GEP-NETs, DIAGNOSIS, AND RADIOLIGAND THERAPY
GEP-NETs AND THE TREATMENT LANDSCAPE
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common subtype of neuroendocrine tumors (NETs), a heterogeneous group of tumors that arise from neuroendocrine cells throughout the body with varied, nonspecific symptoms.1,2
Although GEP-NETs are rare, their prevalence is rising1
GEP-NETs
are most commonly found in the rectum, small intestine, pancreas, stomach, and appendix1
They account for
55% to 70%
of all NET diagnoses3
The path to diagnosis can be long and complex4
Patients see an average of
6 HCPs
before diagnosis4
Patients require an average of
12 doctor visits
before final diagnosis4
There is typically a
5- to 7-year delay
from symptom onset to diagnosis4,5
More than 50% of GEP-NETs are diagnosed at an advanced or metastatic stage.6
Due to the complexity of GEP-NETs and the long path to diagnosis, precise staging and multidisciplinary evaluation are essential to guide treatment decisions.6
Abbreviation
HCP, healthcare professional.
Diagnosing GEP-NETs
Learn about a diagnostic agent that can help meet the challenges of NET diagnosis and inform treatment planning.7
ADDRESSING REAL-WORLD CHALLENGES OF RADIOLIGAND THERAPY
The treatment landscape for GEP-NETs has evolved considerably, including advancements in radioligand therapy (RLT) to help improve the ability to manage disease progression. Although RLT has demonstrated clinical benefit in patients with unresectable, metastatic somatostatin receptor–positive GEP-NETs as a first- and second-line therapy, real-world challenges can still impact continuity of care.8
SUPPLY AND LOGISTICS CONSTRAINTS8
Complex distribution networks can make timely delivery unpredictable.
EVOLVING EDUCATIONAL NEEDS8,9
Rapidly evolving therapies, terminology, and clinical policies require ongoing learning and coordination among oncologists and nuclear medicine physicians.
PATIENT PATHWAY COORDINATION9
Multidisciplinary scheduling, communication, and patient education can create operational friction.
REGULATORY AND
REIMBURSEMENT VARIABILITY8
Differences in regional reimbursement approvals, coverage, and policies can slow therapy initiation and access.
Reducing barriers to RLT with a focused approach
With more than 30 years of commitment to the NET community, Curium’s focused approach to addressing these challenges has led to a new RLT option, helping expand access to GEP-NET care.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
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Risk From Radiation Exposure: Bexlutry contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. These risks of radiation associated with the use of Bexlutry are greater in pediatric patients than in adults.
Radiation can be detected in the urine for up to 30 days following Bexlutry administration. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with Bexlutry consistent with institutional good radiation safety practices, patient management procedures, Nuclear Regulatory Commission patient-release guidance, and instructions to the patient for follow-up radiation protection at home.
-
Myelosuppression: In NETTER-1, myelosuppression occurred more frequently in patients receiving lutetium Lu 177 dotatate injection with long-acting octreotide compared to patients receiving high-dose long-acting octreotide (all Grades/Grade 3 or 4): anemia (81%/0) versus (54%/1%); thrombocytopenia (53%/1%) versus (17%/0); and neutropenia (26%/3%) versus (11%/0). In NETTER-1, platelet nadir occurred at a median of 5.1 months following the first dose. Of the 59 patients who developed thrombocytopenia, 68% had platelet recovery to baseline or normal levels. The median time to platelet recovery was 2 months. Fifteen of the nineteen patients in whom platelet recovery was not documented had post-nadir platelet counts. Among these 15 patients, 5 improved to Grade 1, 9 to Grade 2, and 1 to Grade 3. Monitor blood cell counts. Withhold dose, reduce dose, or permanently discontinue Bexlutry based on the severity of myelosuppression.
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Secondary Myelodysplastic Syndrome (MDS) and Leukemia: In NETTER-1, with a median follow-up time of 76 months in the main study, myelodysplastic syndrome (MDS) was reported in 2.3% of patients receiving lutetium Lu 177 dotatate injection with long-acting octreotide compared to no patients receiving high-dose long-acting octreotide.
In ERASMUS, 16 patients (2.0%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to onset was 29 months (9 to 45 months) for MDS and 55 months (32 to 125 months) for acute leukemia.
-
Renal Toxicity: In ERASMUS, 8 patients (< 1%) developed renal failure 3 to 36 months following lutetium Lu 177 dotatate injection. Two of these patients had underlying renal impairment or risk factors for renal failure (e.g., diabetes or hypertension) and required dialysis.
Administer the recommended amino acid solution before, during and after Bexlutry to decrease the reabsorption of lutetium Lu 177 dotatate through the proximal tubules and decrease the radiation dose to the kidneys. Advise patients to hydrate and to urinate frequently before, on the day of, and the day after administration of Bexlutry.
Monitor serum creatinine and calculated creatinine clearance. Withhold dose, reduce dose, or permanently discontinue Bexlutry based on the severity of renal toxicity.
Patients with baseline renal impairment may be at increased risk of toxicity due to increased radiation exposure.
-
Hepatotoxicity: In ERASMUS, 2 patients (< 1%) were reported to have hepatic tumor hemorrhage, edema, or necrosis, with one patient experiencing intrahepatic congestion and cholestasis. Patients with hepatic metastasis may be at increased risk of hepatotoxicity due to radiation exposure.
Monitor transaminases, bilirubin, serum albumin, and international normalized ratio (INR) during treatment. Withhold dose, reduce dose, or permanently discontinue Bexlutry based on the severity of hepatotoxicity.
