About GEP-NETs

NETs are malignancies recognized with increasing frequency

Neuroendocrine tumors (NETs) are malignancies that arise from neuroendocrine cells, which are specialized cells that secrete hormones and other bioactive substances and are found throughout the body. These cancers may or may not secrete bioactive substances at levels high enough to cause symptoms.1

Although classified as an orphan and rare disease, NETs are being diagnosed with increasing frequency.2 The reported incidence of NETs has increased >6-fold over the last 4 decades, according to SEER data from 1973-2012. The estimated incidence of NETs was 6.98/100,000 based on SEER data from 2012, while the estimated prevalence in 2012 was 48/100,000. The increase is thought to reflect improved awareness and diagnosis at earlier stages of the disease, though NETs are still often diagnosed at an advanced or metastatic stage.3

NETs are generally considered as indolent (slowly growing) tumors; however, the prognosis varies widely, according to2:

  • Primary tumor site
  • Tumor differentiation and grade
  • Stage

Although NETs can arise from a wide variety of organs and tissues, most NETs are gastroenteropancreatic (GEP-NETs), originating in the gastrointestinal (GI) tract and pancreas.2

Classification of GEP-NETs

GEP-NETs may be grouped according to the embryologic origin of the primary tumor site1:

  • Foregut: gastric, duodenal, and pancreatic
  • Midgut: jejunal, ileal, appendiceal, cecal, ascending, and right transverse colonic
  • Hindgut: left transverse colonic to hindgut

Advanced GEP-NETs may be fatal, even for patients with low-grade disease1

SEER, Surveillance, Epidemiology, and End Results.

References: 1. Alexandraki KI, Kaltsas G. Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy. Endocrine. 2012;41(1):40-52. 2. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335-1342. 3. Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumors. Lancet Oncol. 2008;9(1):61-72.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

  • Radiation Exposure: Treatment with LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure and is associated with an increased risk for cancer. Radiation can be detected in the urine for up to 30 days following LUTATHERA administration. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with LUTATHERA 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 clinical trial, myelosuppression occurred more frequently in patients receiving LUTATHERA with long acting octreotide at the following rates (all grades/grade 3 or 4): anemia (81%/0), thrombocytopenia (53%/1%), and neutropenia (26%/3%). Blood cell counts must be monitored prior to, during, and after treatment. Withhold, reduce dose, or permanently discontinue based on severity of myelosuppression.
  • Secondary Myelodysplastic Syndrome and Leukemia: In NETTER-1, with a median follow-up time of 24 months, myelodysplastic syndrome (MDS) was reported in 2.7% of patients receiving LUTATHERA with long-acting octreotide. In ERASMUS, a Phase II clinical study, 16 patients (2%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to the development of MDS was 28 months (9 to 41 months) and 55 months (32 to 155 months) for acute leukemia.
  • Renal Toxicity: Treatment with LUTATHERA will expose kidneys to radiation, which may impair renal function. In ERASMUS <1% of patients developed renal failure 3 to 36 months following LUTATHERA. Monitor serum creatinine and creatinine clearance to assess changes in renal function. Advise patients to urinate frequently during and after administration of LUTATHERA. A concomitant intravenous infusion of amino acids before, during, and after LUTATHERA administration is mandatory for renal protection. Patients with baseline renal impairment may be at greater risk of toxicity. Perform more frequent assessments of renal function in patients with mild or moderate impairment. Withhold, reduce dose, or permanently discontinue based on severity of renal toxicity. Do not decrease the dose of amino acid solution if the dose of LUTATHERA is reduced. LUTATHERA has not been studied in patients with severe renal impairment (CrCL < 30 mL/min).
  • Hepatotoxicity: In ERASMUS, <1% of patients 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, and serum albumin during treatment. Withhold, reduce dose, or permanently discontinue based on severity of hepatic impairment.
  • Neuroendocrine hormonal crisis: Manifesting with flushing, diarrhea, bronchospasm and hypotension, neuroendocrine hormonal crisis occurred in <1% of patients in ERASMUS and typically occurred during or within 24 hours following the initial LUTATHERA dose. 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: LUTATHERA can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the final dose. Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA.
  • Risk of Infertility: LUTATHERA may cause infertility in males and females. Radiation absorbed by testes and ovaries from the recommended cumulative LUTATHERA dose falls within the range in which 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 LUTATHERA arm) observed in NETTER-1 were lymphopenia (44%), increased GGT (20%), vomiting (7%), nausea (5%), elevated AST (5%), increased ALT (4%), hyperglycemia (4%), and hypokalemia (4%).

In ERASMUS, the following serious adverse reactions have been observed with a median follow-up time of more than 4 years after treatment with LUTATHERA: myelodysplastic syndrome (2%), acute leukemia (1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%). Patients should be counseled and monitored in accordance with the LUTATHERA Prescribing Information.

DRUG INTERACTIONS

Somatostatin and its analogs competitively bind to somatostatin receptors and may interfere with the efficacy of LUTATHERA. Discontinue long-acting somatostatin analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each LUTATHERA dose. Administer short- and long-acting octreotide during LUTATHERA treatment as recommended.

Corticosteroids can induce down-regulation of subtype 2 somatostatin receptors (SSTR2). Avoid repeated administration of high doses of glucocorticosteroids during treatment with LUTATHERA.

SPECIFIC POPULATIONS

  • Lactation: Because of the potential risk for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with LUTATHERA and for 2.5 months after the final dose.

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or www.report.novartis.com/, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information.

Distributed by: Advanced Accelerator Applications USA, Inc., NJ 07041

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