Lutetium Lu 177 Dotatate (Lutathera)

Number: 0929

Policy

1. Criteria for Initial Approval

   Aetna considers lutetium Lu 177 dotatate (Lutathera) medically necessary for members with the following indications:

1. Neuroendocrine tumors (NETs)

   1. Tumors of the gastrointestinal (GI) tract (carcinoid tumor) - four doses total for treatment of somatostatin receptor-positive NETs of the gastrointestinal tract when both of the following criteria are met:

      1. Member has clinically significant tumor burden or progressive locoregional advanced disease and/or distant metastases; and
      2. Member experienced disease progression on octreotide or lanreotide;

   2. Tumors of the pancreas - four doses total for treatment of somatostatin receptor-positive NETs of the pancreas when both of the following criteria are met:

      1. Member has symptomatic disease, clinically significant tumor burden, progressive locoregional advanced disease and/or distant metastases; and
      2. Member experienced disease progression on octreotide or lanreotide;

   3. Neuroendocrine tumors (NETs) of the lung and thymus (carcinoid tumors) - four doses total for treatment of somatostatin receptor-positive NETs of the lung and thymus when one of the following criteria is met:

      1. Member has locoregional unresectable disease and has progressed on octreotide or lanreotide; or
      2. Member has distant metastatic disease, has experienced progression on octreotide or lanreotide, and meets one of the following criteria:
         
         
         1. Clinically significant tumor burden and low grade (typical) histology; or
         2. Evidence of progression; or
         3. Intermediate grade (atypical) histology; or
            
         4. Symptomatic disease;

2. Carcinoid Syndrome

    - four doses total for treatment of poorly controlled carcinoid syndrome when all of the following criteria are met:
   
   

   1. Member has somatostatin receptor-positive neuroendocrine tumor of the gastrointestinal tract, lung or thymus; and
   2. Member experienced progression on octreotide or lanreotide; and
   3. Lutathera will be used in combination with either
      
      
      1. octreotide LAR or lanreotide for persistent symptoms (i.e., flushing, diarrhea) or
      2. telotristat for persistent diarrhea;
         

3. Pheochromocytoma/paraganglioma

    - four doses total for treatment of somatostatin receptor-positive pheochromocytoma/paraganglioma when the member has locally unresectable disease or distant metastases.

2. Aetna considers lutetium Lu 177 dotatate experimental and investigational for all other indications.

3. Continuation of Therapy

   See Dosage and Administration section.

Dosage and Administration

Lutathera (lutetium Lu 177 dotatate) is available for injection as 370 MBq/mL (10 mCi/mL) in single-dose vial for intravenous use.

Somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults: The recommended dose is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses. Administer pre- and concomitant medications and administer Lutathera as recommended.

Source: Advanced Accelerator Applications USA, 2020

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults

Compendial Uses

• Carcinoid syndrome
• Neuroendocrine tumors (NETs) of the lung and thymus (carcinoid tumors)
• Pheochromocytoma/paraganglioma

Lutetium Lu 177 dotatate (Lutathera) is a radiolabeled somatostatin analog. Lutetium Lu 177 dotatate binds to somatostatin receptors with highest affinity for subtype 2 receptors (SSRT2). Upon binding to somatostatin receptor expressing cells, including malignant somatostatin receptorpositive tumors, the compound is internalized. The beta emission from Lu 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighboring cells (Advanced Accelerator Applications USA, 2020).

Lutathera carries the following warnings and precautions: 

• Risk from radiation exposure: Minimize radiation exposure during and after treatment with Lutathera consistent with institutional good radiation safety practices and patient management procedures;
• Myelosuppression: Monitor blood cell counts. Withhold, reduce dose, or permanently discontinue based on severity;
• Secondary myelodysplastic syndrome (MDS) and leukemia: Median time to development: MDS is 28 months; acute leukemia is 55 months;
• Renal toxicity: Advise patients to urinate frequently during and after administration of Lutathera. Monitor serum creatinine and calculated creatinine clearance. Withhold, reduce dose, or permanently discontinue based on severity;
• Hepatotoxicity: Monitor transaminases, bilirubin and albumin;
• Neuroendocrine hormonal crisis: Monitor for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms;
• Embryo-fetal toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception;
• Risk of Infertility.

The most common Grade 3-4 adverse reactions (≥ 4% with a higher incidence in the Lutathera arm) are lymphopenia, increased GGT, vomiting, nausea, increased AST, increased ALT, hyperglycemia and hypokalemia. 

Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

On January 26, 2018, The FDA approved lutetium Lu 177 dotatate (Lutathera) in adult patients for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs. Lutathera was approved under priority review and received Orphan Drug designation. GEP-NETs can be present in the pancreas and in different parts of the gastrointestinal tract such as the stomach, intestines, colon and rectum. It is estimated that approximately one out of 27,000 people are diagnosed with GEP-NETs per year.

Lutetium Lu 177 dotatate is a radioactive drug that binds to a part of a cell called a somatostatin receptor, which may be present on certain tumors. After binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells.

The approval of lutetium Lu 177 dotatate was supported by two studies. In the NETTER-1 trial, Strosberg et al (2017) stated patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. The study randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-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) (177Lu-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 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-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 177Lu-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 that treatment with 177Lu-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.

The second study, ERASMUS, was based on data patients with somatostatin receptor-positive tumors, including GEP-NETS, who received lutetium Lu 177 dotatate at a single site in the Netherlands. A total of 1214 patients received lutetium Lu 177 dotatate, of which 601 (50%) were assessed per RECIST criteria. Of the 601 patients evaluated by investigators using RECIST criteria, 360 (60%) had gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Lutetium Lu 177 dotatate 7.4 GBq (200 mCi) was administered every 6 to 13 weeks for up to 4 doses concurrently with the recommended amino acid solution. The major efficacy outcome was investigator-assessed ORR. The median age in the efficacy subset was 61 years (25 to 88 years), 52% were male, 61% had a baseline Karnofsky performance status ≥ 90 (60 to 100), 60% had progressed within 12 months of treatment, and 15% had received prior chemotherapy. Fifty five percent (55%) of patients received a concomitant somatostatin analog. The median dose of lutetium Lu 177 dotatate was 29.6 GBq (800 mCi). Baseline tumor assessments were obtained in 39% of patients. The investigator assessed ORR was 16% (95% CI 13, 20) in the 360 patients with GEP-NETs. Three complete responses were observed (< 1%). Median DoR in the 58 responding patients was 35 months (95% CI: 17, 38).

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
79101	Radiopharmaceutical therapy, by intravenous administration
84307	Somatostatin
HCPCS codes covered if selection criteria are met:
A9513	Lutetium lu 177, dotatate, therapeutic, 1 millicurie
Other HCPCS codes related to the CPB:
J1930	Injection, lanreotide, 1 mg
J2353	Injection, octreotide, depot form for intramuscular injection, 1 mg
J2354	Injection, octreotide, nondepot form for subcutaneous or intravenous injection, 25 mcg
ICD-10 codes covered if selection criteria are met:
C25.4	Malignant neoplasm of endocrine pancreas
C7A.00 - C7A.8	Malignant neuroendocrine tumors
C7B.00 – C7B.09	Secondary carcinoid tumors
C74.10	Malignant neoplasm of medulla of unspecified adrenal gland [pheochromocytoma]
D44.7	Neoplasm of uncertain behavior of aortic body and other paraganglia [paraganglioma]
E34.0	Carcinoid syndrome

The above policy is based on the following references: