SSTR2

Purpose: Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using (90)Y-Edotreotide to treat symptomatic patients with carcinoid tumors. Patients and methods: Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) (90)Y-edotreotide each, once every 6 weeks. Results: Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days. Conclusion: (90)Y-Edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile. [1]

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Background: We retrospectively aimed to assess the prognostic significance of somatostatin receptor (SSTR) standardized uptake value (SUVmaxsstr), SSTR representative tumor volume (RTVsstr) and total lesion SSTR expression (TLsstr) obtained by [68Ga]Ga-Edotreotide PET/CT ([68Ga]Ga-SSTR PET/CT) in patients with primary gastroenteropancreatic neuroendocrine tumors (GEP-NET) before surgery. Material and methods: We analyzed patients who underwent [68Ga]Ga-SSTR PET/CT 3-6 weeks before surgery from February 2020 to April 2022. The mean SUVmaxsstr value, the RTVsstr (cm3; 42% threshold) and the TLsstr (g) were registered. Thereafter the patients were followed up 10.3 months (range 3-27). The PET/CT results were compared to the event free survival (EFS). Results: Forty-two patients (61 ± 13 years) have been enrolled. At multivariate analysis only RTVsstr values were predictive. The Kaplan-Meier survival analysis for RTVsstr showed a significant better EFS in patients presenting lower values as compared to those having greater (P = .003, log-rank test). SUVmaxsstr was not suitable for predicting EFS, TLsstr mildly. Conclusion: RTVsstr represents a valuable volumetric parameter able to predict the outcome in GEP-NET patients who underwent surgery. The magnitude of the SSTR representative tumor burden holds a predominant value for determining the response to therapy in GEP-NET patients before surgery, rather than the maximal SSTR representation at single voxel. Keywords: gastoenteropancreatic tumors-neuroendocrine tumors; positron emission tomography/computed tomography; quantitative assessment; survival; volumetric parameters. [2]

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Background: Everolimus is the only approved therapy for patients with advanced neuroendocrine tumors (NET) of lung and thymus and new treatment options are urgently needed. Expression of somatostatin receptor 2 (SSTR2) is frequently seen in functional imaging in lung-NETs opening the opportunity to treat SSTR2 positive patients with radioligand therapies (RLT). Retrospective data suggest a potential meaningful benefit of RLT directed to SSTR2 in lung-NET patients. Methods: The LEVEL trial is a randomized, open-label, phase III international trial of 177Lu-Edotreotide versus everolimus in patients with progressive, locally advanced or metastatic, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment-naïve or have progressed (PD) on somatostatin analogues or ≤ 2 additional systemic treatments. Prior RLT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of 177Lu-edotreotide (total administered activity 7.5 ± 0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Only patients with positivity in somatostatin receptor imaging will be included. CT or MRI scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is progression-free survival (PFS) according to RECIST v1.1 based on local investigator assessment. Secondary endpoints include overall survival, overall response rate, safety, and quality of life (EORTC QLQ-C30). The expected sample size is 120 patients to demonstrate statistical significant risk reduction of 46.4% (HR = 0.536) in PFS with the experimental treatment using an overall 5% two-sided alpha error with 80% power. An interim PFS analysis was included using the Lan-DeMets with O'Brian-Fleming-like boundaries. Discussion: The LEVEL trial will investigate if 177Lu-edotreotide has the potential to be incorporated as a standard treatment option for patients with NETs from the lung and Thymus [3].

Medication [1]
\n90Y-Edotreotide was infused intravenously over 10 to 15 minutes. Patients were treated in an outpatient setting and were to receive three individual doses of 4.4 GBq (120 mCi) administered in 6- to 9-week cycles apart for a total cumulative dose of 13.3 GBq (360 mCi). Two liters of an amino acid solution (Aminosyn II; or equivalent) with approximately 28 g of both lysine and arginine diluted to lower than 800 mOsmol/L were infused intravenously at 500 mL/h over 4 hours beginning 30 minutes before each 90Y-Edotreotide infusion. Patients were not eligible for re-treatment until a minimum of 6 weeks (maximum 9 weeks) had passed from the last administration of study drug. Patients had to meet the following criteria for re-treatment at each subsequent cycle: serum creatinine ≤ baseline value plus 30%, or a measured creatinine clearance of ≥ 40 mL/min; absolute neutrophil count ≥ 1,500/mm3 and platelets ≥ 75,000/mm3; liver function tests (total bilirubin, aminotransferases) lower than grade 3. In addition, all grade 3 to 4 adverse events must have resolved to ≤ grade 2.\n\nSafety Assessments and Efficacy Measures [1]
\nSafety assessments consisted of adverse events, serious adverse events, laboratory tests (hematology, clinical chemistry, urinalysis), vital signs, ECGs, and physical examinations.\n\nThe primary objective of this study was to evaluate the efficacy of 90Y-Edotreotide in relieving symptoms in patients with malignant carcinoid tumors. Patients reported on these symptoms at baseline, at day 1 of each cycle, at weeks 6 and 10 of cycle 3 (or on early discontinuation), and every 6 months for up to 5 years or death. The 12 symptoms were diarrhea, hot flushes, abdominal pain, nausea/vomiting, feeling tired, decreased strength, heartburn, loss of appetite, difficulty sleeping, pain in muscles or joints, shortness of breath, and fever. Patients reported on the presence of these symptoms in the past 2 weeks, and, if present, the impact of the symptom(s) using a 7-point Likert scale (0, not at all bothered by symptom; 6, extremely bothered).\n

