Pending Policies - Prescription Drugs
Lanreotide (Somatuline Depot)
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Lanreotide (Somatuline® Depot) may be considered medically necessary for the following U.S. Food and Drug Administration (FDA)-approved indications:
• Long-term treatment of patients with acromegaly who have had either an inadequate response to or cannot be treated with surgery and/or radiotherapy.
• Treatment of patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival.
• Treatment of adults with carcinoid syndrome.
NOTE: The safety and effectiveness of Lanreotide in pediatric patients has not been established. Additionally, due to the lack of adequate and well-controlled studies in pregnant women, Lanreotide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Acromegaly is a rare hormonal disorder that occurs when the pituitary gland produces too much growth hormone (GH) during adulthood. The overproduction of GH in most cases is due to a pituitary adenoma, a benign pituitary gland tumor. When GH is released into the bloodstream, the liver manufactures a hormone called insulin-like growth factor-1 (IGF-1). An excessive amount of IGF-1 can lead to atypical growth of skeletal and soft tissue. Physical changes can include an increase in size of extremities, examples include enlargement of hands, feet and face (protruding lower jaw and brow). Other symptoms may include headache, fatigue and vision impairment. Symptoms of acromegaly vary and may be gradual, due to the insidious onset; the condition may not be diagnosed immediately. Acromegaly could lead to serious life-threatening complications, therefore early diagnosis and treatment is important.
Tests used to help diagnosis and monitor acromegaly may include, but are not limited to, MRI of the brain, IGF-1 levels, Prolactin, and GH levels. Treatment may consist of surgical, medical and radiotherapeutic options or a combination of these therapies. Surgery to remove the pituitary tumor may be the initial treatment in patients with microadenomas. There are situations in which the tumor is unable to be removed completely; radiation or medical therapy may be used as adjunct to surgery. One class of medication that may be used to treat acromegaly is somatostatin analogs (SSA). (1)
Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)
Neuroendocrine tumors (NETs) are epithelial neoplasms that arise from neuroendocrine cells. These cells can originate in nearly any anatomic location, but the most common are the gastrointestinal (GI) tract and the pancreas. These tumors are known as gastroenteropancreatic (GET) NETs. These tumors are often slow-growing, but can metastasize. “Functional” NETs secrete amines and/or peptides that can lead to clinical symptoms. Approximately 40% of NETs arising in the pancreas and 10% of those arising in the small intestine are “functional”.
Locally advanced and unresectable or metastatic GEP-NETs are considered incurable. Instead, the primary treatment goals are to prolong progression-free survival (PFS) and to provide symptom management. Treatment options include surgery, radiology, and pharmacotherapy. In recent years there has been an increase in the available pharmacologic agents, which would include SSA. (2)
A carcinoid tumor is a specific type of neuroendocrine tumor that most often develops in the GI tract in organs such as the stomach or intestines. (6) Carcinoid syndrome results when a carcinoid tumor secretes certain vasoactive substances such as serotonin, bradykinin, histamine, prostaglandins, and polypeptide hormones. The most common symptoms of carcinoid syndrome, include flushing, diarrhea, bronchospasm, and valvular heart disease. Treatment options may include both surgical resection or debulking and pharmacotherapy. (7)
Lanreotide (Somatuline® Depot)
Although there are other SSAs on the market, lanreotide (Somatuline® Depot) is the specific SSA addressed in this medical policy. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin. Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 and a reduced binding affinity for human SSTR1, 3 and 4. Activity at human SSTR2 and 5 is the primary mechanism believed responsible for GH inhibition. In acromegalic patients, lanreotide administration results in a reduction and normalization of GH and/or IGF-1 levels. In GPE-NETs, lanreotide functions in controlling the symptoms associated with hormone hypersecretion, as these types of tumors often overexpress receptors for somatostatin. (3)
Lanreotide (Somatuline® Depot) was originally approved by the U.S. Food & Drug Administration (FDA) on August 30, 2007 for the long-term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy. (4) On December 16, 2014, the FDA approved Lanreotide (Somatuline® Depot) for the new indication of treatment of patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GETP-NETs) to improve PFS. (3) A third indication was FDA approved for Lanreotide (Somatuline® Depot) as of September 15, 2017 for treatment of adults with carcinoid syndrome. (5)
Dosage and Administration
Lanreotide (Somatuline® Depot) 90mg is given via deep subcutaneous injection at 4-week intervals for the first 3 months. After 3 months, the dosage may be adjusted as follows:
• GH greater than 1ng/mL to less than or equal to 2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain dose at 90mg every 4 weeks.
