Medical Policy: 06.01.38 

Original Effective Date: May 2018 

Reviewed: May 2018 

Revised:  

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Lutathera® (Lutetium Lu 177 dotatate) is a radiolabeled somatostatin analog indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut (gastroduodenal), midgut (distal small intestine and proximal colon), and hindgut (distal colorectal and pancreas) neuroendocrine tumors in adults.

 

Neuroendocrine cells are widely distributed throughout the body, and tumors arising from these cells can occur in most organs. GEP-NETs in the digestive system, including the tubular gastrointestinal tract and the pancreas (gastroenteropancreatic), are generally divided into two major categories, well-differentiated neuroendocrine tumors (NETs) and poorly differentiated (high-grade) neuroendocrine carcinomas. These two major categories of neuroendocrine tumors behave differently in terms of biologic aggressiveness and in approach to treatment.

 

Well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which have been referred to as carcinoid tumors or pancreatic islet cell tumors, are generally indolent, but all are potentially malignant, and the clinical course may be highly variable. Symptomatic disease may be due to either tumor bulk, including pain and/or bowel obstruction, or due to secretion of serotonin and other vasoactive substances, sometimes referred to as carcinoid syndrome.

 

The general treatment approach to well-differentiated GEP-NETs involves resecting potentially resectable disease, including metastasectomy (surgical removal of metastases). Unresectable, asymptomatic disease may involve observation, especially if tumor burden is limited, or initial therapy with a somatostatin analog if tumor burden is high. Unresectable, symptomatic disease usually involves initial therapy with a somatostatin analog (e.g. octreotide or lanreotide), and dose escalation as needed for control of symptoms of carcinoid symdrome and control of tumor growth. Patients with radiologic or symptom progression despite somatostatin analog therapy may benefit from non-curative debulking therapy or nonsurgical liver-directed therapy. Patients with more widespread disease that is not eligible for liver-directed therapy may benefit from systemic treatment with molecularly targeted agents, such as everolimus.

 

Lutathera® is a targeted form of systemic radiotherapy (radioactive drug) that binds to cell surface somatostatin receptors which may be present in certain tumors, and after binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells. Most GEP-NETs express high-affinity receptors for somatostatin, and somatostatin-based imaging can provide information on tumor burden and location. Lutathera® has been proposed as a treatment option in adult patients with GEP-NETs who progress despite first-line therapy.

 

Lutathera® is given by intravenous infusion every 8 weeks for a total of 4 doses. It is a radiopharmaceutical and must be handled with appropriate safety measures to minimize radiation exposure.

The FDA approval for the use of Lutathera® is based on the results of two published studies: 

In January 2018, the U.S. Food and Drug Administration approved Lutathera® (Lutetium Lu 177 Dotatate) for the treatment of somatostatin receptor-positive GEP-NETs in adults, largely based on support from the NETTER-1 trial. This phase 3, open-label, randomized, multicenter clinical trial included 229 patients with advanced, progressive, well-differentiated midgut neuroendocrine tumors. The 229 patients were randomly assigned to receive either 177-Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a pre-specified interim analysis of overall survival was conducted and is reported here. At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177-Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177-Lu-Dotatate group and 26 in the control group (P = 0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177-Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. The authors concluded treatment with Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239)

 

Long-term safety and survival were evaluated in an investigator-sponsored, open-label, single-arm, single-institution (Erasmus) retrospective study of over 1200 patients with somatostatin receptor positive neuroendocrine tumors who received 177-Lu-Dotatate treatment. Primary tumor sites included bronchus, foregut, midgut, hindgut, pancreas and unknown. Patient populations were heterogeneous for baseline tumor status (progressive versus non-progressive) and treatments received prior to 177-Lu-Dotatate. Of these patients, the safety analysis included 610 patients, 360 (60%) of which had metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), treated with a cumulative dose of at least 100 mCi (3.7 GBq) 177-Lu-Dotatate. Median follow-up was 78 months. Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). There was no therapy-related long-term renal or hepatic failure. Overall response rate, defined as complete or partial response, in patients with midgut and pancreatic NETs with progressive disease at baseline was 84% and 81%, respectively. Median overall survival for GEP-NETs was only reported for pancreas (71 months [95% CI 56-86]) and midgut (60 months [52-68]), due to small numbers of other gastrointestinal primaries. A subset analysis of PFS in patients with midgut tumors and progressive disease at baseline was 24 months [95% CI 18-30].

