestinal pancreatic NET (GEP-NET). 34. The method of claim 33, wherein the NET is a pancreatic NET (pNET). 35. The method of claim 33, wherein the NET is a small intestinal NET. 36. The method as described in any of the preceding claims, wherein the NET is a late NET. 37. The method of any of the preceding claims, wherein the NET is metastatic or locally advanced and inoperable. 38. The method as described in any of the preceding claims, wherein the NET is SSTR positive (SSTR+). 39. The method of claim 38, wherein the SSTR positivity of the NET is determined by CT or MRI scanning with a radioligand imaging (RLI) agent. 40. The method of claim 39, wherein the SSR positivity of the NET is determined by performing PET / CT, SPECT / CT, or SRS (somatostatin receptor scintillation imaging) with a radioligand imaging (RLI) agent. 41. The method of claim 39 or claim 40, wherein the RLI agent is selected from the group consisting of: 68Ga-Oxodotriptide, 68Ga-Edotriptide, 68Ga-Trutan-Sartoretide, 64Cu-Oxodotriptide, 64Cu-Edotriptide, 64Cu-Trutan-Sartoretide, 111In-Pentroptide, and 99mTc-Tektrotyd. 42. The method as described in any of the preceding claims, wherein the median time for a 10-point deterioration in overall health status on the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire) is at least 9 months, for example at least 10 months, for example at least 11 months, for example at least 12 months, for example at least 13 months. 43. The method as described in any of the preceding claims, wherein the NET has been transferred to the bone. 44. The method as described in any of the preceding claims, wherein the NET has been transferred to the liver. 45. The method as described in any of the preceding claims, wherein the NET has been transferred to the lymph node. 46. ​​The method as described in any of the preceding claims, wherein the NET has been transferred to the peritoneum. 47. The method as claimed in any of the preceding claims, wherein the overall response rate is at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, for example at least 35%, for example at least 40%. 48. The method of any of the preceding claims, wherein chromogranin A (CgA) > 2 prior to treatment with the radioligand therapeutic agent (RLT) targeting the somatostatin receptor (SSTR). 49. The method of any one of claims 1 to 47, wherein chromogranin A (CgA) is ≤ 2 prior to treatment with the radioligand therapeutic agent (RLT) targeting the somatostatin receptor (SSTR).

Claims

1. A method for treating a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET), the method comprising administering to the patient a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as a first-line therapy.

2. A method for delaying the time to first progression or death in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET), the method comprising administering the patient a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as first-line therapy.

3. A method for delaying the need to initiate chemotherapy in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET), the method comprising administering to the patient a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as first-line therapy.

4. A method for controlling disease in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET), the method comprising administering treatment to the patient as a first-line therapy with a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR).

5. A method for alleviating well-differentiated G2 or G3 neuroendocrine tumors (NETs) in patients in need, the method comprising administering treatment to the patient with a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as a first-line (1L) therapy.

6. A method for reducing the risk of progression of well-differentiated G2 or G3 neuroendocrine tumors (NETs) or reducing the risk of death in patients in need, the method comprising administering treatment to the patient with a radioligand therapy (RLT) agent containing a therapeutically effective dose of a somatostatin receptor (SSTR) as a first-line (1L) therapy.

7. The method of any of the preceding claims, wherein the RLT agent comprises a radionuclide selected from the group consisting of: 47Sc, 67Cu, 153Sm, 161Tb, 169Er and 177Lu.

8. The method of any of the preceding claims, wherein the RLT agent comprises a radionuclide selected from the group consisting of 161Tb and 177Lu.

9. The method of any of the preceding claims, wherein the RLT agent comprises a radionuclide selected from the group consisting of 161Tb and 177Lu.

10. The method of any of the preceding claims, wherein the RLT agent comprises the radionuclide 177Lu.

11. The method of claim 10, wherein the 177Lu is carrier-free (nca)177Lu or carrier-added (ca)177Lu.

12. The method of claim 11, wherein the 177Lu is nca177Lu (also known as NCA 177Lu).

13. The method of claim 12, wherein the 177Lu is carrier-added (ca)177Lu (also known as CA177Lu).

14. The method of any of the preceding claims, wherein the RLT agent comprises a ligand selected from the group consisting of: dotatate, dototoc, and titan-sartoretide.

