Method of treating cancer

Abstract

The present disclosure relates to a method of treating well-differentiated Grade 1 or Grade 2 advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in a patient in need thereof, comprising administering to said patient a treatment comprising a therapeutically effective dose of a somatostatin receptor (SSTR) targeting radioligand therapeutic (RLT) agent, in particular [177Lu]Lu-DOTA-TATE, as first line therapy.

Description

[0001] 768795: NIT-59885PC

[0002] METHOD OF TREATING CANCER

[0003] CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to European Patent Application No. 24220000.4, filed on December 13, 2024, and European Patent Application No. 25179053.1 , filed on May 27, 2025, which are incorporated herein by reference in their entirety.

[0005] BACKGROUND

[0006] Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of neoplasms that arise from the neuroendocrine cells of the gastrointestinal tract and pancreas. The incidence and prevalence of GEP-NETs have been rising, primarily due to improvements in diagnostic techniques and increased awareness. While the prognosis for localized NETs has improved, patients with distant metastasis and high tumor burden continue to face poor outcomes.

[0007] For patients with inoperable NET, the primary goals of treatment are to extend survival, enhance and sustain quality of life (QoL), control tumor growth, and control secretory symptoms if the tumor is functional. Somatostatin analogs (SSAs) such as octreotide long-acting 30 mg (Sandostatin® LAR®) or lanreotide ATG 120 mg (lanreotide ATG, SOMATULINE® DEPOT or SOMATULINE® AUTOGEL®) have become the mainstay of treatment in patients with low- or intermediate-grade GEP-NET.

[0008] Despite the effectiveness of SSAs, there remains a significant unmet need for more effective treatments especially for patients with high disease burden and / or in patients with symptomatic tumors as they may experience a more rapid disease progression.

[0009] SUMMARY

[0010] The present disclosure provides a method of treating a well-differentiated Grade 1 or Grade 2 gastroenteropancreatic neuroendocrine tumor (GEP-NET) in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu- DOTA-TOC, or a pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki67 index less than 10%.

[0011] The present disclosure further provides a method of treating well-differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, b) administering octreotide LAR after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and d) administering octreotide LAR after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line 768795: NIT-59885PC therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%.

[0012] The present disclosure further provides a method of treating well-differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 3-15 GBq of radiation, b) administering a dose of 20-40 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA- TATE, c) repeating steps a) and b) once every 42 to 112 days, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 20-40 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki67 index less than 10%.

[0013] The present disclosure further provides a method of treating well-differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 7.4 ± 10% GBq of radiation, b) administering a dose of about 30 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) repeating steps a) and b) once every 8 ± 1 weeks for 3 additional (4 total) cycles, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 30 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu- DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki67 index less than 10%.

[0014] The present disclosure further provides a method of treating well-differentiated Grade 1 or Grade 2 gastrointestinal neuroendocrine tumor (GI-NET) in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, b) administering octreotide LAR after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and d) administering octreotide LAR after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GI-NET demonstrates a Ki-67 index less than 10%.

[0015] The present disclosure further provides a method of treating well-differentiated Grade 1 or Grade 2 GI-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 3-15 GBq of radiation, b) administering a dose of 20-40 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) repeating steps a) and b) once every 42 to 112 days, d) discontinuing the lutetium [177Lu]Lu- DOTA-TATE treatment, and e) administering 20-40 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GI-NET demonstrates a Ki67 index less than 10%. 768795: NIT-59885PC

[0016] The present disclosure further provides a method of treating well-differentiated Grade 1 or Grade 2 GI-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 7.4 ± 10% GBq of radiation, b) administering a dose of about 30 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA- TATE, c) repeating steps a) and b) once every 8 ± 1 weeks for 3 additional (4 total) cycles, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 30 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GI-NET demonstrates a Ki67 index less than 10%.

[0017] BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 is a schematic showing the phases of the clinical trial described in Example 5. FIG. 2 is a schematic of the clinical trial efficacy assessment described in Example 5.

[0019] DETAILED DESCRIPTION

[0020] Neuroendocrine tumors (NET) are rare malignant neoplasms that can arise throughout the body, and account for approximately 1% of all human tumors. Gastroenteropancreatic NET (GEP-NETs) are a heterogeneous group of neoplasms that arise from the neuroendocrine cells of the gastrointestinal tract and pancreas. Their incidence and prevalence continue to rise mainly due to improvement in diagnostic techniques and awareness. The World Health Organization staging system classifies GEP-NET based on primary tumor localization, size, mitotic activity, invasiveness, and functional status. Based on the recent World Health Organization classification, GEP-NETs are categorized by tumor differentiation status and tumor grade (Rindi, G. et al. (2022) Endocr Pathol 33(1 ): 115-154). Tumor differentiation refers to the resemblance of the tumor histology to its normal counterparts, whereas tumor grade describes the proliferative activity of the tumor, as measured by mitotic rate or Ki-67 proliferative index.

[0021] Histologic 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, I. et al. (2003) Cancer 97(4) :934-959).

[0022] For patients with inoperable NET, the primary goals of treatment are to extend survival, enhance and sustain quality of life (QoL), control tumor growth, and control secretory symptoms if the tumor is functional. Somatostatin analogs (SSAs) such as octreotide long-acting 30 mg (Sandostatin® LAR®) or lanreotide ATG 120 mg (lanreotide ATG, SOMATULINE® DEPOT or SOMATULINE® AUTOGEL®) have become the mainstay of treatment in patients with low- or intermediate-grade GEP-NET. 768795: NIT-59885PC

[0023] A PROMI D study revealed that 42 patients with metastatic midgut NET who were treated with octreotide long-acting (LAR) 30 mg / month experienced over double the time to tumor progression compared to 43 patients given a placebo (14.3 vs. 6.0 months; P=0.000072). Additionally, 67% of octreotide-treated patients achieved stable disease versus 37% in the placebo group (Rinke, A. et al. (2009) J Clin Oncol 27(28):4656-4663). In a CLARINET study, patients with Grade 1-2 midgut and pancreatic NET treated with lanreotide 120 mg / month showed significant improvement in progression-free survival (PFS) 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% Cl 0.30 to 0.73) (Caplin, M. et al. (2014) N Engl J Med 371(2):224-233).

[0024] According to the European Neuroendocrine Tumor Society (ENETS), the North American Neuroendocrine Society (NANETS) and the National Comprehensive Cancer Network (NCCN), somatostatin analogues are commonly used as the initial treatment for patients with unresectable, asymptomatic, well-differentiated pancreatic NET (pNETs) and a high tumor burden (Kos-Kudla, B. et al. (2023) J Neuroendocrinol 35(12):e13343; Hofland, J. et al. (2023) J Neuroendocrinol 35(8):e13318; Kunz, P. et al. (2013) Pancreas 42(4):557- 577; NCCN Guidelines (2024) NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors Version 2.2024, Accessed on September 05, 2024). A combination of capecitabine and temozolomide (CAPTEM) is often used in patients with well-differentiated pNET, who are highly symptomatic from tumor bulk or who have rapidly enlarging metastases, but there is no robust evidence to support the use of chemotherapy in patients with NETs of other origin (Pavel, M. et al. (2012) Neuroendocrinology 95(2):157- 176; Kunz, P. et al. (2023) J Clin Oncol 41 (7): 1359-1369).

[0025] [177Lu]Lu-DOTA-TATE has shown significant efficacy in treating GEP-NET patients, particularly those with advanced disease. The Phase III NETTER-1 study demonstrated that [177Lu]Lu-DOTA-TATE significantly improved progression-free survival (PFS) in patients with progressive, well-differentiated [Grade 1 and Grade 2], somatostatin receptor-positive (SSTR+) midgut NETs (Strosberg, J. et al. (2017) Neuroendocrine Tumors 376(2): 125-135). The Phase III NETTER-2 study further supported these findings, showing positive results in advanced, well-differentiated Grade 2 and Grade 3 (Ki-67: 10-55%) SSTR+ GEP-NETs (Singh, S. et al. (2024) Lancet 403(10446):2807-2817). Both studies demonstrated a similar and favorable safety profile.

[0026] DEFINITIONS

[0027] Before the present disclosure is described, it is to be understood that this disclosure is not limited to particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for 768795: NIT-59885PC the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0028] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, exemplary methods and materials are now described. All publications mentioned herein are incorporated herein by reference to describe in their entirety.

[0029] “A,” “an,” or “a(n)” are indefinite articles and, unless expressly stated otherwise, are intended to include one or more of the referenced element, component, or group. These terms when used in reference to a group of substituents or “substituent group” herein, mean at least one. “About” when referring to a value includes the stated value + / - 10% of the stated value. For example, about 50% includes a range from 45% to 55%, while about 20 molar equivalents includes a range of from 18 to 22 molar equivalents. Accordingly, when referring to a range, “about” refers to each of the stated values + / - 10% of the stated value of each end of the range. For instance, a ratio of from about 1 to about 3 (weight / weight) includes a range of from 0.9 to 3.3.

[0030] As used herein, the term “individual,” "subject," or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. Typically, the subject is a human, and preferably is a human having or suspected of having GEP-NET.

[0031] As used herein, the phrase “therapeutically effective dose” or “therapeutic dose” refers to the amount of active compound or pharmaceutical agent such as an amount of any of the solid forms or salts thereof as disclosed herein that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. An appropriate “effective” amount in any individual case may be determined using techniques known to a person skilled in the art.