 

Summary

Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are a rare group of cancers that affects the pancreas or different parts of the gastrointestinal tract, such as the stomach, intestines, colon and rectum. Approximately one of 27,000 people are diagnosed with GEP-NET each year. GEP-NETs have limited treatment options after initial therapy fails to keep the cancer from growing. Lutathera® (Lutetium Lu 177 Dotatate) is the first radioactive drug, or radiopharmaceutical, that has been approved for the treatment of GEP-NETs. More spefically Lutathera® is indicated for adult patients with somatostatin receptor-positive GEP-NETs, including foregut, midgut and hindgut neuroendocrine tumors. Lutathera received an orphan drug designation and is also the first available FDA approved Peptide Receptor Radionuclide Therapy (PRRT), a form of treatment comprising of a targeting molecule that carries a radioactive component. The safety and effectiveness of Lutathera® (Lutetium Lu 177 Dotatate) for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults has been evaluated in a multi-center open label phase 3 trial the NETTER-1 trial and the Erasmus retrospective study. Based on the clinical data from these two trials the evidence is sufficient to determine that this technology results in meaningful improvement in net health outcomes for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut (gastroduodenal), midgut (distal small intestine and proximal colon), and hindgut (distal colorectal and pancreas) neuroendocrine tumors in adults.

 

Practice Guideline and Position Statements

National Comprehensive Cancer Network (NCCN)

Neuroendocrine and Adrenal Tumors Version 2.2018
Principles of Peptide Receptor Radionuclide Therapy (PRRT) with Lu-Dotatate

Lutetium Lu 177 Dotatate (Lu-Dotatate) is a radiolabeled somatosatatin analog used as PRRT (peptide receptor radionuclide therapy). It is approved by the FDA for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (NET) including foregut, midgut, and hindgut NET in adults.

 

Key Eligibility

  • Low or intermediate grade NET (Ki-67 < 20%)
  • Somatostatin receptor expression of NET as detected by somatostatin receptor based imaging (i.e. Ga-dotatate PET/CT preferred or somatostatin receptor scintigraphy
  • Adequate bone marrow, renal and hepatic function

 

Preparing Eligible Patients for Lu-Dotatate

  • Do not administer long-acting somatostatin analogs (such as lanreotide, octreotide) for 4-6 weeks prior to each Lu-dotatate treatment. Administer short-acting octreotide as needed for symptom control of carcinoid syndrome; discontinue at least 24 hours prior to initiating Lu-Dotatate.
  • Counsel patients about the risks of
    • Radiation exposure to themselves and others
    • Myelosuppression
    • Secondary myelodysplastic syndrome (NDS) and leukemia
    • Renal toxicity
    • Hepatic toxicity
    • Embryo fetal toxicity
    • Infertility
    • Neuroendocrine hormonal crisis or carcinoid crisis: flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms
    • Nausea/vomiting related to amino acid infusion required as part of therapy
  • Discuss radiation safety precautions during and after Lu-dotatate
  • Verify pregnancy status in females of reproductive potential
  • Advise on use of effective contraception for up to 7 months (females) and 4 months (males) after last dose of Lu-dotatate

 

Dose and Administration

  • Lu-dotatate is administered intravenously (IV) via peripheral IV at dose of 200 mCi over 30-40 mintues every 8 weeks for a total of 4 treatments
  • Amino acid solution
    • IV infusion of amino acids is a critical part of Lu-dotatate therapy for nephroprotection
    • Amino acids are administered 30 minutes before, concurrently with, and 3 hours after Lu-dotatate
    • Commercial amino acid formulation infused at high rates are more emetogenic than compound amino acids
    • Solutions containing only arginine/lysine are only available through compounding pharmacies, but are less emetogenic than commercial amino acid solutions. Options for amino acids are as follows:
      • Arginine 2.5% lysine2.5% in 1000 mL NaCl infused at 250 mL/hour for 4 hours
      • Commercial amino acid formulation (typically containing approximately 20 amino acids) mixed in sterile water for total volume of approximately 2000 mL. Infusion rate can be increased to roughly 300-500 mL/hr, as tolerated. Recommend starting at low rate of 50 mL/hr and increasing by 10 mL/hr every 10 minutes as tolerated based on symptoms such as nausea. Lu-dotatate infusion should begin after at least 250 mL of amino acids have been infused.
  • Aggressive anti-emetic prophylaxis is recommended with a 5HT3 receptor antagonist with or without NK1 receptor blocker