15. The method of any of the preceding claims, wherein the RLT agent comprises a ligand selected from the group consisting of: dotatate and dotatoc.

16. The method of any of the preceding claims, wherein the RLT agent comprises the ligand dotatate.

17. The method of any of the preceding claims, wherein the RLT agent is selected from the group consisting of: lutetium (177Lu) oxodotriptide, lutetium (177Lu) edotoriptide, lutetium (177Lu) titan-sartoreptide, terbium (161Tb) oxodotriptide, terbium (161Tb) edotoriptide and terbium (161Tb) titan-sartoreptide.

18. The method of any of the preceding claims, wherein the RLT agent is selected from the group consisting of: lutetium (177Lu) oxodotriptide, lutetium (177Lu) edotoriptide, terbium (161Tb) oxodotriptide and terbium (161Tb) edotoriptide.

19. The method of any of the preceding claims, wherein the RLT agent is selected from the group consisting of lutetium (177Lu) oxodotriptide and lutetium (177Lu) edotoriptide.

20. The method as described in any of the preceding claims, wherein the RLT agent is lutetium ( 177 Lu) Ossodutritide (also known as 177 Lu[Lu]-DOTA-(Tyr 3 )-Octrenic acid or 177 Lu[Lu]-DOTA-0-Tyr3-octreotic acid).

21. The method as claimed in any of the preceding claims, wherein the dose of the RLT agent is 5 to 10 GBq, 6 to 9 GBq, 6.5 to 8.5 GBq, 7.4 ± 10% GBq, or 7.5 ± 0.7 GBq.

22. The method of claim 21, wherein the dose is administered once every 40 to 100 days, once every 49 to 90 days, once every 90 days, or once every 8 ± 1 weeks.

23. The method of claim 22, wherein the dose is administered up to four times (four cycles).

24. The method of any of the preceding claims, wherein the RLT agent is administered at a dose of 7.4 ± 10% GBq every 8 ± 1 weeks for up to 4 times (4 cycles).

25. The method as claimed in any of the preceding claims, wherein after the initial first cycle up to four cycles, the patient receives two additional cycles of retreatment, optionally followed by two more cycles (2 + opt. 2).

26. The method as described in any of the preceding claims, wherein the treatment further comprises supportive care.

27. The method of claim 26, wherein the supportive care is 30 mg long-acting octreotide (e.g., octreotide LAR) once a month (obtained under the pharmaceutical name Sandostatin LAR).

28. The method of claim 26, wherein the supportive care is 30 mg of long-acting octreotide (e.g., octreotide LAR, for example, obtained under the pharmaceutical name Sandostatin LAR) every 8 weeks.

29. The method of claim 26, wherein the RLT agent is administered at a dose of 7.4 ± 10% GBq every 8 ± 1 weeks for up to 4 times (4 cycles), and the supportive care is 30 mg of long-acting octreotide (e.g., octreotide LAR, for example, obtained under the pharmaceutical name Sandostatin LAR) every 8 weeks during treatment with the 177Lu-DOTA-TATE.

30. The method of claim 26, wherein the RLT agent is administered at a dose of 7.4 ± 10% GBq every 8 ± 1 weeks for up to 4 times (4 cycles), and the supportive care is 30 mg of long-acting octreotide (e.g., octreotide LAR, obtained for example under the pharmaceutical name Sandostatin LAR) every 8 weeks during treatment with the 177Lu-DOTA-TATE (e.g., wherein the 30 mg of long-acting octreotide is administered 4 to 24 hours after each dose of the RLT agent), and the octreotide LAR is administered every 4 weeks after completion of 4 cycles of 177Lu-DOTA-TATE treatment.

31. The method of any of the preceding claims, wherein the treatment further comprises intravenous (IV) administration of a 2.5% lysine-arginine solution.

32. The method of any of the preceding claims, wherein the treatment is characterized in that the centrally assessed progression-free survival (PFS) is at least 18, 20, or 22 months.

33. The method of claim 32, wherein the progress is radiological progress based on central assessment according to RECIST (v.1.1).

34. The method of any of the preceding claims, wherein the treatment is characterized in that the disease control rate (DCR, i.e., complete response (CR) rate + partial response (PR) rate + stable disease (SD) rate) is at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89% or 90%.

35. The method of any of the preceding claims, wherein the treatment is characterized in that the objective response rate (ORR, i.e., complete response (CR) rate + partial response (PR) rate) is at least 25%, 30%, 35%, 40%, 41%, 42% or 43%.

36. The method as claimed in any of the preceding claims, wherein the treatment reduces the risk of progression or death by at least 50%, 60%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, or 75% compared to comparable treatments without the use of the RLT agent.

37. The method as claimed in any of the preceding claims, wherein when calculating risk relative to comparable treatments without the RLT agent, the reduced risk of progression or death associated with the treatment corresponds to a hazard ratio (HR) of less than 0.5, 0.4, 0.35, 0.34, 0.33, 0.32, 0.32, 0.30, 0.29, 0.28, 0.27, 0.26, or 0.25 (95% CI).

38. The method of claim 36 or claim 37, wherein the comparable treatment without the use of the RLT agent comprises administration of a drug selected from the group consisting of: octreotide, such as high-dose long-acting octreotide (e.g., 60 mg long-acting octreotide (octreotide LAR)), lanreotide, everolimus, interferon-α (IFN-α), sunitinib, surufatinib, lenvatinib, streptozotocin (STZ), etoposide, irinotecan, and chemotherapy (e.g., including capecitabine, temozolomide, dacarbazine, leucovorin, 5-fluorouracil (5FU), and platinum-based chemotherapy (e.g., oxaliplatin, cisplatin)) or combinations thereof (e.g., STZ-5FU, CAPTEM, CAP-5FU, FOLFOX, FOLFIRI).

39. The method of any one of claims 36 to 38, wherein the comparable treatment without the use of the RLT agent is 60 mg long-acting octreotide (octreotide LAR, for example, obtained as Sandostatin LAR).

40. The method as described in any of the preceding claims, wherein the treatment is characterized in that treatment-related grade ≥ 3 adverse events (AEs) do not exceed 30%, 25%, 20%, 18%, or 16%.

41. The method as described in any of the preceding claims, wherein the treatment is characterized in that the number of treatment-related grade ≥ 3 serious adverse events (SAEs) does not exceed 10%, 9%, 8%, 7%, 6% or 5%.

42. The method as described in any of the preceding claims, wherein the patient is ≥ 15 years old.

43. The method as claimed in any of the preceding claims, wherein the patient is newly diagnosed with advanced G2 or G3 GEP-NET.

44. The method as described in any of the preceding claims, wherein the patient is newly diagnosed with advanced G2 GEP-NET.

45. The method as claimed in any of the preceding claims, wherein the patient is newly diagnosed with advanced G3 GEP-NET.

46. ​​The method of any of the preceding claims, wherein the 1L therapy is characterized in that no prior treatment with interferon, mTOR inhibitors or chemotherapy agents has been used.

47. The method of any of the preceding claims, wherein the 1L therapy is characterized in that the patient has not previously been treated with a sandostatin analogue (no SSA), or, in cases of prior SSA treatment, has not experienced progression under the SSA therapy.

48. The method as described in any of the preceding claims, wherein the NET is a gastrointestinal pancreatic NET (GEP-NET).

49. The method as described in any of the preceding claims, wherein the NET is a pancreatic NET (pNET).

50. The method as claimed in any of the preceding claims, wherein the NET is a small intestinal NET.

51. The method as described in any of the preceding claims, wherein the NET is a late NET.

52. The method of any of the preceding claims, wherein the NET is metastatic or locally advanced and inoperable.

53. The method as described in any of the preceding claims, wherein the NET is SSTR positive (SSTR+).

54. The method of claim 53, wherein the SSTR positivity of the NET is determined by CT or MRI scanning with a radioligand imaging (RLI) agent.