[0032] The phrase “pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0033] As used herein, the term “treating” or “treatment” refers to inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder ( / .e., arresting further development of the pathology and / or symptomology) or ameliorating the 768795: NIT-59885PC disease; for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder ( / .e., reversing the pathology and / or symptomology) such as decreasing the severity of the disease.

[0034] The term “prevent,” “preventing,” or “prevention” as used herein, comprises the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.

[0035] “Treatment naive” refers to patients who have not yet received any prior treatment or have not been administered any therapeutic agent directed toward the disease of interest, in this instance GEP-NET. The first round of therapy directed towards a specific disease is referred to as a “first line therapy,” also called “first line treatment,” “induction therapy,” “primary therapy,” and “primary treatment.” Thus, treatment naive patients have not received a first line therapy directed toward GEP-NET including any therapeutic radiopharmaceuticals for GEP-NET, interferons, mTOR-inhibitors (mammalian Target of Rapamycin), chemotherapy or other systemic therapies. Additionally, treatment naive patients have not received more than 4 cycles of a somatostatin analog (SSA, e.g., octreotide LAR).

[0036] As used herein, “radiation” refers to high-energy particles or waves, including, but not limited to, x-rays, gamma rays, electron beams, or protons. Radiation can damage cells by causing small breaks in the cell’s DNA. Such breaks in cancer cells inhibits their growth and division and can induce cell death. Radiation can be delivered externally and / or internally. External radiation is most commonly delivered in the form of a beam of high-energy rays or particles directed at the tumor. Internal radiation therapy is administered by introducing radioactive elements into the body locally or systemically. Localized internal radiation therapy, also known as brachytherapy, is administered by introducing a radioactive implant in or near the tumor. Systemic internal radiation treatments are administered topically (including transdermally, epidermally, ophthalmicly and to mucous membranes including intranasally, vaginally and rectally), pulmonarily (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheally or intranasally), orally or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Although systemically administered, some radiotherapies are targeted to cancer cells, thus reducing their effects on non-cancerous cells. “Progression-free survival” (“PFS”) is the time from date of randomization / start of treatment to the date of event defined as the first documented progression or death due to any cause.

[0037] A “complete response” (“CR”) is demonstrated by the disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. 768795: NIT-59885PC

[0038] The “sum of diameters” (“SOD”) is the total length of all non-nodal lesions as measured along the long axis and all nodal target lesions along the short axis measured on a medical image.

[0039] A “partial response” (“PR”) is demonstrated by at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD.

[0040] A “stable disease” (“SD”) is demonstrated by neither sufficient shrinkage to qualify for PR or OR nor an increase in lesions.

[0041] “Best overall response” (“BOR”) is the best response recorded from the start of the treatment until disease progression / recurrence.

[0042] “Full analysis set” (“FAS”) comprises all participants to whom study treatment has been assigned by randomization.

[0043] “Disease control rate” (“DOR”) is defined as the proportion of participants with BOR of PR, OR, or SD (centrally assessed according to RECIST v1.1 ). More precisely, it counts the presence of at least one OR or PR or SD. The DOR will be calculated based on FAS according to the intent to treat principle. DOR and its 95% Cl will be presented by treatment group. As a supportive analysis, DCR as per local review will be presented by treatment group, along with 95% confidence intervals (Cis).

[0044] “Time to deterioration” (“TTD”) is the time from randomization to the first deterioration by an absolute change of at least 15% (i.e. 15 points, based on IQWiG General Methods Version 7.0) compared with baseline score or death from any causeTTD is calculated for the Gl scale of EORTC-QLQ-GI.NET21 and fatigue, diarrhea, and global health scales of EORTC QLQ-C30. Of note, any deterioration for the diarrhea domain would correspond to a change of at least 33%.

[0045] “Objective response rate” also known as “Overall Response Rate” (“ORR”) is defined as the proportion of participants with BOR of CR or PR, as per central review and according to RECIST v1.1.

[0046] “Hazard ratio” (“HR”) is a summary comparison between the two treatment arms. It is estimated using the Cox proportional hazards model adjusted for randomization stratification factors.

[0047] “Duration of response” (“DOR”), as per RECIST v1.1 defined as time from CR or PR to progression or death due to underlying cancer only. DOR only applies to participants with BOR of CR or PR according to RECIST v1.1 based on BIRC assessment. The start date is the date of first documented response of CR or PR, and the end date is defined as the date of the first documented progression per BIRC or death due to underlying cancer. Participants continuing without progression or death due to underlying cancer will be censored at the date of their last adequate tumor assessment. DOR will be listed and summarized by treatment group for all participants in the FAS with BOR of CR or PR. As a supportive 768795: NIT-59885PC analysis, DOR as per local review will be also presented by treatment group.

[0048] “Overall survival” (“OS”) is defined as the time from date of randomization to date of death due to any cause. If a participant is not known to have died, then OS will be censored at the latest date the participant was known to be alive (on or before the cut-off date). OS will be analyzed in the FAS population according to the randomized treatment group and strata assigned at randomization. The OS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% Cis of the medians will be presented for each treatment group. The HR for OS will be calculated, along with its 95% Cl, using a stratified Cox model.

[0049] “Time to progression” (“TTP”) is the time from date of randomization / start of treatment to the date of event defined as the first documented progression or death due to underlying cancer.

[0050] “High disease burden” refers to conditions in which participants demonstrate one or more of the symptoms selected from the group consisting from primary tumor or a metastatic lesion > 4 cm, more than one tumor or metastatic lesions measuring > 2 cm, elevated alkaline phosphatase > 2.5 X upper limit of normal (ULN), presence of bone metastasis, presence of peritoneal metastasis, symptoms due to tumor volume such as pain, fatigue, weight loss, anorexia etc, and / or symptoms due to hormone excess requiring active management.

[0051] “Symptomatic disease” encompasses conditions where participants experience symptoms linked to tumor volume, such as pain, fatigue, weight loss, anorexia, Gl bleeding, jaundice, and intestinal obstruction, or symptoms caused by hormone excess that necessitate active management.

[0052] The “Ki-67 index” is a measure of how fast cancer cells are dividing, calculated as the percentage of cells that are positive for the Ki-67 protein.

[0053] [177Lu]Lu-DOTA-TATE

[0054] [177Lu]Lu-DOTA-TATE is a radiopharmaceutical consisting of a ligand (an oligopeptide, coupled to the metal chelating moiety 1 ,4,7,10-tetraazacyclododecane- 1 ,4,7,10-tetraacetic acid (DOTA)), and is radiolabeled with lutetium-177 (177Lu). The ligand binds to SSTRs with the highest affinity for subtype 2 (SSTR2), thus making it a treatment option for patients with tumors that express SSTRs.

[0055] The biological basis for the use of [177Lu]Lu-DOTA-TATE in treatment of SSTR- expressing tumors is the receptor-mediated internalization and intracellular retention of radiolabeled somatostatin analogs. SSTR2 is an attractive target because the receptor density is higher on tumors than on non-tumor, and because SSTR2 internalize into cells after ligand binding tissue (Reubi, J. et al. (2001) EurJ Nucl Med 28(7):836-46; Reubi, J. 768795: NIT-59885PC

[0056] (2003) Endocr Rev; 24(4):389-427). After binding to SSTR2, the p particle emission from 177Lu forms free radicals that result in DNA damage and cell death.

[0057] [177Lu]Lu-DOTA-TATE has been approved in 40 countries for the treatment of SSTR-positive GEP-NETs. The recommended [177Lu]Lu-DOTA-TATE dose in the approved indications is 7.4 Gigabecquerel (GBq) (200 Millicurie (mCi)) every 8 weeks for a total of 4 doses.

[0058] DOTA-TOC

[0059] DOTA-TOC is an eight amino acid long peptide with a covalently bonded DOTA bifunctional chelator (Blom E. and Koziorowski, J. Somatostatin: Synthesis, Mechanisms-of- Action and Physiological Effects (2013), 41-78). DOTA-TOC can be reacted with radionuclides such as yttrium-90, gallium-68, lutetium-177, and copper-64 to form radiopharmaceuticals for positron emission tomography (PET) imaging or radionuclide therapy. Radionuclide therapy with DOTA-TOC targets somatostatin receptors (SSR) (Id.).

[0060] METHODS OF ADMINISTRATION, TREATMENT, AND / OR USES

[0061] In an aspect, provided herein are methods of treating well-differentiated Grade 1 or Grade 2 gastroenteropancreatic neuroendocrine tumor (GEP-NET) in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu- DOTA-TOC, or a pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%.

[0062] In some embodiments, the GEP-NET is a gastrointestinal neuroendocrine tumor (Gl- NET).

[0063] In an aspect, provided herein are methods of treating well-differentiated Grade 1 or Grade 2 gastroenteropancreatic neuroendocrine tumor (GEP-NET) in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%.

[0064] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the GEP-NET is a gastrointestinal neuroendocrine tumor (Gl- NET).

[0066] In an aspect, provided herein are methods of treating well-differentiated Grade 1 or Grade 2 gastroenteropancreatic neuroendocrine tumor (GEP-NET) in a patient in need 768795: NIT-59885PC thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%.

[0067] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient has previously been treated with one or more somatostatin analogues. In an embodiment, the GEP-NET is a GI-NET.

[0068] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient has not received more than 4 cycles of one or more somatostatin analogues. In an embodiment, the GEP-NET is a GI-NET. In some embodiments, the present disclosure relates to methods of treating well-differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient has not received more than 4 cycles, 3 cycles, 2 cycles, or 1 cycle of one or more somatostatin analogues. In an embodiment, the GEP-NET is a GI-NET.

