Commercial

Medical Policy

Notification

Lutathera® (Lutetium Lu 177 Dotatate) (Independence Administrators)

Notification Issue Date:

This version of the policy will become effective 07/01/2019.

The following new policy has been developed to communicate the Company's coverage criteria for Lutathera® (Lutetium Lu 177 Dotatate).

Title:

Lutathera® (Lutetium Lu 177 Dotatate) (Independence Administrators)

Policy #:

08.01.57a

Policy

This policy only applies to members for whom Independence Administrators serves as the claims administrator and whose group has not enrolled in the UM vendor program. For those groups who have been given the option to enroll in the UM vendor program, this policy is no longer applicable upon their renewal effective date. Individual member benefits must be verified before/prior to providing services.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

MEDICALLY NECESSARY

Lutathera® (Lutetium Lu 177

Dotatate) is considered medically necessary and, therefore, covered in adult and pediatric individuals ages 12 years and older, for the treatment of low- (G1), intermediate- (G2), or high-grade (G3) well-differentiated neuroendocrine tumors (NET) who have progressed on somatostatin analogues (SSAs) when BOTH of the following are met:

ONE of the following indications:

Inoperable or metastatic somatostatin receptor–positive gastroenteropancreatic NETs (GEP-NETs) of the pancreas, foregut, midgut, and hindgut
Inoperable or metastatic somatostatin receptor–positive bronchopulmonary or thymic tumors or pheochromocytomas and paragangliomas

ALL of the following are met:

For well-differentiated G1 or G2 NETs with a Ki67 <20 percent OR well-differentiated G3 NETs with a Ki-67 <55 percent
Positive somatostatin receptor scintigraphy with correlative magnetic resonance imaging (MRI) or computed tomography (CT) imaging of metastatic measurable disease or 68-Ga-dotatate positron emission tomography (PET) scan positive for metastatic disease
In the absence of metastatic disease, a surgical or medical consult documenting the reason for inoperability
Progression of disease following treatment with SSA therapy
Serum creatine <1.7 mg/dl or creatinine clearance is <50 ml/min
Hemoglobin >8 g/dL; white blood cells 2000 mm³ or higher; platelets 75,000 mm³ or higher

EXPERIMENTAL/INVESTIGATIONAL

Lutathera (Lutetium Lu 177

Dotatate) is considered experimental/investigational and, therefore, not covered for poorly differentiated tumors and for G3 well-differentiated tumors with a Ki-67 of 55 percent or greater.

Lutathera (Lutetium Lu 177

Dotatate) is considered experimental/investigational and, therefore, not covered in all other situations in which the above criteria are not met because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the health care professional's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

The recommended dose of Lutathera (Lutetium Lu 177

dotatate) is 7.4

GBq (200

mCi) every 8 weeks for a total of four doses.

There are concerns regarding the competition between somatostatin analogues and Lutathera (Lutetium Lu 177

dotatate) for somatostatin receptor binding. Therefore, the following is recommended:

Do not administer long-acting somatostatin analogues for 4 to 6 weeks prior to each Lutathera (Lutetium Lu 177 dotatate) dose.
Discontinue short-acting somatostatin analogues at least 24 hours before each Lutathera (Lutetium Lu 177 dotatate) dose.
Both long-acting and short-acting somatostatin analogues can be resumed 4 to 24 hours after each Lutathera (Lutetium Lu 177 dotatate) dose.

Lutathera (Lutetium Lu 177

dotatate) should be discontinued permanently if the individual develops recurrent hepatotoxicity defined as bilirubinemia greater than 3 times the upper limit of normal (grade 3 or 4), or hypoalbuminemia less than 30 g/L with an international normalized ratio (INR) greater than 1.5.

Lutathera (Lutetium Lu 177

dotatate) should be discontinued permanently if the individual develops recurrent renal toxicity defined as a creatinine clearance of less than 40 mL/min (calculated using Cockcroft-Gault equation with actual body weight), or 40 percent increase from baseline serum creatinine, or 40 percent decrease from baseline creatinine clearance (calculated using Cockcroft-Gault equation with actual body weight).

Common Toxicity Criteria for Adverse Events

Grade	Description
1	Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
2	Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living and refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
3	Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living and refer to refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
4	Life-threatening consequences; urgent intervention indicated.
5	Death related to adverse event.

KARNOFSKY PERFORMANCE STATUS (KPS)

A scale measuring the ability of individuals to perform ordinary tasks. KPS scores range from 0 to 100; a higher score means a person is better able to carry out daily activities.