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\n\nPatients [2]
\nWe retrospectively reviewed data of two hundred 6 patients with positive biopsy for gastro-entero-pancreatic-neuroendocrine tumor (GEP-NET). Patients were addressed for a baseline [68Ga]Ga-edotreotide PET/CT scan from February 2020 to April 2022. The enrolled patients satisfied the inclusion criteria, such as: age at entry above 18 years, primary GEP-NET with G1 or G2 grading and only locoregional disease, scan performed before surgery. Exclusion criteria were: Patients who previously underwent surgery for GEP-NET, patients with metastatic disease, if any, patient who formerly received radioligand therapy, chemotherapy or somatostatin analogues. Patients with grade 3 NEC, multiple endocrine neoplasia as well as patients with less than 6 months follow-up period after PET/CT (apart from the ones with early tumor progression), constituted additional exclusion criteria. A flowchart of patient selection is shown in Figure 1. Diagnoses were confirmed according to the WHO 5th ed. (2019) classification.\n

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\n\nImaging Technique [2]
\nAll patients underwent [68Ga]Ga-Edotreotide PET/CT. The patients received [68Ga]Ga-edotreotide intravenously (median:181; range:148-259 MBq; weight-based). Sixty minutes after the tracer injection, PET and modulated low dose CT were carried out with a PET/CT scanner (GE Discovery VCT scanner; Waukesha, WI) that combined a PET scanner and a Light Speed VCT sixty-four row MDCT system. MDCT (pitchx 1.5; 120 mAs; 120 kVp) was performed without contrast medium. The PET scanning was subsequently performed, acquiring 3 minutes per bed position and 6 to eight beds per patient depending on patient height encompassing the whole skeleton. The raw CT data were reconstructed into transverse images with a 3.75-mm section thickness. Sagittal and coronal CT images was generated by reconstruction of the transverse data. Raw PET data were reconstructed with and without attenuation correction into transverse, sagittal, and coronal images. Attenuation correction was based on CT attenuation coefficients, which were determined by iterative reconstruction.\n

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\n\nDesign [3]
\nThe LEVEL trial is a randomized, prospective, international, open-label, phase III study comparing everolimus and 177Lu-Edotreotide in advanced SSTR2-positive lung-NETs and ThC. The primary objective of the study is to evaluate the efficacy of 177Lu-edotreotide in terms of PFS and its safety profile. Secondary endpoints include parameters of morphological and functional tumor response, such as ORR, duration of response (DoR), disease control rate (DCR), as well as OS. In addition, the current trial includes QoL and translational research. The study is planning to recruit patients in Spain, France, Belgium and Italy.\n

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\n\nStudy treatment [3]
\nPatients randomized to the experimental arm will receive treatment with 6 cycles of 7.5 ± 0.7 GBq 177Lu-Edotreotide. The prescribed treatment administration is as follows: a 6 (+ 2) weeks interval between cycles 1 and 2 followed by all remaining cycles (3– 6) given 8 (± 1) weeks after the previous cycle, where possible, or until disease progression, intolerable toxicity or death, whichever occurs first (Fig. 2). The selected dose was based on COMPOSE studies and the dosimetry data showing that the administered activity of 7.5 ± 0.7 GBq does not exceed an average cumulative renal absorbed dose of 23 Gy. The dose is chosen also based on the worse prognosis of progressive lung disease, justifying the use of COMPOSE with two more cycles than COMPETE and NETTER trials. The LEVEL trial does not include dosimetry.