[0069] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient has not received more than 4 cycles, 3 cycles, 2 cycles, or 1 cycle of a somatostatin analog. In an embodiment, the GEP-NET is a GI-NET.

[0070] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient has not been administered a somatostatin analog. In an embodiment, the GEP-NET is a GI- NET. 768795: NIT-59885PC

[0071] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the patient has not been administered interferons, an mTOR-inhibitor, chemotherapy, or other systemic therapies of GEP-NET for more than 1 month prior to treatment. In an embodiment, the GEP-NET is a GI-NET.

[0072] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the patient has not been administered interferons, an mTOR-inhibitor, chemotherapy, or other systemic therapies of GEP-NET within 12 weeks prior to treatment. In an embodiment, the GEP-NET is a GI-NET.

[0073] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the patient has not been administered interferons, an mTOR-inhibitor, chemotherapy, or other systemic therapies of GEP-NET for more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks prior to treatment wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0074] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy. In an embodiment, the GEP-NET is a GI-NET.

[0075] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or pharmaceutically acceptable salt thereof, as a first line therapy, wherein the treatment is a first line therapy, and the Grade 1 GEP-NET demonstrates a Ki-67 index less than 1% or less than 2%. In an embodiment, the GEP-NET is a GI-NET.

[0076] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or 768795: NIT-59885PC pharmaceutically acceptable salt thereof, as a first line therapy, wherein the Grade 2 GEP- NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a Gl- NET.

[0077] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or pharmaceutically acceptable salt thereof, wherein the Grade 2 GEP-NET demonstrates a Ki- 67 index less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0078] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0079] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the GEP- NET is metastasized or locally advanced, curatively inoperable, and histologically proven. In an embodiment, the GEP-NET is a GI-NET.

[0080] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the GEP- NET is metastasized or locally advanced, curatively inoperable, or histologically proven. In an embodiment, the GEP-NET is a GI-NET.

[0081] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the patient demonstrates high disease burden. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET. 768795: NIT-59885PC

[0082] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient demonstrates one or more symptoms selected from the group consisting a primary tumor or a metastatic lesion > 4 cm, more than one tumor or metastatic lesions measuring > 2 cm, elevated alkaline phosphatase > 2.5 X upper limit of normal (ULN), presence of bone metastasis, presence of peritoneal metastasis, symptoms due to tumor volume such as pain, fatigue, weight loss, anorexia etc., and symptoms due to hormone excess requiring active management. In an embodiment, the GEP-NET is a GI-NET.

[0083] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the patient demonstrates symptomatic disease. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0084] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient demonstrates one or more symptoms selected from the group consisting of fatigue, weight loss, anorexia, Gl bleedingjaundice, intestinal obstruction, and pain. In an embodiment, the GEP-NET is a GI-NET.

[0085] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the patient has been diagnosed for less than 6 months. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0086] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line 768795: NIT-59885PC therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient has been diagnosed for about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 18 months, about 2 years, about 30 months, or about 3 years. In an embodiment, the GEP-NET is a GI-NET.

[0087] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein a therapeutic dose comprises 7.4 ± 10% GBq of radiation. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP- NET is a GI-NET.

[0088] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, comprises about 3 GBq, about 4 GBq, about 5 GBq, about 6 GBq, about 7 GBq, about 8 GBq, about 9 GBq, about 10 GBq, about 11 GBq, about 12 GBq, about 13 GBq, about 14 GBq, or about 15 GBq of radiation. In an embodiment, the GEP-NET is a GI-NET.

[0089] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the therapeutic dose is administered once every 42 to 112 days. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0090] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the therapeutic dose is administered once every 49 to 90 days. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0091] In some embodiments, the present disclosure relates to methods of treating well- 768795: NIT-59885PC differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the therapeutic dose is administered once every 8 ± 1 weeks. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0092] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the therapeutic dose is administered once about every 6 weeks, about every 7 weeks, about every 8 weeks, about every 9 weeks, about every 10 weeks, about every 11 weeks, about every 12 weeks, about every 13 weeks, about every 14 weeks, about every 15 weeks, about every 16 weeks, about every 17 weeks, about every 18 weeks, about every 19 weeks, or about every 20 weeks. In an embodiment, the GEP-NET is a GI-NET.

[0093] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the therapeutic dose is administered for 4 to 8 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0094] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the therapeutic dose is administered for 4 to 6 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0095] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the therapeutic dose is administered for 6 to 8 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET. 768795: NIT-59885PC

[0096] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the therapeutic dose is administered for 4 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP- NET is a GI-NET.

[0097] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the therapeutic dose is administered for 6 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP- NET is a GI-NET.

[0098] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the therapeutic dose is administered for 8 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP- NET is a GI-NET.

[0099] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the therapeutic dose is administered for 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, or 9 cycles. In an embodiment, the GEP-NET is a GI-NET.

[0100] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the therapeutic dose is administered once every 8 ± 1 weeks for 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, or 9 cycles. In an embodiment, the GEP-NET is a GI-NET.

[0101] In an aspect, provided herein is [177Lu]Lu-DOTA-TATE, or a pharmaceutically 768795: NIT-59885PC acceptable salt thereof, or [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use in the treatment of well-differentiated Grade 1 or Grade 2 gastroenteropancreatic neuroendocrine tumor (GEP-NET), wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment of this use, the GEP-NET is a gastrointestinal neuroendocrine tumor (GI-NET).

[0102] In another aspect, provided herein is [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use in the treatment of well-differentiated Grade 1 or Grade 2 gastroenteropancreatic neuroendocrine tumor (GEP-NET), wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment of this use, the GEP-NET is a gastrointestinal neuroendocrine tumor (GI-NET).

[0103] In still another aspect, provided herein is [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, for use in the treatment of Grade 1 or Grade 2 gastroenteropancreatic neuroendocrine tumor (GEP-NET), wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0104] Combination Therapies

[0105] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 gastroenteropancreatic neuroendocrine tumor (GEP-NET) in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0106] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0107] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient has previously been treated with one or more 768795: NIT-59885PC somatostatin analogues. In an embodiment, the GEP-NET is a GI-NET.

[0108] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the patient has not been administered interferons, an mTOR-inhibitor, chemotherapy, or other systemic therapies of GEP-NET for more than 1 month prior to treatment. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0109] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the patient has not been administered interferons, an mTOR-inhibitor, chemotherapy, or other systemic therapies of GEP-NET within about 12 weeks prior to treatment. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0110] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient has not been administered interferons, an mTOR- inhibitor, chemotherapy, or other systemic therapies of GEP-NET for more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks prior to treatment. In an embodiment, the GEP-NET is a GI-NET.

[0111] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0112] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or a 768795: NIT-59885PC pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, and the Grade 1 GEP-NET demonstrates a Ki-67 index less than 1% or less than 2%. In an embodiment, the GEP-NET is a GI-NET.

[0113] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP- NET is a GI-NET.

[0114] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the Grade 2 GEP-NET demonstrates a Ki-67 index about 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0115] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index about 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0116] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the GEP-NET is metastasized or locally advanced, curatively inoperable, and histologically proven. In an embodiment, the GEP-NET is a GI-NET.

[0117] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the GEP-NET is metastasized or locally advanced, curatively inoperable, or histologically proven. In an embodiment, the GEP-NET is a GI-NET. 768795: NIT-59885PC

[0118] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the patient demonstrates high disease burden. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0119] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient demonstrates one or more symptoms selected from the group consisting a primary tumor or a metastatic lesion > 4 cm, more than one tumor or metastatic lesions measuring > 2 cm, elevated alkaline phosphatase > 2.5 X upper limit of normal (ULN), presence of bone metastasis, presence of peritoneal metastasis, symptoms due to tumor volume such as pain, fatigue, weight loss, anorexia etc., and symptoms due to hormone excess requiring active management. In an embodiment, the GEP-NET is a GI- NET.

[0120] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the patient demonstrates symptomatic disease. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0121] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient demonstrates one or more symptoms selected from the group consisting of fatigue, weight loss, anorexia, Gl bleeding jaundice, intestinal obstruction, and pain. In an embodiment, the GEP-NET is a GI-NET.

[0122] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- 768795: NIT-59885PC

[0123] TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the patient has been diagnosed for less than 6 months. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0124] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient has been diagnosed for 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5, months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 18 months, 2 years, 30 months, or 3 years. In an embodiment, the GEP-NET is a GI-NET.

[0125] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, comprises 7.4 ± 10% GBq of radiation. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0126] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, comprises about 3 GBq, about 4 GBq, about 5 GBq, about 6 GBq, about 7 GBq, about 8 GBq, about 9 GBq, about 10 GBq, about 11 GBq, about 12 GBq, about 13 GBq, about 14 GBq, or about 15 GBq of radiation. In an embodiment, the GEP-NET is a GI-NET.

[0127] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, wherein a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein a therapeutic dose further comprises 20 - 40 mg of octreotide LAR. In an embodiment, the GEP-NET is a GI-NET. 768795: NIT-59885PC

[0128] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, wherein a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein a therapeutic dose further comprises about 30 mg of octreotide LAR. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0129] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, wherein a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and a therapeutic dose further comprises about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg of octreotide LAR. In an embodiment, the GEP-NET is a GI-NET.

[0130] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the therapeutic dose is administered once every 42 to 112 days. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0131] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the therapeutic dose is administered once every 49 to 90 days. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0132] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the therapeutic dose is administered once every 8 ± 1 weeks. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET. 768795: NIT-59885PC

[0133] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the therapeutic dose is administered once every about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, or about 20 weeks. In an embodiment, the GEP-NET is a GI-NET.

[0134] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the therapeutic dose is administered for 4 to 8 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0135] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the therapeutic dose is administered for 4 to 6 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0136] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the therapeutic dose is administered for 6 to 8 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0137] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the therapeutic dose is administered for 4 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. 768795: NIT-59885PC

[0138] In an embodiment, the GEP-NET is a GI-NET.

[0139] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the therapeutic dose is administered for 6 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0140] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the therapeutic dose is administered for 8 cycles. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0141] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the therapeutic dose is administered for 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, or 9 cycles. In an embodiment, the GEP-NET is a GI-NET.

[0142] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the therapeutic dose is administered once every 8 ± 1 weeks for 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, or 9 cycles. In an embodiment, the GEP-NET is a GI-NET.

[0143] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the dose of octreotide LAR is administered between 4 hours after a [177Lu]Lu-DOTA- TATE dose and 4 weeks before the following [177Lu]Lu-DOTA-TATE dose. In an 768795: NIT-59885PC embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In an embodiment, the GEP-NET is a GI-NET.

[0144] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the dose of octreotide LAR is administered between 4 hours after a [177Lu]Lu-DOTA-TATE dose and 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks before the following [177Lu]Lu-DOTA-TATE dose. In an embodiment, the GEP-NET is a GI-NET.

[0145] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the dose of octreotide LAR is administered between about 4 hours and 24 hours after a [177Lu]Lu-DOTA-TATE dose. In an embodiment, the GEP-NET is a GI-NET.

[0146] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the dose of octreotide LAR is administered between 4 hours and about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks after a [177Lu]Lu-DOTA-TATE dose. In an embodiment, the GEP-NET is a GI- NET.

[0147] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the dose of octreotide LAR is administered about 24 hours after a [177Lu]Lu-DOTA- TATE dose. In an embodiment, the GEP-NET is a GI-NET.

[0148] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, 768795: NIT-59885PC wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the dose of octreotide LAR is administered about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after a [177Lu]Lu-DOTA-TATE dose. In an embodiment, the GEP-NET is a GI-NET.

[0149] In an aspect, provided herein are methods of treating well-differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, b) administering octreotide LAR after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and d) administering octreotide LAR after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%.

[0150] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 GEP-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, b) administering octreotide LAR after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and d) administering octreotide LAR after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy.

[0151] In an aspect, provided herein are methods of treating well-differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 3-15 GBq of radiation, b) administering a dose of 20-40 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) repeating steps a) and b) once every 42 to 112 days, d) discontinuing the lutetium [177Lu]Lu- DOTA-TATE treatment, and e) administering 20-40 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%.

[0152] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 GEP-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 3-15 GBq of radiation, b) administering a dose of 20-40 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA- TATE, c) repeating steps a) and b) once every 42 to 112 days, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 20-40 mg of octreotide LAR every 4 768795: NIT-59885PC weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy.

[0153] In an aspect, provided herein are methods of treating well-differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 7.4 ± 10% GBq of radiation, b) administering a dose of about 30 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA- TATE, c) repeating steps a) and b) once every 8 ± 1 weeks for 3 additional (4 total) cycles, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 30 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%.

[0154] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 GEP-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 7.4 ± 10% GBq of radiation, b) administering a dose of about 30 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) repeating steps a) and b) once every 8 ± 1 weeks for 3 additional (4 total) cycles, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 30 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu- DOTA-TATE; wherein the treatment is a first line therapy.

[0155] In an aspect, provided herein are methods of treating well-differentiated Grade 1 or Grade 2 gastrointestinal neuroendocrine tumor (GI-NET) in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, b) administering octreotide LAR after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and d) administering octreotide LAR after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GI-NET demonstrates a Ki-67 index less than 10%.

[0156] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 GI-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, b) administering octreotide LAR after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and d) administering octreotide LAR after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy.

[0157] In an aspect, provided herein are methods of treating well-differentiated Grade 1 or 768795: NIT-59885PC

[0158] Grade 2 GI-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 3-15 GBq of radiation, b) administering a dose of 20-40 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) repeating steps a) and b) once every 42 to 112 days, d) discontinuing the lutetium [177Lu]Lu-DOTA- TATE treatment, and e) administering 20-40 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GI-NET demonstrates a Ki-67 index less than 10%.

[0159] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 GI-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 3-15 GBq of radiation, b) administering a dose of 20-40 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA- TATE, c) repeating steps a) and b) once every 42 to 112 days, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 20-40 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy.

[0160] In an aspect, provided herein are methods of treating well-differentiated Grade 1 or Grade 2 GI-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 7.4 ± 10% GBq of radiation, b) administering a dose of about 30 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) repeating steps a) and b) once every 8 ± 1 weeks for 3 additional (4 total) cycles, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 30 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GI-NET demonstrates a Ki-67 index less than 10%.

[0161] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 GI-NET in a patient in need thereof, comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 7.4 ± 10% GBq of radiation, b) administering a dose of about 30 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) repeating steps a) and b) once every 8 ± 1 weeks for 3 additional (4 total) cycles, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 30 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu- DOTA-TATE; wherein the treatment is a first line therapy.

[0162] In an aspect, provided herein is a combination of Lutetium [177Lu]Lu-DOTA-TATE and 768795: NIT-59885PC octreotide LAR for use in the treatment of well-differentiated Grade 1 or Grade 2 GEP-NET, wherein a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, is administered, followed by a therapeutic dose of octreotide LAR, whereafter, the lutetium [177Lu]Lu-DOTA-TATE treatment is discontinued, and octreotide LAR is administered. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In another embodiment, the present disclosure relates to a first line therapy treating well-differentiated Grade 1 GEP-NET. In yet another embodiment, the GEP-NET is a GI-NET.

[0163] In another aspect, provided herein is a combination of Lutetium [177Lu]Lu-DOTA- TATE and octreotide LAR for use in the treatment of well-differentiated Grade 1 or Grade 2 GEP-NET, wherein a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, comprising 3-15 GBq of radiation, is administered, followed by a therapeutic dose of 20-40 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, which is repeated once every 42 to 112 days, whereafter the lutetium [177Lu]Lu-DOTA-TATE treatment is discontinued, and 20-40 mg of octreotide LAR are administered every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In another embodiment, the present disclosure relates to a first line therapy treating well-differentiated Grade 1 GEP-NET. In yet another embodiment, the GEP-NET is a GI-NET.

[0164] In still another aspect, provided herein is a combination of Lutetium [177Lu]Lu-DOTA- TATE and octreotide LAR for use in the treatment of well-differentiated Grade 1 or Grade 2 GEP-NET, wherein a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, comprising 7.4 ± 10% GBq of radiation, is administered, followed by a therapeutic dose of about 30 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, which is repeated once every 8 ± 1 weeks for 3 additional (4 total) cycles, whereafter the lutetium [177Lu]Lu-DOTA-TATE treatment is discontinued, and 30 mg of octreotide LAR are administered every about 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. In another embodiment, the present disclosure relates to a first line therapy treating well-differentiated Grade 1 GEP-NET. In yet another embodiment, the GEP-NET is a GI-NET.

[0165] Additional Therapeutics

[0166] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- 768795: NIT-59885PC

[0167] TATE, or a pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the treatment further comprises the administration of an antiemetic.

[0168] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the treatment further comprises the administration of a short acting octreotide.

[0169] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and a therapeutic further comprises the administration of an antiemetic.

[0170] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the treatment further comprises the administration of a short acting octreotide.

[0171] Formulation

[0172] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment further comprises the administration of an about 2.5% Lysine-Arginine solution. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%.

[0173] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the treatment further comprises the administration of an about 0.5%, about 1.0%, about 1.5%, 768795: NIT-59885PC about 2.0%, about 2.5%, about 3.0%, about 3.5%, or about 4.0% Lysine-Arginine solution.

[0174] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein a therapeutic dose further comprises the administration of a 2.5% Lysine-Arginine solution. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%.

[0175] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and a therapeutic dose further comprises the administration of an about 0.5%, about 1.0%, about 1 .5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, or about 4.0% Lysine-Arginine solution.

[0176] Discontinuation

[0177] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the patient is further treated with 30 mg of octreotide LAR every about 4 weeks after discontinuation of [177Lu]Lu-DOTA-TATE. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%.

[0178] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient is further treated with 30 mg of octreotide LAR every about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks after discontinuation of [177Lu]Lu- DOTA-TATE.

[0179] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, 768795: NIT-59885PC wherein the patient is further treated with 30 mg of octreotide LAR every about 4 weeks after discontinuation of [177Lu]Lu-DOTA-TATE. In an embodiment, the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%.

[0180] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the patient is further treated with 30 mg of octreotide LAR every about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks after discontinuation of [177Lu]Lu-DOTA- TATE.

[0181] Outcomes

[0182] As discussed above, disclosed herein are a number of treatments for well- differentiated Grade 1 or Grade 2 GEP-NET. The treatments comprise administration of [177Lu]Lu-DOTA-TATE, with or without octreotide LAR, wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%. Below are non-limiting embodiments of outcomes associated with this treatment.

[0183] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the treatment is characterized by a centrally assessed progression free survival (PFS) of at least about 18 months.

[0184] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is characterized by a centrally assessed PFS of at least about 20 months.