-
Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema, occurred in patients treated with lutetium Lu 177 dotatate injection. Monitor patients closely for signs and symptoms of hypersensitivity reactions, including anaphylaxis, during and following Bexlutry administration for a minimum of 2 hours in a setting where cardiopulmonary resuscitation medication and equipment are available. Discontinue the infusion upon the first observation of any signs or symptoms consistent with a severe hypersensitivity reaction and initiate appropriate therapy.
Premedicate patients with a history of Grade 1 or 2 hypersensitivity reactions to Bexlutry before subsequent doses. Permanently discontinue Bexlutry in patients who experience Grade 3 or 4 hypersensitivity reactions.
-
Neuroendocrine Hormonal Crisis: Neuroendocrine hormonal crises, manifesting with flushing, diarrhea, bronchospasm and hypotension, occurred in < 1% of patients in ERASMUS and typically occurred during or within 24 hours following the initial lutetium Lu 177 dotatate injection dose. Two (< 1%) patients were reported to have hypercalcemia. Monitor patients for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms of tumor-related hormonal release. Administer intravenous somatostatin analogs, fluids, corticosteroids, and electrolytes as indicated.
-
Embryo-Fetal Toxicity: Based on its mechanism of action, Bexlutry can cause fetal harm when administered to a pregnant woman. Verify pregnancy status of females of reproductive potential prior to initiating Bexlutry. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Bexlutry and for 7 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Bexlutry and for 4 months after the last dose.
-
Risk of Infertility: Bexlutry may cause infertility in males and females. The recommended cumulative dose of 29.6 GBq of Bexlutry results in a radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy.
ADVERSE REACTIONS
The most common Grade 3-4 adverse reactions (≥ 4% with a higher incidence in lutetium Lu 177 dotatate injection arm) reported in NETTER-1 were lymphopenia, increased GGT, vomiting, nausea, increased AST, increased ALT, hyperglycemia and hypokalemia.
With a median follow-up time of more than 4 years, the following rates of serious adverse reactions were reported in ERASMUS: myelodysplastic syndrome (2%), acute leukemia (1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%).
DRUG INTERACTIONS
Somatostatin Analogs: Somatostatin and its analogs competitively bind to somatostatin receptors and may interfere with the efficacy of Bexlutry. Discontinue long-acting somatostatin analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each Bexlutry dose. Administer short- and long-acting octreotide during Bexlutry treatment as recommended.
Glucocorticoids: Glucocorticoids can induce down-regulation of subtype 2 somatostatin receptors (SSTR2). Avoid repeated administration of high doses of glucocorticoids during treatment with Bexlutry.
USE IN SPECIFIC POPULATIONS
Lactation
Advise women not to breastfeed during treatment with Bexlutry and for 2.5 months after the last dose.
Pediatric Use
Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors: The risks of radiation exposure associated with Bexlutry are greater in pediatric patients than in adult patients due to longer life expectancy. The safety and effectiveness of Bexlutry have not been established in pediatric patients younger than 12 years old with somatostatin receptor-positive GEP-NETs.
Pediatric use information is approved for Advanced Accelerator Applications USA INC’s LUTATHERA (lutetium Lu 177 dotatate) injection for intravenous use. However, due to Advanced Accelerator Applications USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
LUTATHERA® is a registered trademark of Advanced Accelerator Applications International SA.
INDICATIONS AND USAGE
Bexlutry™ (lutetium Lu 177 dotatate injection) is indicated for the treatment of adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors.
References
- Xu Z, Wang L, Dai S, et al. Epidemiologic trends of and factors associated with overall survival for patients with gastroenteropancreatic neuroendocrine tumors in the United States. JAMA Netw Open. 2021;4(9):e2124750. doi:10.1001/jamanetworkopen.2021.24750
- Dillon J. Workup of gastroenteropancreatic neuroendocrine tumors. Surg Oncol Clin N Am. 2020;29(2):165-183. doi:10.1016/j.soc.2019.10.002
- Das S, Dasari A. Epidemiology, incidence, and prevalence of neuroendocrine neoplasms: are there global differences? Curr Oncol Rep. 2021;23(4):43. doi:10.1007/s11912-021-01029-7
- Wolin EM, Leyden J, Goldstein G, et al. Patient-reported experience of diagnosis, management, and burden of neuroendocrine tumors: results from a large patient survey in the United States. Pancreas. 2017;46(5):639-647. doi:10.1097/MPA.0000000000000818
- Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9(1):61-72. doi:10.1016/S1470-2045(07)70410-2
- Stiefel R, Lehmann K, Winder T, Siebenhüner AR. What have we learnt from the past – would treatment decisions for GEP-NET patients differ between 2012 to 2016 by the new recommendations in 2022? BMC Cancer. 2023;23(1):148. doi:10.1186/s12885-023-10567-1
- Johnbeck CB, Knigge U, Loft A, et al. Head-to-head comparison of 64Cu-DOTATATE and 68Ga-DOTATOC PET/CT: a prospective study of 59 patients with neuroendocrine tumors. J Nucl Med. 2017;58(3):451-457. doi:10.2967/jnumed.116.180430
- Ninatti G, Lee ST, Scott AM. Radioligand therapy in cancer management: a global perspective. Cancers. 2025;17(21):3412. doi.org/10.3390/cancers17213412
- Kasi PM, Maige CL, Shahjehan F, et al. A care process model to deliver 177Lu-dotatate peptide receptor radionuclide therapy for patients with neuroendocrine tumors. Front Oncol. 2019;8:663. doi:10.3389/fonc.2018.00663