55. The method of claim 54, wherein the SSR positivity of the NET is determined by performing PET / CT, SPECT / CT, or SRS (somatostatin receptor scintillation imaging) with a radioligand imaging (RLI) agent.

56. The method of claim 54 or claim 55, wherein the RLI agent is selected from the group consisting of: 68Ga-Oxodotriptide, 68Ga-Edotriptide, 68Ga-Trentan-Sartoretide, 64Cu-Oxodotriptide, 64Cu-Edotriptide, 64Cu-Trentan-Sartoretide, 111In-Pentan-Tektrotyd, and 99mTc-Tektrotyd.

57. The method as described in any of the preceding claims, wherein the median time for a 10-point deterioration in overall health status on the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire) is at least 9 months, for example at least 10 months, for example at least 11 months, for example at least 12 months, for example at least 13 months.

58. The method as described in any of the preceding claims, wherein the NET has been transferred to the bone.

59. The method as described in any of the preceding claims, wherein the NET has been transferred to the liver.

60. The method as described in any of the preceding claims, wherein the NET has been transferred to the lymph node.

61. The method as described in any of the preceding claims, wherein the NET has been transferred to the peritoneum.

62. The method as claimed in any of the preceding claims, wherein the overall response rate is at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, for example at least 35%, for example at least 40%.

63. The method as claimed in any of the preceding claims, wherein chromogranin A (CgA) > 2 prior to treatment with the radioligand therapeutic agent (RLT) targeting the somatostatin receptor (SSTR).

64. The method of any one of claims 1 to 62, wherein chromogranin A (CgA) is ≤ 2 prior to treatment with the radioligand therapeutic agent (RLT) targeting the somatostatin receptor (SSTR).

65. A method for treating a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET) using a radioligand therapy (RLT) agent targeting a somatostatin receptor (SSTR), the method comprising administering treatment to the patient containing a therapeutically effective dose of the radioligand therapy (RLT) agent targeting the somatostatin receptor (SSTR) as a first-line (1L) therapy.

66. A method for delaying the time of first progression or death in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET) using a radioligand therapy (RLT) agent targeting the somatostatin receptor (SSTR), the method comprising administering treatment to the patient containing a therapeutically effective dose of the radioligand therapy (RLT) agent targeting the somatostatin receptor (SSTR) as a first-line (1L) therapy.

67. A method for delaying the need to initiate chemotherapy in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET), the method comprising administering to the patient treatment containing a therapeutically effective dose of the radioligand therapy (RLT) targeting the somatostatin receptor (SSTR) as first-line (1L) therapy.

68. A radioligand therapy (RLT) agent targeting the somatostatin receptor (SSTR) used in a method for controlling the disease of a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET), the method comprising administering treatment to the patient containing a therapeutically effective dose of the radioligand therapy (RLT) agent targeting the somatostatin receptor (SSTR) as a first-line (1L) therapy.

69. A radioligand therapy (RLT) agent targeting the somatostatin receptor (SSTR) used in a method for alleviating a patient’s well-differentiated G2 or G3 neuroendocrine tumor (NET), the method comprising administering treatment to the patient containing a therapeutically effective dose of the SSTR-targeting RLT agent as a first-line (1L) therapy.

70. A radioligand therapy (RLT) agent targeting the somatostatin receptor (SSTR) for use in a patient with a well-differentiated G2 or G3 neuroendocrine tumor (NET) or in a method of reducing the risk of death in said patient, said method comprising administering to said patient treatment containing a therapeutically effective dose of the radioligand therapy (RLT) agent targeting the somatostatin receptor (SSTR) as a first-line (1L) therapy.

71. The RLT agent for use targeting SSTRs as described in any one of claims 65 to 70, wherein the RLT agent comprises a radionuclide selected from the group consisting of 47Sc, 67Cu, 153Sm, 161Tb, 169Er, and 177Lu.

72. The RLT agent for use targeting SSTRs as described in any one of claims 65 to 71, wherein the RLT agent comprises a radionuclide selected from the group consisting of 161Tb and 177Lu.

73. The RLT agent for use targeting SSTRs as described in any one of claims 65 to 72, wherein the RLT agent comprises a radionuclide selected from the group consisting of 161Tb and 177Lu.