[0185] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is characterized by a centrally assessed PFS of at least about 22 months. 768795: NIT-59885PC

[0186] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the treatment is characterized by a centrally assessed PFS of at least about 12 months, at least about 13 months, at least 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, or at least about 24 months.

[0187] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, 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 about 50%.

[0188] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is characterized by a DCR of at least about 80%.

[0189] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is characterized by a DCR of at least about 90%.

[0190] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the treatment is characterized by a DCR of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%.

[0191] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising 768795: NIT-59885PC administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the time to deterioration is increased by at least about 5% as indicated by changes in scores of EORTC QLQ-GI.NET21 and EORTC QLQ-C20 questionnaires.

[0192] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the time to deterioration is increased by at least about 10% as indicated by changes in scores of EORTC QLQ-GI.NET21 and EORTC QLQ-C20 questionnaires.

[0193] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the time to deterioration is increased by at least about 15% as indicated by changes in scores of EORTC QLQ-GI.NET21 and EORTC QLQ-C20 questionnaires.

[0194] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the time to deterioration is increased by at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11% at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% as indicated by changes in scores of EORTC QLQ- GI.NET21 and EORTC QLQ-C20 questionnaires.

[0195] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is characterized by an objective response rate (ORR, i.e. complete response (CR) rate + partial response (PR) rate) of at least about 25%.

[0196] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising 768795: NIT-59885PC administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is characterized by an ORR of at least about 35%.

[0197] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is characterized by an ORR of at least about 43%.

[0198] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the treatment is characterized by an ORR of at least about 5%, of at least 10%, of at least about 15%, of at least about 20% of at least about 25%, of at least about 30%, of at least about 35%, of at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% compared to a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

[0199] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment reduces the risk of progression or death by at least about 60% compared to a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

[0200] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment reduces the risk of progression or death by at least about 70% compared to a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

[0201] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment reduces the risk of progression or death by at least about 80% 768795: NIT-59885PC compared to a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

[0202] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 index less than 10%, and the treatment reduces the risk of progression or death by at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% compared to a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

[0203] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment reduces the risk of progression or death corresponding to a hazard ratio (HR) of less than 0.5 (95% Cl) when the risk is calculated relative to patients a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

[0204] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment reduces the risk of progression or death corresponding to a hazard ratio (HR) of less than 0.35 (95% Cl) when the risk is calculated relative to patients a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

[0205] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment reduces the risk of progression or death corresponding to a hazard ratio (HR) of less than 0.25 (95% Cl) when the risk is calculated relative to patients a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

[0206] In some embodiments, the present disclosure relates to methods of treating well- differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or pharmaceutically acceptable salt thereof, in combination with octreotide LAR, wherein the treatment is a first line therapy, the Grade 2 GEP-NET demonstrates a Ki-67 768795: NIT-59885PC index less than 10%, and the treatment reduces the risk of progression or death corresponding to a hazard ratio (HR) of less than 0.6 (95% Cl), less than 0.55 (95% Cl), less than 0.5 (95% Cl), less than 0.45 (95% Cl), less than 0.4 (95% Cl), less than 0.35 (95% Cl), less than 0.3 (95% Cl), less than 0.25 (95% Cl), less than 0.2 (95% Cl), less than 0.15 (95% Cl), less than 0.1 (95% Cl), or less than 0.05 (95% Cl) when the risk is calculated relative to patients a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

[0207] The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non- critical parameters which can be changed or modified to yield essentially the same results.

[0208] EXAMPLES

[0209] Example 1: Adult Efficacy

[0210] The initial approval of [177Lu]Lu-DOTA-TATE was supported by two studies in SSTR-positive tumors. The randomized, controlled Phase III NETTER-1 study compared treatment with [177Lu]Lu-DOTA-TATE plus best supportive care (30 mg octreotide LAR) to treatment with high dose (60 mg) octreotide LAR in participants with SSTR-positive progressive midgut neuroendocrine tumors. The study enrolled 231 patients, randomized in a 1 :1 ratio to receive [177Lu]Lu-DOTA-TATE in combination with octreotide LAR 30 mg ([177Lu]Lu-DOTA-TATE arm, N=116) or octreotide LAR 60 mg monotherapy (control arm, N=113). At the time of the primary endpoint analysis (cut-off date 24-Jul 2015), the improvement in median progression free survival (mPFS) was statistically significant (p<0.0001) with a hazard ratio (HR) of 0.18 (95% confidence interval (Cl): 0.11-0.29), demonstrating a risk reduction of 82% of the risk of a progression or death event in the ([177Lu]Lu-DOTA-TATE arm compared to the control arm (Strosberg, J. et al. (2017) Neuroendocrine Tumors 376(2): 125-135). The originally published results from this analysis were subsequently updated (cut-off 14-Jan-2016) and reported a mPFS for the [177Lu]Lu- DOTA-TATE arm of 28.4 (28.4; NE) months versus 8.5 (5.8; 11.0) months for control arm (HR 0.21 with 95% Cl: 0.14, 0.33). The final overall survival (OS) analysis occurred 5 years after the last participant was randomized (cut-off date 18-Jan-2021), with a median follow-up of 76 months in each study arm. The median OS was prolonged by a clinically relevant extent of 11.7 months in participants randomized to the [177Lu]Lu-DOTA-TATE arm compared to participants randomized to control arm, with a median OS of 48.0 months (95% Cl: 37.4, 55.2) and 36.3 months (95% Cl: 25.9, 51.7), respectively. However, these results did not reach statistical significance (unstratified Log-rank test p=0.3039, two-sided 95% Cl: 0.60, 1.17) (Strosberg, J. et al. (2021) Lancet Oncol 22(12):1752-1763). 768795: NIT-59885PC

[0211] The other study was a single-institution, single-arm, open-label trial of 1 ,214 participants with SSTR-positive tumors, who received [177Lu]Lu-DOTA-TATE at the Erasmus Medical Centre in the Netherlands (Kwekkeboom, D. et al. (2008) J Clin Oncol 26(13):2124-2130; Brabander, T. et al. (2017) Clin Cancer Res 23(16):4617-4624; Brabander, T. et al. (2017) Endocr Relat Cancer 24(5):243-251.). The treatment effect observed across participants with GEP-NET in the Erasmus MC study was consistent with what was seen in NETTER-1 study.

[0212] [177Lu]Lu-DOTA-TATE is also being investigated in first line setting in the Phase III NETTER-2 study which is a randomized, open-label, multicenter study in participants with newly diagnosed, well differentiated, Grade 2 and Grade 3 advanced GEP-NET. The study enrolled 226 patients, randomized in a 2:1 ratio to receive [177Lu]Lu-DOTA-TATE in combination with octreotide LAR 30 mg ([177Lu]Lu-DOTA-TATE arm, N=151) or octreotide LAR 60 mg monotherapy (control arm, N=75). The study met its primary objective of PFS based on central radiology review (data cutoff for the analysis 20-Jul-2023) which was statistically significant (p < 0.0001 ) with an estimated 72% risk reduction in the [177Lu]Lu- DOTA-TATE arm compared to the control arm (HR: 0.276 with 95% Cl: 0.182, 0.418). The mPFS (95% Cl) was 22.8 months (19.4, NE) and 8.5 months (7.7, 13.8) in the [177Lu]Lu- DOTA-TATE and control arms respectively. The key secondary objective of superior objective response rate (ORR) was also met (43.0% [95% Cl: 35.0-51 .3] versus 9.3% [3.8- 18.3]) with statistically significant benefit in favor of [177Lu]Lu-DOTA-TATE arm (Singh, S. et al. (2024) Lancet 403(10446):2807-2817). Further, a subgroup analysis of NETTER-2 demonstrated [177Lu]Lu-DOTA-TATE efficacy across tumor origin and grade (Singh, S. et al. (2024) Ann Oncol; 35:92-93).

[0213] Example 2: Adult Dosimetry

[0214] Dosimetry data from NETTER-1 showed that highest absorbed dose coefficients are detected in the spleen (0.846 ± 0.804 Gray (Gy) / Gigabecquerel (GBq)), the kidneys (0.654 ± 0.295 Gy / GBq) and the liver (0.299 ± 0.226 Gy / GBq) with an absorbed dose in the red marrow of 0.035 ± 0.029 Gy / GBq. Kidney and bone marrow were identified as the main organs at risk considering the cumulative absorbed dose and the margin to the EBRT thresholds. The mean cumulative absorbed doses calculated after 4 administrations of [177Lu]Lu-DOTA-TATE with a total activity of 29.6 GBq were estimated to be 19.4 ± 8.7 Gy for the kidneys and 1 .0 ± 0.8 Gy for the bone marrow, below the EBRT thresholds. Overall, the dosimetry results from NETTER-1 and the Erasmus MC Phase l / ll study are similar and indicate that the standard protocol for [177Lu]Lu-DOTA-TATE administration is safe.

[0215] Dosimetry data from NETTER-P in adolescents of age equal or greater than 12 and lower than 18 years, showed comparable organ dosimetry to adults. The high and prolonged 768795: NIT-59885PC uptake of the radiolabeled compound in the tumor lesions observed in the NETTER-1 study confirms [177Lu]Lu-DOTA-TATE tumor uptake data reported in literature, reinforcing the basis for [177Lu]Lu-DOTA-TATE therapeutic efficacy in SSTR2-expressing tumors.