KPS	Definition
100	Normal; no complaint; no evidence of disease
90	Able to carry on normal activity; minor signs of symptoms of disease
80	Normal activity with effort; some sign or symptoms of disease
70	Cares for self; unable to carry on normal activity or do active work
60	Requires occasional assistance, but is able to care for most personal needs
50	Requires considerable assistance and frequent medical care
40	Disabled; requires special care and assistance
30	Severely disabled; hospitalization is indicated, although death not imminent
20	Very sick; hospitalization necessary; active support treatment is necessary
10	Moribund; fatal processes progressing rapidly
0	Dead

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, Lutathera (Lutetium Lu 177

dotatate) is covered under the medical benefits of the Company’s products when the medical necessity criteria and Dosing and Frequency Requirements listed in this medical policy are met.

Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Lutathera (lutetium Lu 177

dotatate) was approved by the FDA on January 26, 2018, for the treatment of somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors, including foregut, midgut, and hindgut neuroendocrine tumors in adults. Supplemental approvals for Lutathera (lutetium Lu 177

dotatate) have since been issued by the FDA.

PEDIATRIC USE
Lutathera (Lutetium Lu 177

dotatate) is not indicated for use in pediatric individuals less than 12 years of age.

Description

NEUROENDOCRINE TUMORS

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that originate from the neuroendocrine cells in the diffuse neuroendocrine system anywhere in the body but more commonly in the gastrointestinal tract and the respiratory system. Approximately 61 percent of all NETs originate from the gastrointestinal system or pancreas and are referred to as gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Lung NETs may also be referred to as pulmonary NETs, pulmonary carcinoids, or bronchopulmonary NETs. GEP-NETs may further be characterized as functional or nonfunctional based on whether they secrete hormones (functional) that result in clinical symptoms, particularly serotonin, which results in “carcinoid syndrome” that is characterized by flushing and diarrhea, or not (nonfunctional).

NETs are classified as orphan diseases by the US Food and Drug Administration (FDA). Based on an analysis of Surveillance, Epidemiology, and End Results Program registry data from 1973 to 2012 (Dasari et al., 2017), the overall incidence of NETs has been reported to be approximately 6.98 per 100,000 people per year.

DIAGNOSIS

NETs are not easy to diagnose because the condition is rare. Symptoms are often nonspecific or mimic other disorders such as irritable bowel syndrome (in the case of GEP-NETs) or asthma (in the case of a lung NET) resulting in an average diagnosis delay of 5 to 7 years after symptom onset (Frilling et al., 2012). In many cases, diagnosis is incidental to imaging for other unrelated cause. Most GEP-NETs express somatostatin receptors that can be imaged using a radiolabeled form of the somatostatin analogue octreotide (e.g.,¹¹¹In pentetreotide).

TREATMENT APPROACH

There is a general lack of prospective data to guide the treatment of NETs. GEP-NETs are chemotherapy-responsive neoplasms, and platinum-based chemotherapy represents the backbone of treatment for both early and advanced-stage tumors (Sorbye et al., 2014). Surgery alone, or followed by chemotherapy, along with treatment of hormone-related symptoms, may be the initial approach for localized disease. For asymptomatic individuals with slow progression, observation with routine surveillance imaging is an option. The prognosis for individuals with metastatic well-differentiated GEP-NETs is highly variable. Based on retrospective analyses of large databases, the prognosis for individuals with metastatic GEP-NETs is variable. The median overall survival (OS) (from diagnosis) for individuals with metastatic pancreatic neuroendocrine tumors (pNETs) has been reported to range from 2 to 5.8 years (Yao et al., 2008; Strosberg et al., 2009), while the median OS for small bowel NETs has been reported as 7.9 years (Ter-Minassian et al., 2013).

PHARMACOLOGICAL TREATMENT
First-Line Treatment Options

Somatostatin Analogues (Octreotide and Lanreotide)

Somatostatin is a peptide that binds to somatostatin receptors that are expressed in a majority of carcinoid tumors and inhibits the secretion of a broad range of hormones. Somatostatin analogues (e.g., octreotide, lanreotide) were initially developed to manage the hormonal symptoms related to NETs. They were found to exert antiproliferative activity, and clinical studies have demonstrated prolonged progression-free survival (PFS) in individuals with NETs treated with somatostatin analogues (Rinke et al., 2009; Caplin et al., 2015). However, the role of somatostatin analogues in individuals with nonfunctioning/nonsecretory NETs is unclear (Ramage et al., 2012).

Commercially available long-acting release forms of octreotide and lanreotide (e.g., Sandostatin LAR, Somatuline Depot), which are administered intramuscularly on a monthly basis, have largely eliminated the need for daily self-injection of short-acting subcutaneous formulations (Öberg et al., 2015; O'Toole et al., 2000).

Second-Line Treatment Options

For years, there were no data to support a specific sequence of therapies and only streptozocin, everolimus, and sunitinib were FDA approved for the treatment of pNETs. Treatment options have now increased as research on the treatment of pNETs has continued to evolve.

Mechanistic Target of Rapamycin Inhibitors

The mechanistic (or mammalian) target of rapamycin (mTOR) is an enzyme that regulates cell metabolism and proliferation in response to environmental stimuli. It is upregulated in a variety of malignancies in response to stimulation by growth factors and cytokines. Whole-exome genomic analysis has shown that approximately 15 percent of pNETs are associated with somatic variants in genes associated with the mTOR pathway (Strosberg et al,, 2013). Everolimus, an oral mTOR inhibitor, has been shown to significantly prolong PFS versus placebo in individuals with pNETs (RADIANT-3 trial) (Yao et al., 2011). Everolimus had the same results for nonfunctional lung and gastrointestinal NETs (RADIANT-4 trial) (Yao et al., 2016). Note that everolimus is approved by the FDA for adults with progressive NETs of pancreatic origin and adults with progressive, well-differentiated, nonfunctional NETs of gastrointestinal or lung origin that are unresectable, locally advanced, or metastatic. The RADIANT-2 trial, comprising individuals with progressive advanced NETs associated with carcinoid syndrome, failed to show a statistically significant improvement in the primary endpoint of PFS (Pavel et al., 2011).

Tyrosine Kinase Receptor Inhibitors

NETs frequently overexpress the vascular endothelial growth factor (VEGF) ligand and receptor (VEGFR). Sunitinib is a tyrosine kinase inhibitor that targets multiple cell-surface proteins that help propagate cancer growth including VEGFRs 1, 2, and 3 (Strosberg et al., 2013). It has been shown that daily sunitinib at a dose of 37.5 mg improves PFS, OS, and the objective response rate (ORR) as compared with placebo among individuals with advanced pNETs (Raymond et al., 2011). Note that sunitinib is FDA approved for the treatment of progressive, well-differentiated pNETs in individuals with unresectable locally advanced or metastatic disease.

Chemotherapy

Response to chemotherapy for advanced NETs of the gastrointestinal tract and lung is highly variable and, at best, modest. Tumor response rates are generally low and no PFS benefit has been clearly demonstrated. Therefore, the careful selection of individuals is critical to maximize the chance of response and avoid unnecessary toxicity. In advanced NETs, platinum-based regimens are generally used. They include cisplatin and etoposide (most widely used), carboplatin and etoposide, 5-fluorouracil, capecitabine, dacarbazine, oxaliplatin, streptozocin, and temozolomide (Garcia-Carbonero et al., 2016).

Lutetium 177 Dotatate

Lutetium 177 dotatate is a radiolabeled-somatostatin analogue that binds to somatostatin receptor–expressing cells, including malignant somatostatin receptor–positive tumors. It is then internalized and beta particle emission from lutetium 177 induces cellular damage by formation of free radicals in somatostatin receptor–positive and neighboring cells.

Lutathera (Lutetium Lu 177 dotatate) [Advanced Accelerator Applications (AAA), New York, NY] received FDA approval on January 26, 2018. Lutathera is approved for the treatment of somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors, in adults. Lutathera is the first available FDA-approved peptide receptor radionuclide therapy (PRRT), a form of treatment comprising a targeting molecule that carries a radioactive component. Currently, there are no other radiolabeled somatostatin analogue conjugates that are FDA approved for therapy.

FDA approval for Lutathera (Lutetium Lu 177 dotatate) was based on the results from two studies: NETTER-1 (Strosberg et al., 2017; FDA, 2018) and ERASMUS (Kwekkeboom DJ, 2008; Brabander T, 2017; FDA, 2018).