• GH greater than 2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled: increase dose to 120mg every 4 weeks.
• GH less than or equal to 1 ng/mL, IGF-1 normal, and clinical symptoms controlled: reduce dose to 60mg every 4 weeks.
Thereafter, the dose should be adjusted according to the response of the patient as judged by a reduction in serum GH and/or IGF-1 levels; and/or changes in symptoms of acromegaly. Patients who are controlled on 60mg or 90mg may be considered for an extended dosing interval of 120mg every 6 to 8 weeks. GH and IGF-1 levels should be obtained 6 weeks after this change in dosing regimen to evaluate persistence of patient response. Continued monitoring of patient response with dose adjustments for biochemical and clinical symptom control, as necessary, is recommended. It is important to note that the starting dose in patients with moderate or severe renal impairment or moderate or severe hepatic impairment should be 60mg via the deep subcutaneous route at 4-week intervals for 3 months followed by dose adjustment as described above. (3)
Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)
The recommended dose of Lanreotide (Somatuline® Depot) is 120mg administered every 4 weeks by deep subcutaneous injection. (3)
The recommended dose of Lanreotide (Somatuline® Depot) is 120mg administered every 4 weeks by deep subcutaneous injection. If patients are already being treated with Lanreotide (Somatuline® Depot) for GEP-NETs, an additional dose for the treatment of carcinoid syndrome should not be administered. (5)
The U.S. Food & Drug Administration (FDA) approval of Lanreotide (Somatuline® Depot) for acromegaly was based on two long-term, multiple-dose, randomized, multicenter studies which looked at the effect of the drug on reducing growth hormone (GH) and insulin-like growth factor (IGF)-levels, and control of symptoms. (3)
The first study was a one-year study consisting of a 4-week, double-blind, placebo-controlled phase; a 16-week single-blind, fixed-dose phase; and a 32-week, open-label, dose-titration phase. A total of 108 patients (51 males, 57 females) were enrolled in the initial placebo-controlled phase of the study. One hundred and seven patients completed the placebo-controlled phase, 105 patients completed the fixed-dose phase, and 99 patients completed the dose-titration phase. (3)
In the double-blind phase of study 1, a total of 52 (63%) of the 83 lanreotide-treated patients had a > 50% decrease in mean GH from baseline to Week 4, including 52%, 44%, and 90% of patients in the 60mg, 90mg, and 120mg groups, respectively, compared to placebo (0%, 0/25). In the fixed-dose phase at Week 16, 72% of all 107 lanreotide-treated patients had a decrease from baseline in mean GH of > 50%, including 68% (23/34), 64% (23/36), and 84% (31/37) of patients in the 60mg, 90mg, and 120mg lanreotide treatment groups, respectively. Efficacy achieved in the first 16 weeks was maintained for the duration of the study. (3)
The second study was a 48-week, open-label, uncontrolled, multicenter study that enrolled patients who had an IGF-1 concentration ≥ 1.3 times the upper limit of the normal age-adjusted range. Participants were initially enrolled in a 4-month, fixed-dose phase where they received 4 deep subcutaneous injections of 90mg, at 4-week intervals. Patients then entered a dose-titration phase where the dose was adjusted based on GH and IGF-1 levels at the beginning of the dose-titration phase and, if necessary, again after another 4 injections. Patients titrated up to the maximum dose (120mg) were not allowed to titrate down again. A total of 63 patients (38 males, 25 females) entered the fixed-dose phase of the trial and 57 patients completed 48 weeks of treatment. (3)
After 48 weeks of treatment at 4-week intervals, 43% (27/63) of the acromegalic patients in this study achieved normal age-adjusted IGF-1 concentrations. Mean IGF-1 concentrations after treatment completion were 1.3 ± 0.7 times the upper limit of normal compared to 2.5 ± 1.1 times the upper limit of normal at baseline. The reduction in IGF-1 concentrations over time correlated with a corresponding marked decrease in mean GH concentrations. The proportion of patients with mean GH concentrations < 2.5 ng/mL increased significantly from 35% to 77% after the fixed-dose phase and 85% at the end of the study. At the end of treatment, 24/63 (38%) of patients had both normal IGF-1 concentrations and a GH concentration of ≤ 2.5 ng/mL and 17/63 patients (27%) had both normal IGF-1 concentrations and a GH concentration of < 1 ng/mL. (3)
Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)