[0216] Example 3: Adult Safety

[0217] The limiting organs for radiation toxicities are bone marrow and kidneys (Bergsma, H. et al. (2016) Eur J Nucl Med Mol Imaging 43(3):453-63; Bergsma, H. et al. (2016) Eur J Nucl Med Mol Imaging 43(10): 1802-1 1 ). The kidney related toxicity is mitigated by the co-infusion of 2.5% Lysine - Arginine (Lys-Arg) amino acid solutions during administration of [177Lu]Lu- DOTA-TATE, which reduces the radiation dose to the kidney by approximately 45% (Rolleman, E. et al. (2003) Eur J Nucl Med Mol Imaging 30(1 ):9-15). In the NETTER-1 study, most nephrotoxicity in [177Lu]Lu-DOTA-T ATE-treated participants was mild or moderate: 45 participants (40.5%) had grade 1 or 2 events and 6 participants (5.4%) had > grade 3 events. There were no severe cases of acute radiation toxicity during the study (Strosberg, J. et al. (2021 ) Lancet Oncol 22(12):1752-1763). In the treatment phase of N ETTER-2 study, nephrotoxicity was reported in 9% patients in [177Lu]Lu-DOTA-TATE arm vs. 5% in the control arm. Grade >3 nephrotoxicity was reported in 2% of participants in [177Lu]Lu-DOTA- TATE arm vs. 1% in the control arm (Singh, S. et al. (2024) Lancet 403(10446):2807-2817; Singh, S. et al. (2024) Ann Oncol 35:92-93).

[0218] Bone marrow toxicities include anemia, thrombocytopenia, lymphopenia and neutropenia which are usually mild, transient and can be monitored by hematological assessments between treatments. During the treatment period in NETTER-1 and NETTER-2 studies, based on laboratory evaluations, grade >3 neutropenia and grade >3 thrombocytopenia occurred in 7 participants (2.7%) and 4 participants (1.6%), respectively. The lymphocyte toxicity observed following [177Lu]Lu-DOTA-TATE was demonstrated to affect only B cells, with no evidence of opportunistic infection reported (Sierra, M. (2009) Cancer Biother Radiopharm 24(6):659-65).

[0219] The long-term risks of secondary hematological malignancies (i.e. MDS and leukemia) were reported in 2.3% GEP-NET participants treated with [177Lu]Lu-DOTA-TATE and with a follow up of 76 months in NETTER-1 study. In NETTER-2 study after a median follow-up of 23.2 months, one participant (0.7%) developed MDS ([177Lu]Lu-DOTA-TATE IB).

[0220] At the time of the NETTER-1 final analysis, after a median follow-up duration of 76 months in each study arm, the safety profile of [177Lu]Lu-DOTA-TATE remained favorable and consistent with that previously reported (Strosberg, J. et al. (2021 ) Lancet Oncol 22(12):1752-1763). Safety findings in NETTER-2 study (median follow-up duration of 23.2 months) were consistent with known safety profiles for [177Lu]Lu-DOTA-TATE and 768795: NIT-59885PC octreotide LAR. No new safety concerns emerged in the newly diagnosed GEP-NET patient population (Singh, S. et al. (2024) Lancet 403(10446):2807-2817; Singh, S. et al. (2024) Ann Oncol 35:92-93).

[0221] Example 4: Pediatric Safety and Dosimetry

[0222] NETTER-P is a multicenter open-label study to evaluate the safety and dosimetry of [177Lu]Lu-DOTA-TATE in adolescent participants with SSTR positive GEP-NET tumors and pheochromocytoma and paraganglioma (PPGL). The study enrolled 11 adolescent participants, 4 with GEP-NET and 7 with PPGL, aged 13 to 17 years old. The theoretical cumulative absorbed radiation doses of [177Lu]Lu-DOTA-TATE in the target organs at risk (i.e., kidney and bone marrow) extrapolated from single cycle dosimetry measurements were within the reference limits (i.e., <29 Gy for kidney and <2 Gy for bone marrow) in adolescents and comparable to adults. Comparative assessment of pharmacokinetics (PK) metrics using population PK model predictions and observed data revealed that the exposure results were comparable between the adolescent and adult populations. Based on the safety data collected up to the primary cut-off date, no new safety signals have been identified. [177Lu]Lu-DOTA-TATE 7.4 GBq (200 mCi) every 8±1 weeks administered over 4 cycles (cumulative dose: 29.6 GBq 1800 mCi) showed a consistent safety and tolerability profile in adolescents with GEP-NET or PPGL, which is similar to that reported in adults in the NETTER-1 study.

[0223] Example 5: Study to evaluate the efficacy and safety of [177Lu]Lu-DOTA-TATE in patients with Grade 1 and Grade 2 advanced GEP-NET (NETTER-3).

[0224] This is a multicenter, stratified, randomized, open-label, comparator-controlled, Phase III study to evaluate the efficacy and safety of [177Lu]Lu-DOTA-TATE compared to Octreotide LAR, in newly diagnosed patients with somatostatin receptor positive, well- differentiated Grade 1 and Grade 2 (Ki-67 <10%), advanced GEP-NETs. OBJECTIVES AND ENDPOINTS

[0225] Table 1: Objectives And Related Endpoints Phase III Multi-Center, Randomized,

[0226] Open-Label Study To Evaluate The Efficacy And Safety Of [177Lu]Lu-DOTA-TATE In Patients Newly Diagnosed With Grade 1 And Grade 2 (Ki-67 <10%) Advanced GEP- NET With High Disease Burden (NETTER-3) 768795: NIT-59885PC 768795: NIT-59885PC 768795: NIT-59885PC

[0227] STUDY DESIGN

[0228] This is a Phase III multi-center, stratified, randomized, open-label study to evaluate the efficacy and safety of [177Lu]Lu-DOTA-TATE plus octreotide LAR versus octreotide LAR alone in newly diagnosed patients with SSTR+, well differentiated Grade 1 and Grade 2 (Ki- 67 <10%) advanced unresectable GEP-NETs with high disease burden.

[0229] Overall, 240 participants will be randomized in a 1:1 ratio to receive treatment with [177Lu]Lu-DOTA-TATE [7.4 GBq (200 mCi) x 4 administrations every 8±1 weeks] plus octreotide LAR (30 mg every 8 weeks during the [177Lu]Lu-DOTA-TATE treatment period and every 4 weeks thereafter until disease progression) or octreotide LAR alone (30 mg every 4 weeks until disease progression). Participants in the control arm will not be permitted to cross over to the experimental arm after disease progression in this study.

[0230] Randomization will be stratified by tumor Grade (1 vs 2) and tumor origin (pNET vs other origin).

[0231] The primary endpoint of the study is PFS centrally assessed by BIRC. The primary analysis will be performed after 88 PFS events (88 evaluable and centrally confirmed disease progressions or death events) have occurred which is estimated to be observed after 33.5 months.

[0232] If the primary endpoint is statistically significant, key secondary endpoints of TTD in the below domains from European Organization for Research and Treatment of Cancer 768795: NIT-59885PC

[0233] (EORTC) QLQ-GI.NET21 and EORTC QLQ-C30 will be tested hierarchically, at the time of the primary analysis, in this order:

[0234] 1. EORTC QLQ-GI.NET21 Gl scale

[0235] 2. EORTC QLQ-C30 Fatigue domain

[0236] 3. EORTC QLQ-C30 Diarrhea domain

[0237] 4. EORTC QLQ-C30 Global health scale

[0238] The study consists of the following phases (FIG. 1 ):

[0239] • Screening Phase

[0240] • Treatment Phase

[0241] • Follow-up Phase

[0242] Screening Phase

[0243] The screening phase consists of a maximum of 28 days.

[0244] The randomization and [177Lu]Lu-DOTA-TATE order must be performed immediately after all eligibility criteria are verified.

[0245] All participants in the current study will undergo RLI with an SSTR-targeting agent at screening or within 3 months prior to randomization. Eligibility will be based on the uptake of RLI in tumor lesions at least as high as normal liver uptake.

[0246] Table 2: Allowable window for participant assessments

[0247] Treatment Phase

[0248] Tumor assessments will be performed 16±1 weeks, 24±1 weeks and then every 12±1 weeks thereafter from randomization, according to Response Evaluation Criteria In 768795: NIT-59885PC

[0249] Solid Tumors (RECIST) v1.1 criteria (central + local assessment up to disease progression).

[0250] Before the PFS primary analysis, participants continue the Treatment Phase until progression.

[0251] After the PFS primary analysis, the Treatment Phase duration for participants who have not progressed will be limited to 76 weeks.

[0252] At any time during the study any participant who experience disease progression will immediately ceases the Treatment Phase and proceeds to the Follow-up Phase.

[0253] Experimental Arm

[0254] [177Lu]Lu-DOTA-TATE will be given at the dose of 7.4 GBq (200 mCi) x 4 administrations every 8±1 weeks.

[0255] All participants in [177Lu]Lu-DOTA-TATE arm will receive octreotide LAR (30 mg every 8 weeks during the [177Lu]Lu-DOTA-TATE treatment and every 4 weeks thereafter) until disease progression (or participant withdrawal / unacceptable toxicity). For the octreotide LAR doses coinciding with [177Lu]Lu-DOTA-TATE doses, octreotide should be administered between 4 to 24 hours (h) after each [177Lu]Lu-DOTA-TATE dose (same day or the following day). In addition, the washout of at least 4 weeks should be maintained for [177Lu]Lu-DOTA-TATE doses after the previous octreotide LAR dose and the washout of at least 24 h after the previous octreotide short-acting dose, if applicable.