 

Post Treatment Instructions

  • Detailed instructions on post treatment radiation risk reduction strategies should be provided per institutional radiation safety guidelines
  • Complete blood counts, serum chemistry including renal and hepatic functions should be monitored
  • SSAs (octreotide or Lanreotide) can be administered 4-24 hours after each Lu-dotatate treatment

 

Timing of Somatostatin Analogs (SSAs) (Octreotide or Lanreotide) in relation to Lu-Dotatate

  • Most patients treated with PRRT will have progressed on a first line SSA
  • Generally, patients with hormonally functional tumors should continue octreotide or lanreotide along Lu-dotatate. It is unclear whether patients with nonfunctional tumors benefit from continuation of SSA treatment during and after Lu-dotatae treatment.
  • There are theorectical concerns regarding the competition between SSAs and Lu-dotatate for somatostatin receptor binding. Therefore, the following is recommended:
    • Do not administer long-acting SSAs for 4-6 weeks prior to each Lu-dotatate treatment
    • Stop short-acting SSAs 24 hours before each Lu-dotatate treatment
    • SSAs (short and long-acting) can be resumed 4-24 hours after each Lu-dotatate treatment

 

Regulatory Status

Lutathera® (Lutetium Lu 177 Dotatate) was FDA approved January 2018 for the treatment of somatostatin receptor-positive gastroenteropacreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.

 

Prior Approval:

Prior Approval is Required

 

Policy:

Lutathera® (Lutetium Lu 177 Dotatate) is considered medically necessary for the treatment somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut (gastroduodenal), midgut (distal small intestine and proximal colon), and hindgut (distal colorectal and pancreas) neuroendocrine tumors in adults when all of the following criteria are met:

  • Patient is 18 years or older; AND
  • The patient has unresectable, locally advanced or metastatic disease; AND
  • The patient has had disease progression despite somatostatin analog therapy (e.g. octreotide or lanreotide) or molecularly targeted therapy (e.g. everolimus); AND
  • Appropriate imaging study has been performed to document over-expression of somatostatin receptor of gastroenteropancreatic neuroendocrine tumor(s) (GEP-NET) (i.e. somatostatin receptor scintigraphy; or 68-Ga-Dotate PET/CT scan); AND
  • The tumor is well differentiated with a Ki-67 index of 20% or less as documented in a pathology report (see Policy Guidelines below); AND
  • The patient has adequate bone marrow, renal and hepatic function (the following would be contraindications: serum creatinine 1.7 mg per deciliter or creatinine clearance of 50 ml/minute; Hgb 8.0 g/dl; WBC < 2000/mm3; platelets < 75,000 mm3; total bilirubin > 3 x upper limit of normal); AND
  • The prescribing regimen must be in compliance with the FDA-approved dosing, with dosing regimen of 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses.

 

Lutathera® (Lutetium Lu 177 Dotatate) is considered investigational when the above criteria is not met, and including but not limited to any of the following:

  • Pediatric patients (17 years or less)
  • Beyond 4 doses
  • For all other indications not indicated above, including but not limited to other neuroendocrine sites such as lung, parathyroid, adrenal or pituitary sites

 

Based on the peer reviewed medical literature the safety and effectiveness for indications other than the medically necessary indication listed above has not been established. Also, the FDA approved label indication state the safety and efficacy beyond 4 doses of Lutathera® (Lutetium Lu 177 Dotatate) has not been studied and the safety and effectiveness of Lutathera has not been established in pediatric patients. Additional studies are needed to further investigate the safety and efficacy of Lutathera® (Lutetium Lu 177 Dotatate) for patient populations for other than gastroenteropancreatic neuroendocrine tumors. The evidence is insufficient to demonstrate the effects on net health outcomes.