The efficacy of Lanreotide (Somatuline® Depot) for GEP-NETs was initially established in a multicenter, randomized, double-blind, placebo-controlled trial of 204 patients with unresectable, well or moderately differentiated, metastatic or locally advanced, gastroenteropancreatic neuroendocrine tumors. Patients were required to have non-functioning tumors without hormone-related symptoms. Patients were randomized 1:1 to receive Somatuline® Depot 120 mg (n=101) or placebo (n=103) every 4 weeks until disease progression, unacceptable toxicity or a maximum of 96 weeks of treatment. Randomization was stratified by the presence or absence of prior therapy and by the presence or absence of disease progression within 6 months of enrollment. The major efficacy outcome measure was progression-free survival (PFS), defined as time to disease progression as assessed by central independent radiological review using the Response Evaluation Criteria in Solid Tumors (RECIST 1.0), or death. Disease progression was present in 9 of 204 patients (4.4%) in the 6 months prior to enrollment and twenty-nine patients (14%) received prior chemotherapy. Ninety-one patients (45%) had primary sites of disease in the pancreas, with the remainder originating in the midgut (35%), hindgut (7%), or unknown primary location (13%). The majority (69%) of the study population had grade 1 tumors. Patients on the Somatuline® Depot arm had a statistically significant improvement in PFS compared to patients receiving placebo. (3)
In a multicenter, double-blind study, 115 patients with histopathologically-confirmed neuroendocrine tumors and a history of carcinoid syndrome (flushing and/or diarrhea) were randomized 1:1 to receive Lanreotide (Somatuline® Depot) 120mg (n=59) or placebo (n=56) by deep subcutaneous injection every 4 weeks. Participation in the study required patients to be either treatment naïve or stable on another somatostatin analog. The patient population had a mean age of 59 years (range 27 to 85 years), 58% were female and 77% were Caucasian. (5)
Patients were instructed to self-administer a short-acting somatostatin analog (octreotide) as rescue medication as needed for symptom control. The use of rescue therapy, along with the severity and frequency of diarrhea and flushing symptoms were reported daily in electronic patient diaries. During the 16-week double-blind phase, the primary efficacy outcome measure was the percentage of days in which patients administered at least one injection of rescue medication for symptom control. Average daily frequencies of diarrhea and flushing events were assessed secondarily. Patients in the Lanreotide (Somatuline® Depot) arm experienced 15% fewer days on rescue medication compared to patients in the placebo arm (34% vs. 49% of days, respective; p=0.02). The average daily frequencies of diarrhea and flushing events in patients treated with Lanreotide (Somatuline® Depot) (and rescue medication) were lower than the patients treated with placebo (and rescue mediation), but the difference was not statistically significant. (5)
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The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
1. Acromegaly-Mayo Clinic. Diseases and Conditions Acromegaly. Available at: <http://www.mayoclinic.org> (accessed on May 19, 2017).
2. Iyer, R, Phan, A, Philip, J. Recent Advances in the Management of Gastroenteropancreatic Neuroendocrine Tumors: Insights From the 2017 ASCO Gastrointestinal Cancers Symposium. Clinical Advances in Hematology & Oncology Vol 15(Suppl 4) April 2017.
3. US Food and Drug Administration (FDA). Highlights of prescribing information: Somatulin® Depot. 2014. Available at: <http://www.accessdata.fda.gov> (accessed on May 19, 2017).
4. US Food and Drug Administration (FDA). Highlights of prescribing information: Somatulin® Depot. 2007. Available at: <http://www.accessdata.fda.gov> (accessed on May 19, 2017).
5. US Food and Drug Administration (FDA). Highlights of prescribing information: Somatulin® Depot. 2017. Available at: <http://www.accessdata.fda.gov> (accessed on November 2, 2017).
6. Carcinoid Tumor. Types of Cancer. Available at: <http://www.cancer.net> (accessed on November 2, 2017).
7. Evers, B. Mark. Carcinoid Syndrome. Available at: <http://www.merckmanuals.com> (accessed on November 2, 2017).
|1/1/2018||Document updated with literature review. The following change was made to Coverage: Added new FDA indication of "Treatment of adults with carcinoid syndrome”.|
|9/1/2017||New medical document. Lanreotide (Somatuline® Depot) may be considered medically necessary for the following U.S. Food and Drug Administration (FDA)-approved indications: 1) Long-term treatment of patients with acromegaly who have had either an inadequate response to or cannot be treated with surgery and/or radiotherapy; 2) Treatment of patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. NOTE: The safety and effectiveness of Lanreotide in pediatric patients has not been established. Additionally, due to the lack of adequate and well-controlled studies in pregnant women, Lanreotide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.|