[0256] If the time interval between treatments with [177Lu]Lu-DOTA-TATE is prolonged for any reason, octreotide LAR administration continues every 4 weeks provided it is not administered within 4 weeks of the next [177Lu]Lu-DOTA-TATE treatment. Otherwise, octreotide LAR administration needs to be adjusted accordingly.

[0257] Crises due to excessive release of hormones or bioactive substances may occur following treatment, therefore, observation of participants by overnight hospitalization should be considered. Recommended treatments of participants with hormonal crises are: i.v. high dose SSAs, i.v. fluids, corticosteroids, and correction of electrolyte disturbances in participants with diarrhea and vomiting.

[0258] Control Arm

[0259] Octreotide LAR (30 mg every 4 weeks) until disease progression (or participant withdrawal / unacceptable toxicity). Participants in the control arm will not be permitted to cross over to the experimental arm after disease progression in this study. 768795: NIT-59885PC

[0260] Additional Study Treatments

[0261] Table 3: Additional Study Treatments 768795: NIT-59885PC

[0262] 2.5% Lys-Arg sterile amino acid solution

[0263] A sterile 2.5% Lys-Arg AA solution (LysaKare®) will be co-administered with each [177Lu]Lu-DOTA-TATE dose, to decrease the retention of radioactivity in kidneys and substantially reduce potential renal toxicity that could be caused by [177Lu]Lu-DOTA-TATE, as per [177Lu]Lu-DOTA-TATE prescribing information.

[0264] The sterile 2.5% Lys-Arg AA solution must be administered i.v. with the infusion rate of 250 mL / h. The infusion will start 30 min prior to the administration of [177Lu]Lu-DOTA- TATE and continue for a total of 4 h (extension up to 6 h is allowed in case of adverse reactions that require infusion interruption or slowing the infusion rate) to achieve optimal renal protection.

[0265] The composition of the sterile 2.5% Lys-Arg AA solution is shown in Table 4 below.

[0266] Table 4: Sterile 2.5% Lys-Arg AA Solution Composition 768795: NIT-59885PC

[0267] Antiemetics

[0268] On the day of each [177Lu]Lu-DOTA-TATE treatment, before the infusion with sterile 2.5% Lys-Arg AA solution is started, an i.v. bolus of antiemetic (ATC codes: A04A and A03FA01 ) must be given with sufficient lead time as per local prescribing information. The choice of antiemetics is at the discretion of the Investigator in accordance with institutional regulations. In case of severe nausea or vomiting during the infusion of the 2.5% Lys-Arg AA solution despite administration of a preventive antiemetic, an antiemetic of a different pharmacological class can be administered. Corticosteroids must be avoided as preventive anti-emetic treatment because of potential SSTR down-regulation.

[0269] In case of development of nausea and vomiting during the infusion, a repeated administration of antiemetics should be performed at the physician judgment. In general, Investigators are advised to use antiemetics which are commonly prescribed in their institutions for treatment of nausea induced by chemotherapeutic drugs.

[0270] Short-acting octreotide

[0271] Subcutaneous, short-acting octreotide injections may be indicated for control of symptoms (i.e. diarrhoea and flushing) in participants in both study arms, in accordance with the manufacturer’s prescribing information. Short-acting octreotide for symptom control may be administered by the participant.

[0272] Follow-up Phase

[0273] At the end of the Treatment Phase or after study treatment discontinuation due to any cause (including disease progression) the participant will enter the Follow-up Phase. The Follow-up Phase is for 5 years and consists of an initial 12-week safety follow up, a follow up for long term efficacy and a follow up for long term safety and survival.

[0274] Safety Follow-up

[0275] After discontinuation of study treatment for any reason, all participants will have a safety follow up 12 weeks after their last study treatment administration, except in case of death, loss to follow-up or withdrawal of consent (WoC).

[0276] Long-term Efficacy Follow-up

[0277] If a participant discontinues study treatment due to toxicity or other reason without disease progression, the participant will be followed up for efficacy using RECIST v1.1 criteria, every 12 weeks until the primary PFS analysis (central tumor assessment) and thereafter every 6 months (local tumor assessment) with CT or MRI until disease 768795: NIT-59885PC progression, WoC, loss to follow-up, death, or until the end of the study, whichever occurs first (see also FIG. 2).

[0278] Long-term Safety and Survival Follow-up

[0279] Beyond the initial 12 weeks of safety follow-up, survival information, post-treatment antineoplastic therapies / surgeries / radiotherapies, treatment related serious adverse events (SAEs) and all AEs of renal toxicities and secondary tumors (hematological and solid tumors) irrespective of causality will be collected until the end of follow up period every 6 months for 5 years.

[0280] Study drug related AEs will be followed until resolution or until the End of Study, whichever comes first.

[0281] Each participant will have hematology and renal function (serum creatinine and creatinine clearance) assessments during the Long-term Follow-up (LTFU) Phase until he / she withdraws consent, is lost to follow-up, dies, or until the end of the study, whichever occurs first. Investigators can decide to perform additional laboratory assessments at their discretion.

[0282] End of the Study

[0283] The End of Study is after 5 years have elapsed from the last participant last treatment.

[0284] STUDY POPULATION

[0285] Overall, 240 participants with newly diagnosed SSTR+, well differentiated Grade 1 and Grade 2 (Ki-67 <10%) advanced GEP-NETs with high disease burden

[0286] Key Inclusion Criteria:

[0287] 1. Presence of metastasized or locally advanced, unresectable (curative intent) histologically proven, well differentiated Grade 1 or Grade 2 (Ki-67 <10%) GEP-NET diagnosed within 6 months prior to screening.

[0288] 2. Participants with high disease burden.

[0289] Following criteria should be used as the guiding principle for determining high disease burden:

[0290] • Primary tumor or a metastatic lesion > 4 cm

[0291] • More than one tumor or metastatic lesions measuring > 2 cm

[0292] • Elevated alkaline phosphatase > 2.5 X upper limit of normal (ULN)

[0293] • Presence of bone metastasis 768795: NIT-59885PC

[0294] • Presence of peritoneal metastasis

[0295] • Symptoms due to tumor volume such as pain, fatigue, weight loss, anorexia etc.

[0296] • Symptoms due to hormone excess requiring active management

[0297] Additionally, participants who, in the Investigator's opinion, have high disease burden due to their disease characteristics not specified above could also be considered eligible.

[0298] 3. Participants > 12 years of age.

[0299] 4. Radioligand imaging (RLI) SSTR uptake on all target lesions (defined by RECIST v1.1 criteria) at least as high as normal liver uptake, assessed within 3 months prior to randomization. Any of the RLI modalities such as, [68Ga]Ga-DOTA-TOC PET / CT or PET / MRI, [68Ga]Ga-DOTA-TATE PET / CT or PET / MRI, [64Cu]Cu-DOTA-TATE PET / CT or PET / MRI, somatostatin receptor scintigraphy (SRS) (planar and / or SPECT / CT) with

[0300] [111 ln]ln-pentetreotide , or SRS (planar and / or SPECT / CT) with [99mTc]Tc-octreotide , can be used as per local practice.

[0301] 5. Adequate bone marrow and organ function as defined by the following laboratory values prior to receiving the first study treatment: a. White blood cells (WBCs) > 2 x 109 / L b. Platelet count > 75 x 109 / L c. Hemoglobin > 8 g / dL d. Creatinine clearance >40 mL / min calculated by the Cockcroft Gault method e. Total bilirubin < 3 x ULN

[0302] 6. Potassium within normal limits. Potassium level of up to 6.0 millimoles per liter (mmol / L) is acceptable at study entry if associated with creatinine clearance within normal limits calculated using Cockcroft-Gault formula. Mild decrease (Grade 1) below lower limit of normal (LLN) is acceptable at study entry if considered not clinically significant by Investigator.

[0303] *No platelet transfusion packed red cell transfusion, or granulocyte-colony stimulating factor (G-CSF) will be allowed during screening after ICF signature.

[0304] 7. ECOG performance status 0-1.

[0305] 8. Presence of at least 1 measurable site of disease.

[0306] Key Exclusion Criteria:

[0307] 1. Prior administration of a therapeutic radiopharmaceutical for GEP-NET at any time prior to randomization in the study.

[0308] 2. Any previous therapy with interferons, mTOR-inhibitors, chemotherapy or other systemic therapies (except SSAs; see exclusion criteria # 3) of GEP-NET. If as per Investigator's opinion a participant is candidate for such therapies, such participant must not be enrolled.

[0309] 3. Participants who received more than 4 cycles of prior somatostatin analogues 768795: NIT-59885PC

[0310] (SSAs) (e.g., octreotide LAR) are not eligible. In addition, any participant receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before the administration of [177Lu]Lu-DOTA-TATE, or any participant receiving treatment with SSAs, which cannot be interrupted for at least 4 weeks before the administration of [177Lu]Lu-DOTA-TATE. 4. Documented RECIST v1.1 progression during previous SSA treatments for the current GEP-NET at any time prior to randomization.

[0311] 5. Any previous radioembolization, chemoembolization and radiofrequency ablation for GEP-NET.

[0312] 6. Any major surgery within 12 weeks prior to randomization in the study.

[0313] 7. Known brain metastases.

[0314] 8. Participant with known intolerance to CT scans with i.v. contrast due to allergic reaction or renal insufficiency. If such a participant can be imaged with MRI, then the participant would not be excluded.

[0315] 9. Hypersensitivity to any somatostatin analogues, to the Investigational Medicinal Products (IMPs) active substance or to any of the excipients.