74. The RLT agent for use targeting SSTRs as described in any one of claims 65 to 73, wherein the RLT agent comprises the radionuclide 177Lu.

75. The RLT agent for targeting SSTRs as described in claim 74, wherein the 177Lu is carrier-free (nca)177Lu or carrier-added (ca)177Lu.

76. The RLT agent for targeting SSTRs as described in claim 75, wherein the 177Lu is nca177Lu (also known as NCA 177Lu).

77. The RLT agent for targeting SSTRs as described in claim 76, wherein the 177Lu is carrier-added (ca)177Lu (also known as CA 177Lu).

78. The RLT agent for use targeting SSTRs as described in any one of claims 65 to 77, wherein the RLT agent comprises a ligand selected from the group consisting of: dotatate, dotatoc, and titan-sartoretide.

79. The RLT agent for use targeting SSTRs as described in any one of claims 65 to 78, wherein the RLT agent comprises a ligand selected from the group consisting of: dotatate and dotatoc.

80. The RLT agent for use targeting SSTRs as described in any one of claims 65 to 79, wherein the RLT agent comprises the ligand dotatate.

81. The RLT agent for use targeting SSTRs as described in any one of claims 65 to 80, wherein the RLT agent is selected from the group consisting of: lutetium (177Lu) oxodotriptide, lutetium (177Lu) edotoriptide, lutetium (177Lu) titan-sartoreptide, terbium (161Tb) oxodotriptide, terbium (161Tb) edotoriptide and terbium (161Tb) titan-sartoreptide.

82. The RLT agent for use targeting SSTR as described in any one of claims 65 to 81, wherein the RLT agent is selected from the group consisting of: lutetium (177Lu) oxodotriptide, lutetium (177Lu) edotoriptide, terbium (161Tb) oxodotriptide and terbium (161Tb) edotoriptide.

83. The RLT agent for use targeting SSTR as described in any one of claims 65 to 82, wherein the RLT agent is selected from the group consisting of lutetium (177Lu) oxodotriptide and lutetium (177Lu) edotoriptide.

84. The RLT agent for targeting SSTRs as described in any one of claims 65 to 83, wherein the RLT agent is lutetium ( 177 Lu) Ossodutritide (also known as 177 Lu[Lu]-DOTA-(Tyr 3 )-Octrenic acid or 177 Lu[Lu]-DOTA-0-Tyr3-octreotic acid).

85. The RLT agent for use targeting SSTR as described in any one of claims 65 to 84, wherein the dose of said RLT agent is 5 to 10 GBq, 6 to 9 GBq, 6.5 to 8.5 GBq, 7.4 ± 10% GBq, or 7.5 ± 0.7 GBq.

86. The RLT agent for targeting SSTRs as described in claim 85, wherein the dose is administered once every 40 to 100 days, once every 49 to 90 days, once every 90 days, or once every 8 ± 1 weeks.

87. The RLT agent for targeting SSTRs as described in claim 86, wherein the dose is administered up to 4 times (4 cycles).

88. The RLT agent for use targeting SSTR as described in any one of claims 65 to 87, wherein the RLT agent is administered at a dose of 7.4 ± 10% GBq every 8 ± 1 weeks for up to 4 times (4 cycles).

89. The RLT agent targeting SSTR as described in any one of claims 65 to 88, wherein after the initial first cycle up to four cycles, the patient receives two additional cycles of retreatment, optionally followed by two more cycles (2 + opt. 2).

90. The RLT agent for use targeting SSTRs as described in any one of claims 65 to 89, wherein the treatment further comprises supportive care.

91. The RLT agent for use targeting SSTR as described in claim 90, wherein the supportive care is 30 mg octreotide LAR once a month (obtained under the pharmaceutical name Sandostatin LAR).

92. The RLT agent for use targeting SSTR as described in claim 91, wherein the supportive care is 30 mg of long-acting octreotide (e.g., octreotide LAR, for example, obtained under the pharmaceutical name Sandostatin LAR) every 8 weeks.

93. The RLT agent for use targeting SSTR as described in claim 91, wherein the RLT agent is administered at a dose of 7.4 ± 10% GBq every 8 ± 1 weeks for up to 4 times (4 cycles), and the supportive care is 30 mg of long-acting octreotide (e.g., octreotide LAR, for example, obtained under the pharmaceutical name Sandostatin LAR) every 8 weeks during treatment with the 177Lu-DOTA-TATE.

94. The RLT agent for use targeting SSTR as described in claim 91, wherein the RLT agent is administered at a dose of 7.4 ± 10% GBq every 8 ± 1 weeks for up to 4 times (4 cycles), and the supportive care is 30 mg of long-acting octreotide (e.g., octreotide LAR, obtained for example under the pharmaceutical name Sandostatin LAR) every 8 weeks during treatment with the 177Lu-DOTA-TATE (e.g., wherein the 30 mg of long-acting octreotide is administered 4 to 24 hours after each dose of the RLT agent) and once every 4 weeks after completion of 4 cycles of 177Lu-DOTA-TATE treatment.

95. The RLT agent for targeting SSTRs as described in any one of claims 65 to 94, wherein the treatment further comprises intravenous (IV) administration of a 2.5% lysine-arginine solution.

96. The RLT agent targeting SSTR for use as described in any one of claims 65 to 95, wherein the treatment is characterized by a centrally assessed progression-free survival (PFS) of at least 18, 20, or 22 months.

97. The RLT agent for use targeting SSTRs as described in claim 96, wherein the progress is radiological progress based on central assessment according to RECIST (v.1.1).

98. The RLT agent for use targeting SSTR as described in any one of claims 65 to 97, wherein the treatment is characterized by a disease control rate (DCR, i.e., complete response (CR) rate + partial response (PR) rate + stable disease (SD) rate) of at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, or 90%.

99. The RLT agent for use targeting SSTR as described in any one of claims 65 to 98, wherein the treatment is characterized in that the objective response rate (ORR, i.e., complete response (CR) rate + partial response (PR) rate) is at least 25%, 30%, 35%, 40%, 41%, 42%, or 43%.

100. The RLT agent targeting SSTR as described in any one of claims 65 to 99, wherein the treatment reduces the risk of progression or death by at least 50%, 60%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, or 75% compared to comparable treatments without the use of the RLT agent.

101. The RLT agent targeting SSTRs for use as described in any one of claims 65 to 100, wherein when calculating risk relative to a patient receiving comparable treatment without the RLT agent, the reduced risk of progression or death associated with the treatment corresponds to a hazard ratio (HR) of less than 0.5, 0.4, 0.35, 0.34, 0.33, 0.32, 0.32, 0.30, 0.29, 0.28, 0.27, 0.26, or 0.25 (95% CI).

102. The RLT agent for use targeting SSTRs as described in claim 100 or claim 101, wherein the comparable treatment without the use of said RLT agent comprises administration of a drug selected from the group consisting of: octreotide, such as high-dose long-acting octreotide (e.g., 60 mg long-acting octreotide (octreotide LAR)), lanreotide, everolimus, interferon-α (IFN-α), sunitinib, surufatinib, lenvatinib, streptozotocin (STZ), etoposide, irinotecan, and chemotherapy (e.g., including capecitabine, temozolomide, dacarbazine, leucovorin, 5-fluorouracil (5FU), and platinum-based chemotherapy (e.g., oxaliplatin, cisplatin)) or combinations thereof (e.g., STZ-5FU, CAPTEM, CAP-5FU, FOLFOX, FOLFIRI).

103. The RLT agent for use targeting SSTR as described in any one of claims 100 to 102, wherein the comparable treatment without the use of the RLT agent is 60 mg long-acting octreotide (octreotide LAR, for example, obtained as Sandostatin LAR).

104. The RLT agent targeting SSTR for use as described in any one of claims 65 to 103, wherein the treatment is characterized in that treatment-related grade ≥ 3 adverse events (AEs) do not exceed 30%, 25%, 20%, 18%, or 16%.

105. The RLT agent for use targeting SSTR as described in any one of claims 65 to 104, wherein the treatment is characterized in that the number of treatment-related grade ≥ 3 serious adverse events (SAE) does not exceed 10%, 9%, 8%, 7%, 6% or 5%.

106. The RLT agent for use targeting SSTR as described in any one of claims 65 to 105, wherein the patient is ≥15 years old.

107. The RLT agent for use targeting SSTR as described in any one of claims 65 to 106, wherein the patient is newly diagnosed with advanced G2 or G3 GEP-NET.

108. The RLT agent for use targeting SSTR as described in any one of claims 65 to 107, wherein the patient is newly diagnosed with advanced G2 GEP-NET.

109. The RLT agent for use targeting SSTR as described in any one of claims 65 to 108, wherein the patient is newly diagnosed with advanced G3 GEP-NET.

110. The RLT agent for targeting SSTRs as described in any one of claims 65 to 109, wherein the 1L therapy is characterized in that no prior treatment with interferon, mTOR inhibitors, or chemotherapy agents has been used.

111. The RLT agent for use targeting SSTR as described in any one of claims 65 to 110, wherein the 1L therapy is characterized in that the patient has not previously been treated with a sandostatin analogue (no SSA), or, in cases of previous SSA treatment, has not experienced progression under the SSA therapy.

112. The RLT agent for use targeting SSTR as described in any one of claims 65 to 111, wherein the NET is a gastrointestinal pancreatic NET (GEP-NET).

113. The RLT agent for use targeting SSTR as described in any one of claims 65 to 112, wherein the NET is pancreatic NET (pNET).

114. The RLT agent for use targeting SSTR as described in any one of claims 65 to 113, wherein the NET is a small intestinal NET.

115. The RLT agent for use targeting SSTR as described in any one of claims 65 to 114, wherein the NET is a late NET.

116. The RLT agent for use targeting SSTR as described in any one of claims 65 to 115, wherein the NET is metastatic or locally advanced and unresectable.

117. The RLT agent for use targeting SSTR as described in any one of claims 65 to 116, wherein the NET is SSR positive (SSR+).

118. The RLT agent for targeting SSTRs as described in claim 117, wherein the SSR positivity of the NET is determined by CT or MRI scanning with a radioligand imaging (RLI) agent.

119. The RLT agent for targeting SSTRs as described in claim 118, wherein the SSR positivity of the NET is determined by PET / CT, SPECT / CT, or SRS (somatostatin receptor scintillation imaging) with a radioligand imaging (RLI) agent.

120. The RLT agent for use targeting SSTRs as described in claim 118 or claim 119, wherein the RLT agent is selected from the group consisting of: 68Ga-oxodotriptide, 68Ga-edottriptide, 68Ga-tritan-sartoretide, 64Cu-oxodotriptide, 64Cu-edottriptide, 64Cu-tritan-sartoretide, 111In-penetride, and 99mTc-tektrotyd.

121. The RLT agent targeting SSTR for use as described in any one of claims 65 to 120, wherein the median time for a 10-point deterioration in overall health status on the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire) is at least 9 months, for example at least 10 months, for example at least 11 months, for example at least 12 months, for example at least 13 months.

122. The RLT agent for use targeting SSTR as described in any one of claims 65 to 121, wherein the NET has been transferred to bone.

123. The RLT agent for use targeting SSTR as described in any one of claims 65 to 122, wherein the NET has been transferred to the liver.

124. The RLT agent for use targeting SSTR as described in any one of claims 65 to 123, wherein the NET has been transferred to the lymph nodes.

125. The RLT agent for use targeting SSTR as described in any one of claims 65 to 124, wherein the NET has been transferred to the peritoneum.

126. The RLT agent for use targeting SSTR as described in any one of claims 65 to 125, wherein the overall response rate is at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, for example at least 35%, for example at least 40%.

127. The RLT agent targeting SSTR as described in any one of claims 65 to 126, wherein chromogranin A (CgA) > 2 prior to treatment with the RLT targeting the somatostatin receptor (SSTR).

128. The RLT agent targeting SSTR as described in any one of claims 65 to 126, wherein chromogranin A (CgA) is ≤ 2 prior to treatment with the RLT targeting the somatostatin receptor (SSTR).

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