 

Policy Guidelines

  • Well-differentiated neuroendocrine tumors include low grade (G1) and intermediate-grade (G2) tumors, which correlate with a defined Ki-67 proliferation index, as determined by an immunohistochemical stain. Well-differentiated, low grade neuroendocrine tumors have a Ki-67 index of < 3%, and well-differentiated, intermediate grade neuroendocrine tumors have Ki-67 index of 3-20%.
  • Before initiating Lutathera® (Lutetium Lu 177 Dotatate), discontinue any long-acting somatostatin analogs for at least 4 weeks and short acting octreotide at least 24 hours prior to each Lutathera® dose. During Lutathera® treatment, administer long acting octreotide 30 mg intramuscularly 4 to 24 hours after each Lutathera® dose and short-acting octreotide for symptomatic management. Do not administer long-acting octreotide within 4 weeks of each subsequent Lutathera® dose and withhold short-acting octreotide for at least 24 hours before each Lutathera® dose. Following Lutathera® treatment, continue using long-acting octreotide 30 mg intramuscularly every 4 weeks after completing Lutathera® until disease progression or for up to 18 months following treatment initiation.
  • Pre-medicate with anti-emetics 30 minutes before recommended amino acid solution. Initiate recommended intravenous amino acid solution 30 minutes before Lutathera® infusion; continue during and for 3 hours after Lutathera® infusion.
  • According to the manufacturer’s safety information, Lutethera must be handled with appropriate safety measures to minimize radiation exposure, and pregnancy status in females of reproductive potential should be verified prior to initiating Lutethera. Other warnings and precautions for Lutathera listed within the prescribing information include: myelosuppression, secondary myelodysplastic syndrome (MDS), and leukemia, renal toxicity, hepatotoxicity, neuroendocrine hormonal crisis, embryo-fetal toxicity, and infertility risk.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • A9513 Lutetium lu 177, dotatate, therapeutic, 1 millicurie

 

Selected References:

  • National Comprehensive Cancer Network (NCCN) Neuroendocrine and Adrenal Tumors Version 2.2018: Principles of Peptide Receptor Radionuclide Therapy (PRRT) with Lu-Dotatate. 
  • FDA News Release. FDA Approves New Treatment for Certain Digestive Tract Cancers. January 26, 2018. 
  • Food and Drug Administration NDA Approval for Lutathera (lutetium Lu 177 dotatate) Reference ID 4212675
  • FDA Labeling for Lutathera. 
  • UpToDate Lutetium Lu-177 Dotatate: Drug Information. 
  • UpToDate. Metastatic Well Differentiated Gastrointestinal Neuroendocrine (Carcinoid) Tumors: Systemic Therapy Options to Control Tumor Growth and Symptoms of Hormone Hypersecretion. Jennifer Ang Chan M.D., MPH, Matthew Kulke M.D.. Topic last updated March 19, 2018. 
  • UpToDate. Metastatic Well-Differentiated Pancreatic Neuroendocrine Tumors: Systemic Therapy Options to Control Tumor Growth and Symptoms of Hormone Hypersecretion. Jennifer Ang Chan M.D., MPH, Matthew Kulke M.D., Thomas E. Clancy M.D.. Topic last updated March 19, 2018. 
  • National Cancer Institute. FDA Approves New Treatment for Certain Neuroendocrine Tumors. 
  • Lutathera (Letetium Lu-177 Dotatate). 
  • Strosberg J, El-Haddad G, Wolin E. et. al. Phase 3 Trial of Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 376;2 January 12, 2017
  • Brabander T, van der Zwan WA, Teunissen JJM, et. al. Long-Term Efficacy, Survival and Safety of Lu DOTA, Tyr Octreotate in Patients with Gastroenteropancreatic and Bronchical Neuroendocrine Tumors. Clin Cancer Res 2017 Aug 15; 23(16):4617-4624. PMID 28428192

 

Policy History:

  • May 2018 - New Policy created

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.