[0316] 10. Active severe urinary incontinence, severe voiding dysfunction, or urinary obstruction requiring an indwelling / condom catheter that, in the judgment of the Investigator, could prevent adhering to radiation safety instructions.

Claims

768795: NIT-59885PCCLAIMS1. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use in a method of treating well-differentiated Grade 1 or Grade 2 gastroenteropancreatic neuroendocrine tumor (GEP-NET) in a patient in need thereof, said method comprising administering to said patient a therapeutically effective dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki67 index less than 10%.

2. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to claim 1 , wherein the method further comprises administering octreotide Long Acting Release (LAR) to the patient.

3. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to claims 1 or 2, wherein the patient has previously been treated with one or more somatostatin analogues.

4. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-3, wherein the patient has not been administered interferons, an mTOR-inhibitor, chemotherapy, or other systemic therapies of GEP-NET for more than 1 month prior to treatment.

5. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-4, wherein the patient has not been administered interferons, an mTOR-inhibitor, chemotherapy, or other systemic therapies of GEP-NET within 12 weeks prior to treatment.

6. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use768795: NIT-59885PC according to any of claims 1-5, wherein the treatment comprises administering a therapeutically effective dose of lutetium [177Lu]Lu-DOTA-TATE.

7. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-6, wherein the GEP-NET is Grade 1.

8. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-6, wherein the GEP-NET is Grade 2.

9. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-8, wherein the GEP-NET is metastasized or locally advanced, curatively inoperable, and histologically proven.

10. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-9, wherein the patient demonstrates high disease burden.11 . Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-10, wherein the patient demonstrates one or more symptoms selected from the group consisting a primary tumor or a metastatic lesion > 4 cm, more than one tumor or metastatic lesions measuring > 2 cm, elevated alkaline phosphatase > 2.5 X upper limit of normal (ULN), presence of bone metastasis, presence of peritoneal metastasis, symptoms due to tumor volume such as pain, fatigue, weight loss, anorexia etc., and symptoms due to hormone excess requiring active management.

12. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-11 , wherein the patient demonstrates symptomatic disease.

13. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to claims 1-12, wherein the patient demonstrates one or more symptoms selected from the group consisting of fatigue, weight loss, anorexia, Gl bleeding, jaundice, intestinal768795: NIT-59885PC obstruction, and pain.

14. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-13, wherein the patient has been diagnosed for less than or equal to 6 months.

15. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-14, wherein a therapeutic dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, comprises 3 - 15 GBq of radiation.

16. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-15, wherein a therapeutic dose of lutetium [177Lu]Lu-DOTA- TATE, or a pharmaceutically acceptable salt thereof, comprises 7.4 ± 10% GBq of radiation.

17. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 2-16, wherein a therapeutic dose further comprises 20 - 40 mg of octreotide LAR.

18. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 2-17, wherein a therapeutic dose further comprises about 30 mg of octreotide LAR.

19. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding claims, wherein the treatment further comprises the administration of a 2.5% Lysine-Arginine solution.

20. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-19, wherein the therapeutic dose is administered once every 42 to 112 days.768795: NIT-59885PC21 . Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-20, wherein the therapeutic dose is administered once every 49 to 90 days.

22. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-21 , wherein the therapeutic dose is administered once every 8 ± 1 weeks.

23. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-22, wherein the therapeutic dose is administered once every 8 ± 1 weeks for 4 to 8 cycles.

24. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-23, wherein the therapeutic dose is administered once every 8 ± 1 weeks for 4 cycles.

25. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-23, wherein the therapeutic dose is administered once every 8 ± 1 weeks for 6 cycles.

26. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-23, wherein the therapeutic dose is administered once every 8 ± 1 weeks for 8 cycles.

27. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 2-26, wherein the dose of octreotide LAR is administered between 4 hours after a [177Lu]Lu-DOTA-TATE dose and 4 weeks before the following [177Lu]Lu-DOTA-TATE dose.

28. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or768795: NIT-59885PC lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 2-27, wherein the dose of octreotide LAR is administered between 4 hours and about 24 hours after a [177Lu]Lu-DOTA-TATE dose.

29. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 2-28, wherein the dose of octreotide LAR is administered about 24 hours after a [177Lu]Lu-DOTA-TATE dose.

30. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-29, wherein the patient is further treated with 30 mg of octreotide LAR every about 4 weeks after discontinuation of [177Lu]Lu-DOTA-TATE.31 . Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-30, wherein the treatment is characterized by a centrally assessed progression free survival (PFS) of at least about 18 months.

32. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-31 , wherein the treatment is characterized by a centrally assessed PFS of at least about 20 months.

33. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-32, wherein the treatment is characterized by a centrally assessed PFS of at least about 22 months.

34. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-33, 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 about 50%.

35. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use768795: NIT-59885PC according to any of claims 1-34, wherein the treatment is characterized by a DCR of at least about 80%.

36. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-35, wherein the treatment is characterized by a DCR of at least about 90%.

37. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-36, wherein the time to deterioration is increased by at least about 5% as indicated by changes in scores of EORTC QLQ-GI.NET21 and EORTC QLQ- C20 questionnaires.

38. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-37, wherein the time to deterioration is increased by at least about 10% as indicated by changes in scores of EORTC QLQ-GI.NET21 and EORTC QLQ- C20 questionnaires.

39. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-38, wherein the time to deterioration is increased by at least about 15% as indicated by changes in scores of EORTC QLQ-GI.NET21 and EORTC QLQ- C20 questionnaires.

40. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-39, wherein the treatment is characterized by an objective response rate (ORR, i.e. complete response (CR) rate + partial response (PR) rate) of at least about 25%.41 . Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-40, wherein the treatment is characterized by an ORR of at least about 35%.768795: NIT-59885PC42. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-41 , wherein the treatment is characterized by an ORR of at least about 43%.

43. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-38, wherein the treatment reduces the risk of progression or death by at least about 60% compared to a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

44. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-43, wherein the treatment reduces the risk of progression or death by at least about 70% compared to a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

45. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-44, wherein the treatment reduces the risk of progression or death by at least about 80% compared to a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

46. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-45, wherein the treatment reduces the risk of progression or death corresponding to a hazard ratio (HR) of less than 0.5 (95% Cl) when the risk is calculated relative to patients a comparable treatment without the lutetium [177Lu]Lu-DOTA- TATE treatment.

47. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-46, wherein the treatment reduces the risk of progression or death corresponding to an HR of less than 0.35 (95% Cl) when the risk is calculated relative to patients a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

48. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, or768795: NIT-59885PC lutetium [177Lu]Lu-DOTA-TOC, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-47, wherein the treatment reduces the risk of progression or death corresponding to an HR of less than 0.25 (95% Cl) when the risk is calculated relative to patients a comparable treatment without the lutetium [177Lu]Lu-DOTA-TATE treatment.

49. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, for use in a method of treating well-differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, said method comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, b) administering octreotide LAR after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and d) administering octreotide LAR after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki67 index less than 10%.

50. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, for use in a method of treating well-differentiated Grade 1 or Grade 2 GEP-NET in a patient in need thereof, said method comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 3-15 GBq of radiation, b) administering a dose of 20-40 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) repeating steps a) and b) once every 42 to 112 days, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 20-40 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki67 index less than 10%.51 . Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, for use in a method of treating well-differentiated Grade 1 or Grade 2 GEP-NET in a patient in need768795: NIT-59885PC thereof, said method comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 7.4 ± 10% GBq of radiation, b) administering a dose of about 30 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) repeating steps a) and b) once every 8 ± 1 weeks for 3 additional (4 total) cycles, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 30 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GEP-NET demonstrates a Ki67 index less than 10%.

52. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, for use according to any of claims 49-51 , wherein the GEP-NET is Grade 1 .

53. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1-52, wherein the GEP-NET is a gastrointestinal neuroendocrine tumor (GI-NET).

54. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, for use in a method of treating well-differentiated Grade 1 or Grade 2 gastrointestinal neuroendocrine tumor (GI-NET) in a patient in need thereof, said method comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, b) administering octreotide LAR after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and d) administering octreotide LAR after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GI-NET demonstrates a Ki67 index less than 10%.

55. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, for use in a method of treating well-differentiated Grade 1 or Grade 2 GI-NET in a patient in need768795: NIT-59885PC thereof, said method comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 3-15 GBq of radiation, b) administering a dose of 20-40 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) repeating steps a) and b) once every 42 to 112 days, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 20-40 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GI-NET demonstrates a Ki67 index less than 10%.

56. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, for use in a method of treating well-differentiated Grade 1 or Grade 2 GI-NET in a patient in need thereof, said method comprising a) administering a therapeutic dose of lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, wherein the therapeutic dose comprises 7.4 ± 10% GBq of radiation, b) administering a dose of about 30 mg octreotide LAR about 24 hours after the dose of lutetium [177Lu]Lu-DOTA-TATE, c) repeating steps a) and b) once every 8 ± 1 weeks for 3 additional (4 total) cycles, d) discontinuing the lutetium [177Lu]Lu-DOTA-TATE treatment, and e) administering 30 mg of octreotide LAR every 4 weeks after the last dose of [177Lu]Lu-DOTA-TATE; wherein the treatment is a first line therapy, and the Grade 2 GI-NET demonstrates a Ki67 index less than 10%.

57. Lutetium [177Lu]Lu-DOTA-TATE, or a pharmaceutically acceptable salt thereof, for use according to any of claims 54-56, wherein the GI-NET is Grade 1.

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