NETTER-1 was an open-label randomized controlled trial (RCT) that compared treatment with Lutathera (Lutetium Lu 177 dotatate) to octreotide in individuals with inoperable, progressive somatostatin receptor–positive midgut carcinoid tumors. Eligibility included a Ki-67 index 20 percent or less, confirmed presence of somatostatin receptors on all lesions (octreoscan uptake greater than or equal to that of the normal liver), Karnofsky Performance Status score of 60 or more, creatinine clearance of 50 mL/min or more, no prior treatment with PRRT, and no prior external radiation therapy to more than 25 percent of the bone marrow. Randomization was stratified by octreoscan tumor uptake score (grade 2, 3, or 4) and the length of time that individuals had been on the most recent constant dose of octreotide prior to randomization (≤6 months or >6 months). The primary outcome was PFS. A total of 229 individuals were randomly assigned to either Lutathera (Lutetium Lu 177 dotatate) (7.4 GBq [200 mCi]) for four infusions every 8 weeks concurrently with 30 mg of long-acting octreotide (n=116) or 60 mg of high-dose octreotide alone (n=113). At the data-cutoff date for the primary analysis, PFS at 20 months was 65.2 percent (95 percent confidence interval [CI], 50.0–76.8) in the Lutathera (Lutetium Lu 177 dotatate) group and 10.8 percent (95 percent CI, 3.5–23.0) in the control group. The response rate was 18 percent in the Lutathera group versus 3 percent in the control group (P<0.001). In the planned interim analysis of OS, 14 deaths occurred in the Lutathera (Lutetium Lu 177 dotatate) group and 26 in the control group ([hazard ratio, 0.40]; P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1 percent, 2 percent, and 9 percent, respectively, of individuals in the Lutathera (Lutetium Lu 177 dotatate) group as compared with no individuals in the control group, with no evidence of renal toxic effects during the observed time frame. Adverse events (AEs) that were considered by the investigator to be related to trial treatment occurred in 129 individuals: 95 individuals (86 percent) in the Lutathera (Lutetium Lu 177 dotatate) group and 34 individuals (31 percent) in the control group. The most common AEs among individuals in the Lutathera (Lutetium Lu 177 dotatate) group were nausea (65 individuals [59 percent]) and vomiting (52 individuals [47 percent]). Other common AEs in the Lutathera (Lutetium Lu 177 dotatate) group included fatigue or asthenia, abdominal pain, and diarrhea.

The ERASMUS study was a single-center, retrospective, case series that included 1214 individuals with somatostatin receptor–positive NETs with various tumor sites who received Lutathera (Lutetium Lu 177 dotatate), 610 of whom were treated with a cumulative dose of at least 100 mCi (3.7 GBq) for safety analysis. Another subgroup of 443 Dutch individuals were treated with a cumulative dose of at least 600 mCi (22.2 GBq). The ORR of the total group of individuals was 39 percent. Stable disease (SD) was reached in 43 percent of individuals. PFS and OS for all individuals with NETs were 29 months (95 percent CI, 26–33 months) and 63 months (95 percent CI, 55–72 months). Long-term toxicity included acute leukemia in four individuals (0.7 percent) and myelodysplastic syndrome in nine individuals (1.5 percent). No therapy-related long-term renal or hepatic failure occurred.

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Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