Safety Results [1] As shown in Table 2, 87 out of 90 patients (96.7%) experienced one or more adverse events, the majority of which (76; 84.4%) were gastrointestinal events, with nausea, vomiting, and diarrhea being the most common. 54 out of 90 patients (60.0%) experienced grade 3 to 4 adverse events, with lymphopenia, nausea, and vomiting being the most common. 3 out of 90 patients (3.3%) experienced grade 3 to 4 renal or urinary toxicity. One patient experienced grade 3 oliguria, one experienced grade 3 dysuria, and one experienced grade 4 renal failure; the latter patient received only 4.3 GBq (115 mCi) of 90Y-Edotreotide. These renal events lasted for 6 days, 42 days, and 6 days, respectively. Serum creatinine levels at 1 year (mean 1.08 mg/dL) were similar to baseline levels (mean 1.14 mg/dL; P = .07; n = 55).
Of the 90 patients, 12 (13.3%) experienced adverse events requiring dose adjustments or discontinuation of the study drug. Nine patients (10.0%) discontinued treatment due to adverse events, including five due to gastrointestinal events. The majority of patients (78 of the 90; 86.7%) experienced adverse events requiring additional significant treatment, primarily nausea, vomiting, and abdominal pain. Thirty-two patients (35.6%) experienced serious adverse events, primarily gastrointestinal disorders (12; 13.3%). Nausea, vomiting, and abdominal pain were often associated with concurrent amino acid infusions. These symptoms almost always subsided after discontinuation of the amino acid infusion.
Eight of the 90 study patients (8.9%) died. Causes of death included atherosclerosis, carcinoid crisis, coma, other malignancies (2), disease progression (2), and sepsis. Two of the deaths are suspected to be related to the investigational drug (carcinoid crisis and coma).

[1]. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol. 2010 Apr 1;28(10):1652-9.
[2]. Ga-68-Edotreotide Positron Emission Tomography/Computed Tomography Somatostatin Receptors Tumor Volume Predicts Outcome in Patients With Primary Gastroenteropancreatic Neuroendocrine Tumors. Cancer Control. 2023 Jan-Dec;30:10732748231152328.
[3]. A Randomized clinical trial evaluating the impact on survival and quality of life of 177Lutetium[Lu]-edotreotide versus everolimus in patients with neuroendocrine tumors of the lung and thymus: the LEVEL study (GETNE T-2217). BMC Cancer. 2025 Apr 4;25(1):613.

Edotreotide is a chelated octreotide derivative with somatostatin activity. Edotreotide is prepared by replacing the phenylalanine residue at the 3-position of octreotide with a tyrosine residue and chelating it with dodecanetetraacetic acid (DOTA). Similar to octreotide, Edotreotide binds to somatostatin receptors (SSTRs), particularly SSTR type 2, which is present on the cell membranes of various neuroendocrine tumors. When radiolabeled, Edotreotide conjugates may cause tissue-specific cytotoxicity.

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Drug Indications
This drug is for diagnostic use only.
Gallium (68Ga) Edotreotide solution, obtained by radiolabeling with gallium chloride (68Ga) solution, is indicated for positron emission tomography (PET) imaging in adult patients with confirmed or suspected well-differentiated gastrointestinal pancreatic neuroendocrine tumors (GEP-NET) to detect somatostatin receptor overexpression, thereby locating the primary tumor and its metastases.

C65H92N14O18S2

1421.65

1420.62

C, 54.92; H, 6.52; N, 13.79; O, 20.26; S, 4.51

204318-14-9

459831-08-4 (G68);204318-14-9;

158782

White to off-white solid powder

1.46g/cm3

1723.7ºC at 760 mmHg

996.2ºC

0mmHg at 25°C

1.684

-7.2

17

25

26

99

2620

10

NCCCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(N[C@H](CO)[C@@H](C)O)=O)CSSC[C@H](NC([C@H](NC(CN2CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC2)=O)CC2=CC=CC=C2)=O)C(=O)N[C@@H](CC2=CC=C(O)C=C2)C(=O)N[C@H](CC)C(=O)N1

RZHKDBRREKOZEW-AAXZNHDCSA-N

InChI=1S/C65H92N14O18S2/c1-39(81)51(36-80)72-64(96)53-38-99-98-37-52(73-60(92)48(28-41-10-4-3-5-11-41)68-54(84)32-76-20-22-77(33-55(85)86)24-26-79(35-57(89)90)27-25-78(23-21-76)34-56(87)88)63(95)70-49(29-42-15-17-44(83)18-16-42)61(93)71-50(30-43-31-67-46-13-7-6-12-45(43)46)62(94)69-47(14-8-9-19-66)59(91)75-58(40(2)82)65(97)74-53/h3-7,10-13,15-18,31,39-40,47-53,58,67,80-83H,8-9,14,19-30,32-38,66H2,1-2H3,(H,68,84)(H,69,94)(H,70,95)(H,71,93)(H,72,96)(H,73,92)(H,74,97)(H,75,91)(H,85,86)(H,87,88)(H,89,90)/t39-,40-,47+,48-,49+,50-,51-,52+,53+,58+/m1/s1

2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(2R,3R)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid

SMT 487; Edotreotide; DOTATOC; 204318-14-9; Edotreotide [USAN]; Edotreotida; Edotreotide [USAN:INN]; SMT-487; Edotreotide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~70.34 mM)
H2O : ~5 mg/mL (~3.52 mM)

Solubility in Formulation 1: 2.5 mg/mL (1.76 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)