MEDICALLY NECESSARY

C25.4	Malignant neoplasm of endocrine pancreas
C74.11	Malignant neoplasm of medulla of right adrenal gland
C74.12	Malignant neoplasm of medulla of left adrenal gland
C74.91	Malignant neoplasm of unspecified part of right adrenal gland
C74.92	Malignant neoplasm of unspecified part of left adrenal gland
C75.5	Malignant neoplasm of aortic body and other paraganglia
C7A.00	Malignant carcinoid tumor of unspecified site
C7A.010	Malignant carcinoid tumor of the duodenum
C7A.011	Malignant carcinoid tumor of the jejunum
C7A.012	Malignant carcinoid tumor of the ileum
C7A.019	Malignant carcinoid tumor of the small intestine, unspecified portion
C7A.020	Malignant carcinoid tumor of the appendix
C7A.021	Malignant carcinoid tumor of the cecum
C7A.022	Malignant carcinoid tumor of the ascending colon
C7A.023	Malignant carcinoid tumor of the transverse colon
C7A.024	Malignant carcinoid tumor of the descending colon
C7A.025	Malignant carcinoid tumor of the sigmoid colon
C7A.026	Malignant carcinoid tumor of the rectum
C7A.029	Malignant carcinoid tumor of the large intestine, unspecified portion
C7A.090	Malignant carcinoid tumor of the bronchus and lung
C7A.091	Malignant carcinoid tumor of the thymus
C7A.092	Malignant carcinoid tumor of the stomach
C7A.093	Malignant carcinoid tumor of the kidney
C7A.094	Malignant carcinoid tumor of the foregut, unspecified
C7A.095	Malignant carcinoid tumor of the midgut, unspecified
C7A.096	Malignant carcinoid tumor of the hindgut, unspecified
C7A.098	Malignant carcinoid tumors of other sites
C7A.1	Malignant poorly differentiated neuroendocrine tumors
C7A.8	Other malignant neuroendocrine tumors
C7B.00	Secondary carcinoid tumors, unspecified site
C7B.01	Secondary carcinoid tumors of distant lymph nodes
C7B.02	Secondary carcinoid tumors of liver
C7B.03	Secondary carcinoid tumors of bone
C7B.04	Secondary carcinoid tumors of peritoneum
C7B.09	Secondary carcinoid tumors of other sites
C7B.8	Other secondary neuroendocrine tumors
D3A.00	Benign carcinoid tumor of unspecified site
D3A.010	Benign carcinoid tumor of the duodenum
D3A.011	Benign carcinoid tumor of the jejunum
D3A.012	Benign carcinoid tumor of the ileum
D3A.019	Benign carcinoid tumor of the small intestine, unspecified portion
D3A.020	Benign carcinoid tumor of the appendix
D3A.021	Benign carcinoid tumor of the cecum
D3A.022	Benign carcinoid tumor of the ascending colon
D3A.023	Benign carcinoid tumor of the transverse colon
D3A.024	Benign carcinoid tumor of the descending colon
D3A.025	Benign carcinoid tumor of the sigmoid colon
D3A.026	Benign carcinoid tumor of the rectum
D3A.029	Benign carcinoid tumor of the large intestine, unspecified portion
D3A.090	Benign carcinoid tumor of the bronchus and lung
D3A.091	Benign carcinoid tumor of the thymus
D3A.092	Benign carcinoid tumor of the stomach
D3A.094	Benign carcinoid tumor of the foregut, unspecified
D3A.095	Benign carcinoid tumor of the midgut, unspecified
D3A.096	Benign carcinoid tumor of the hindgut, unspecified
D3A.098	Benign carcinoid tumors of other sites
D3A.8	Other benign neuroendocrine tumors
E16.1	Other hypoglycemia
E16.3	Increased secretion of gastrin
E16.8	Other specified disorders of pancreatic internal secretion
E34.00	Carcinoid syndrome, unspecified
E34.01	Carcinoid heart syndrome
E34.09	Other carcinoid syndrome

HCPCS Level II Code Number(s)

A9513 Lutetium Lu 177, dotatate, therapeutic, 1 mC i

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 08.01.57a:

01/27/2025

This version of the policy will become effective 01/27/2025.

Use in children ages 12 and older was added to this policy in accordance with the US Food and Drug Administration (FDA) labeling (04/23/2024).

The following indications have been added to this policy:

Use of Lutathera® (Lutetium Lu 177 Dotatate) for pheochromocytoma and paraganglioma

The following ICD-10 codes have been added to this policy:

E16.1 Other hypoglycemia

E16.3 Increased secretion of gastrin

E16.8 Other specified disorders of pancreatic internal secretion

E34.00 Carcinoid syndrome, unspecified

E34.01 Carcinoid heart syndrome

E34.09 Other carcinoid syndrome

The following ICD-10 codes that represent non-specific laterality have been removed from this policy:

C74.10 Malignant neoplasm of medulla of unspecified adrenal gland

C74.90 Malignant neoplasm of unspecified part of unspecified adrenal gland

Revisions From 08.01.57:

11/01/2023	This policy has been reissued in accordance with the Company's annual review process.
07/01/2022	The policy has been reviewed and reissued to communicate the Company's continuing position on Lutathera® (Lutetium Lu 177 Dotatate). Effective July 1, 2022, the policy disclaimer was revised to communicate: This policy only applies to members for whom Independence Administrators serves as the claims administrator and whose group has not enrolled in the UM vendor program. For those groups who have been given the option to enroll in the UM vendor program, this policy is no longer applicable upon their renewal effective date. Individual member benefits must be verified before/prior to providing services.
06/16/2021	This policy has been reissued in accordance with the Company's annual review process.
10/07/2020	This policy has been reissued in accordance with the Company's annual review process.
07/01/2019	The following new policy has been developed to communicate the Company's coverage criteria for Lutathera® (Lutetium Lu 177 Dotatate).

Version Effective Date:

1/27/2025

Version Issued Date:

1/27/2025

Version Reissued Date: