Therapeutic Radiopharmaceuticals for Neuroendocrine Tumors - CAM 60160

Description
Radiopharmaceuticals are composed of a radioisotope bond to an organic molecule and are used for diagnostic and therapeutic purposes. The organic molecule conveys the radioisotope to specific organs, tissues, or cells. Lutetium 177 (Lu 177) dotatate, classified as peptide receptor radionuclide therapy is a radiolabeled-somatostatin analogue that binds to somatostatin receptor expressing cells, including malignant somatostatin receptor-positive tumors such as neuroendocrine tumors. It is then internalized and beta particle emission from Lu 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive and neighboring cells.

Summary of Evidence
For individuals with a treatment-refractory gastroenteropancreatic neuroendocrine tumor including foregut, midgut, and hindgut tumors who receive Lu 177 dotatate, the evidence includes a randomized, open-labeled trial, a multicenter registry, and a retrospective cohort study. Relevant outcomes are overall survival (OS), disease-specific survival, quality of life, and treatment-related mortality and morbidity. The randomized controlled trial results showed a consistent statistically significant and clinically meaningful effect on overall response rate, progression-free survival (PFS), and OS among patients treated with Lu 177 dotatate compared to those treated with long-acting octreotide. The results of the retrospective studies were consistent with the treatment effect observed in the randomized controlled trial and provide additional support for a clinical benefit of Lu 177 dotatate in patients with a gastroenteropancreatic neuroendocrine tumor. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with treatment-refractory bronchopulmonary or thymus neuroendocrine tumors who receive Lu 177 dotatate, the evidence includes a retrospective cohort study, a multicenter registry, and a bicenter, retrospective case series. Relevant outcomes are OS, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The retrospective cohort study included a small number of patients with bronchopulmonary (n=23) or thymus (n=2) neuroendocrine tumors. Among the 23 patients with bronchopulmonary neuroendocrine tumor, the median PFS was 20 months, the median time to progression was 25 months, and median OS was 52 months. Stratified results of 2 patients with thymus neuroendocrine tumors were not reported. The U.S. Food and Drug Administration in its review of the ERASMUS study for patients with gastroenteropancreatic neuroendocrine tumor concluded that time to event analyses such as time to progression, PFS, and OS were not interpretable in the context of the single-arm ERASMUS study because of missing data at baseline, high dropout rates and open-label design of the study. The multicenter registry included 58 patients with bronchopulmonary tumors and reported 0 complete responses, 14 partial responses, a median PFS of 17.6 months, and a median OS of 44.8 months. The case series evaluated 48 patients with predominantly atypical carcinoid bronchopulmonary tumors, finding a median PFS and OS of 23 months and 59 months, respectively. Of note, despite the current evidence base, National Comprehensive Cancer Network guidelines give a category 2A recommendation for use of Lu 177 dotatate for the treatment of bronchopulmonary and thymic locoregional advanced or distant metastases neuroendocrine tumors if there are clinically significant tumor burden and low grade (typical) tumor or evidence of progression or intermediate grade (atypical) tumor. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy and who receive Lu 177 dotatate, the evidence includes systematic reviews and meta-analyses of single-arm studies, a multicenter registry, and 2 case series. Relevant outcomes include OS, disease-specific survival, quality of life, and treatment-related mortality and morbidity. One meta-analysis reported a pooled overall tumor response rate of 26% (95% confidence interval [CI], 18% to 35%). Another meta-analysis found improved PFS with Lu 177 dotatate compared to iobenguane I 131 among studies enriched with pheochromocytomas. One retrospective case series reported that 8/13 patients were able to reduce dosages of antihypertensive treatment at 3 months. Disease regression was reported in 5/14 patients with available computed tomography imaging. Out of 16 patients with available iobenguane scans, 10 patients had mild or negative uptake. However, patient outcomes were not stratified by iobenguane uptake status. No prospective studies directly comparing Lu 177 dotatate to iobenguane I 131 or assessing Lu 177 dotatate response in a fully non-iobenguane avid population were identified. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Background
Neuroendocrine Tumors
NNeuroendocrine tumors 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% of all neuroendocrine tumors originate from the gastrointestinal system or pancreas and are referred to as gastroenteropancreatic neuroendocrine tumors. Gastroenteropancreatic neuroendocrine tumors may further be characterized as functional or nonfunctional based on whether they secrete hormones that result in clinical symptoms particularly serotonin, which results in "carcinoid syndrome" that is characterized by flushing and diarrhea. Lung neuroendocrine tumors may also be referred to as pulmonary neuroendocrine tumors, pulmonary carcinoids, or bronchopulmonary neuroendocrine tumors. Bronchopulmonary neuroendocrine tumors comprise approximately 20% of all lung cancers and are classified into 4 subgroups: typical carcinoid tumor, atypical carcinoid tumor, large-cell neuroendocrine carcinoma, and small-cell lung carcinoma.2, Less than 5% of bronchopulmonary neuroendocrine tumors exhibit hormonally-related symptoms such as carcinoid syndrome. Neuroendocrine tumors of the thymus account for only 5% of all tumors in the thymus and mediastinum.³,

Neuroendocrine tumors are classified as orphan diseases by the U.S. Food and Drug Administration (FDA). Based on an analysis of Surveillance, Epidemiology, and End Results Program registry data from 1973 to 2012, the overall incidence of neuroendocrine tumors has been reported to be in the range of 6.98 per 100,000 people per year.^4,

Diagnosis
Neuroendocrine tumors are not easy to diagnose because of the rarity of the condition. Symptoms are often nonspecific or mimic other disorders such as irritable bowel syndrome (in the case of gastroenteropancreatic neuroendocrine tumors) or asthma (in the case of a lung neuroendocrine tumors) resulting in an average diagnosis delay of 5 to 7 years after symptom onset.^5, In many cases, diagnosis is incidental to imaging for other unrelated causes. Most gastroenteropancreatic neuroendocrine tumors express somatostatin receptors that can be imaged using a radiolabeled form of the somatostatin analogue octreotide (eg, 111In pentetreotide).

Treatment Approach
There is a general lack of prospective data to guide the treatment of neuroendocrine tumors. Gastroenteropancreatic neuroendocrine tumors are chemotherapy-responsive neoplasms, and platinum-based chemotherapy represents the backbone of treatment for both early and advanced-stage tumors.^6, Surgery alone or followed by chemotherapy along with treatment of hormone-related symptoms may be the initial approach for localized disease. For asymptomatic patients with slow progression, observation with routine surveillance imaging is an option. The prognosis for patients with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors is highly variable. The median overall survival (from diagnosis) for patients with metastatic pancreatic neuroendocrine tumors has been reported to range from 2 to 5.8 years^7, while the median overall survival for small bowel neuroendocrine tumors has been reported as 7.9 years.^8,

Pharmacologic 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 (eg, octreotide, lanreotide) were initially developed to manage the hormonal symptoms related to neuroendocrine tumors; they were found to exert antiproliferative activity, and clinical studies have demonstrated prolonged progression-free survival (PFS) in patients with neuroendocrine tumors treated with somatostatin analogues.[Rinke A, Müller HH, Schade-Brittinger C, et a.... 27(28): 4656-63. PMID 19704057]9, However, the role of somatostatin analogues in patients with nonfunctioning neuroendocrine tumors is unclear.^10,

Commercially available long-acting release forms of octreotide and lanreotide (eg, 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.^11,12,

Second-Line Treatment Options
Currently, there are no data to support a specific sequence of therapies and only streptozocin, everolimus, and sunitinib are FDA-approved for the treatment of pancreatic neuroendocrine tumors.

Mechanistic Target of Rapamycin Inhibitors
The mechanistic target of rapamycin 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% of pancreatic neuroendocrine tumors are associated with somatic variants in genes associated with the mechanistic target of rapamycin pathway.^13, Everolimus, an oral mechanistic target of rapamycin inhibitor, has been shown to significantly prolong PFS versus placebo in patients with pancreatic neuroendocrine tumors (RADIANT-3 trial),^14, and lung and gastrointestinal neuroendocrine tumors nonfunctional (RADIANT-4 trial).^15, Everolimus is approved by the FDA for adults with progressive neuroendocrine tumors of pancreatic origin and adults with progressive, well-differentiated, nonfunctional neuroendocrine tumors of gastrointestinal or lung origin that are unresectable, locally advanced or metastatic. The RADIANT-2 trial, conducted in patients with progressive advanced neuroendocrine tumors associated with carcinoid syndrome, failed to show a statistically significant improvement in the primary endpoint of PFS.^16,

Tyrosine Kinase Receptor Inhibitors
Neuroendocrine tumors frequently overexpress the vascular endothelial growth factor and receptor. Sunitinib is a multi-targeted tyrosine kinase inhibitor that targets multiple signaling pathways and growth factors and receptors including vascular endothelial growth factor and receptor 1, 2, and 3.^13, It has been shown that daily sunitinib at a dose of 37.5 mg improves PFS, overall survival, and the overall response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors.^17, Sunitinib is FDA-approved for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.

Chemotherapy
Response to chemotherapy for advanced neuroendocrine tumors 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 patients is critical to maximize the chance of response and avoid unnecessary toxicity. In advanced neuroendocrine tumors, 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.^18,

Peptide Receptor Radionuclide Therapy: 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.

Pheochromocytoma and Paraganglioma
Pheochromocytoma and paraganglioma are rare neuroendocrine tumors that originate from the chromaffin cells of the adrenal glands.^19,Chromaffin cells produce catecholamine neurotransmitters, such as epinephrine, norepinephrine, and dopamine. Compared to the normal chromaffin cells, pheochromocytomas and paraganglioma express high levels of the norepinephrine transporter on their cell surfaces. The excess amount of norepinephrine causes the clinical signs and symptoms like hypertension, headache, sweating, tremor, and palpitation. While most pheochromocytoma and paraganglioma are non-malignant (non-metastatic), about 10% of pheochromocytoma are malignant and about 25% of paraganglioma are malignant (metastatic) which can spread to other parts of the body, such as the liver, lungs, bone, or distant lymph nodes.[Adjallé R, Plouin PF, Pacak K, et al. Treatme.... ; 41(9): 687-96. PMID 19672813]

The average age of diagnosis is 43 years old. The estimated annual incidence of pheochromocytoma and paraganglioma is approximately 1 in 300,000 population.^20, The 5-year mortality rates for patients with metastatic pheochromocytoma and paraganglioma has been reported as 37% depending on the primary tumor site and sites of metastases.^21, In addition, the medical overall and disease-specific survival were 24.6 and 33.7 years for pheochromocytoma and paraganglioma.^22,

Diagnosis
The initial diagnosis of pheochromocytomas and paragangliomas includes biochemical testing, such as blood tests and urinalysis which measure the levels of metanephrine, a catecholamine metabolite in blood and urine. Imaging may be used to detect the location and size of tumors within the organs or tissues. Other advanced diagnostic procedures, such as 123I-metaiodobenzylguanidine (MIBG) scintigraphy, octreotide scan, and fluorodeoxyglucose-positron emission tomography scan are used to further determine whether the tumors are malignant and metastatic.^19,

Certain genetic disorders such as multiple endocrine neoplasia 2 syndrome, von Hippel-Lindau syndrome, Neurofibromatosis type 1, and hereditary paraganglioma syndrome23, are considered risk factors for pheochromocytomas and paragangliomas and therefore genetic testing is recommended for all patients with pheochromocytoma or paraganglioma.^19,

Treatment Approach
Surgical resection is mostly reserved for benign tumors as curative surgical resection is nearly impossible in metastatic disease. For patients with local, unresectable disease, palliative external beam radiotherapy may be used with or without cytoreductive resection for patients with bone metastases.^24,

Peptide Receptor Radionuclide Therapy
Lutetium 177 dotatate has been used off-label in this population. There is limited evidence for chemotherapy. In the case of unresectable progressive pheochromocytoma or paraganglioma, combination use of cyclophosphamide, dacarbazine, vincristine, doxorubicin, temozolomide, and thalidomide have been used.^25,26, Tyrosine kinase receptor inhibitors such as sunitinib have also been used.^27,

Regulatory Status
On January 26, 2018, Lutathera® (lutetium 177 dotatate) was approved by the FDA for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, including foregut, midgut, and hindgut neuroendocrine tumors in adults.

On May 5, 2022, Novartis announced that it had temporarily suspended production of Lutathera at production sites in Ivrea, Italy and Millburn, New Jersey out of an abundance of caution as a result of potential quality issues identified in its manufacturing processes.^28, This production suspension will impact both commercial and clinical trial supply in the US and Canada. At the time of announcement, the company expected resolution of these issues and resumption of some product supply within 6 weeks, subject to confirmation via an ongoing review. Novartis noted that there is currently no indication of risk to patients from doses previously produced at these sites, but has notified treatment sites to closely monitor patients. Production of Lutathera was resumed ahead of schedule in early June 2022.^29,

Policy
Lutetium 177
Initial Treatment

Lutetium 177 (Lu 177) dotatate treatment is considered MEDICALLY NECESSARY when conditions 1 through 8 are met:

Individual is an adult (≥18 years of age).
Individual has documented low or intermediate grade (Ki-67 index ≤20%), locally advanced or metastatic, gastroenteropancreatic (including foregut, midgut, and hindgut) or metastatic bronchopulmonary or thymus neuroendocrine tumor.
Individual has documented somatostatin receptor expression of a neuroendocrine tumor as detected by somatostatin receptor-based imaging (see Policy Guidelines).
Individual has documented disease progression while on octreotide long-acting release or lanreotide therapy.
Individual is not receiving long-acting somatostatin analogues ( eg, octreotide long-acting release or lanreotide) for at least 4 weeks prior to initiating Lu 177 dotatate and has discontinued use of short-acting octreotide for at least 24 hours prior to initiating Lu 177 dotatate.
Individual does not have severe renal impairment (creatinine clearance <30 mL/min).
Individual has adequate bone marrow and hepatic function as determined by the treating physician.
Individual has documented Karnofsky Performance Status score of 60 or greater.

Continuation of Treatment

Continuation of Lu 177 dotatate is considered MEDICALLY NECESSARY when conditions 1 through 5 are met:

No recurrent grade 2, 3, or 4 thrombocytopenia (see Table PG1).
No recurrent grade 3 or 4 anemia and neutropenia (see Table PG1).
No recurrent hepatotoxicity (see definition of hepatotoxicity in the Policy Guidelines section).
No recurrent grade 3 or 4 nonhematologic toxicity (see Table PG1).
No renal toxicity requiring a treatment delay of 16 weeks or longer (see definition of renal toxicity in the Policy Guidelines section).

Lu 177 dotatate treatment is considered investigational/unproven therefore NOT MEDICALLY NECESSARY in all other situations in which the above criteria are not met.

Lu 177 dotatate treatment greater than a total of 4 doses as per the U.S. Food and Drug Administration (FDA)-approved regimen is considered investigational/unproven therefore NOT MEDICALLY NECESSARY.

Lu 177 dotatate treatment is considered investigational/unproven therefore NOT MEDICALLY NECESSARY for all other indications including pheochromocytoma and paraganglioma.

See Policy Guidelines below.

Policy Guidelines
Somatostatin Receptor-Based Imaging
Preferred somatostatin receptor (SSTR)-based imaging options to assess receptor status include SSTR-positron emission tomography (PET)/computed tomography (CT) or SSTR-PET/magnetic resonance imaging (MRI). Octreotide single-photon emission computed tomography (SPECT)/CT may be used only if SSTR-PET is not available, as it is much less sensitive for defining SSTR-positive disease. Appropriate SSTR-PET radiotracers include Gallium 68 (Ga 68) dotatate, Ga 68 dotatoc, or Copper 64 (Cu 64) dotatate. SSTR-positive status is confirmed when uptake in measurable lesions is greater than the liver.

Lutetium 177
The recommended dose of lutetium 177 (Lu 177) dotatate is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses.

There are theoretical concerns regarding the competition between somatostatin analogues and 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 Lu 177 dotatate treatment.
Stop short-acting somatostatin analogues 24 hours before each Lu 177 dotatate treatment.
Both long-acting and short-acting somatostatin analogues can be resumed 4 to 24 hours after each Lu 177 dotatate treatment.

Lu 177 dotatate is a radiopharmaceutical and should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.

Lu 177 dotatate should be discontinued permanently if the patient develops 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 a decreased prothrombin ratio less than 70%.

Lu 177 dotatate should be discontinued permanently if patient develops renal toxicity defined as a creatinine clearance of less than 40 mL/min calculated using Cockcroft-Gault equation with actual body weight, or 40% increase in baseline serum creatinine, or 40% decrease in baseline creatinine clearance calculated using Cockcroft-Gault equation with actual body weight.

Table PG1 describes the grading of severity used in the Common Toxicity Criteria for Adverse Events (version 4.03).

Table PG1. Common Toxicity Criteria for Adverse Events, Version 4.03

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 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.

Coding
See the Codes table for details.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Gastroenteropancreatic Neuroendocrine Tumors including Foregut, Midgut, and Hindgut Tumors
Clinical Context and Therapy Purpose
The purpose of lutetium 177 (Lu 177) dotatate in individuals with locally advanced or metastatic somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor who have progressed on first-line somatostatin analogues is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with inoperable locally advanced or metastatic somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor who have progressed on first-line somatostatin analogues.

Interventions
The therapy being considered is Lu 177 dotatate.

Comparators
The following practices (listed alphabetically with no preference) that are currently being used as second-line treatment options for individuals who have progressed on first-line somatostatin analogues include: cytotoxic chemotherapy (eg, 5-fluorouracil, capecitabine, dacarbazine, oxaliplatin, streptozocin, temozolomide), everolimus, hepatic-directed therapy (eg, arterial embolization, hepatic chemoembolization, hepatic radioembolization, cytoreductive surgery/ablative therapies) for hepatic predominant disease, interferon alfa-2b, and radiotherapy.

Outcomes
The general outcomes of interest are overall survival (OS), median progression-free survival (PFS), and adverse events. In general, acute short-term safety outcomes occurring as a consequence of radiation include monitoring for lymphopenia, vomiting, nausea, increased aspartate aminotransferase, increased alanine aminotransferase, hyperglycemia, and hypokalemia; long-term chronic toxicities that require monitoring are amyelodysplastic syndrome, renal failure, and leukemia.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
The evidence for use of Lu 177 dotatate for patients in midgut carcinoid tumors consists of the open-label NETTER-1 RCT (NCT01578239), and in patients with gastroenteropancreatic neuroendocrine tumors consists of the open-label NETTER-2 RCT (NCT03972488) and the retrospective cohort ERASMUS study. Results of the NETTER-1 study were originally published by Strosberg et al (2017).^30, However, the U.S. Food and Drug Administration (FDA) reviewed updated results and therefore data for the NETTER-1 study reported herein are based on the FDA documents^31,32, and not the published study.^30, Similarly, results of the ERASMUS study were published by Kwekkeboom et al (2008)33, and by Brabander et al (2017).^34, However, the 2017 published results included efficacy data for 443 patients with gastroenteropancreatic and bronchopulmonary and thymus neuroendocrine tumors. In its review, the FDA only assessed data for 360 patients with gastroenteropancreatic neuroendocrine tumors and therefore data for ERASMUS study reported herein are based on the FDA documents^31,32, and not the published studies.^34,33,The NETTER-2 study is ongoing but preliminary results have been published.^35, Study characteristics and results are summarized in Tables 1 and 2.

In the NETTER-1 trial, patients with Ki-67 index of 20% or less (a grading parameter for neuroendocrine tumors index), Karnofsky Performance Status score of 60 or greater, confirmed presence of somatostatin receptors on all lesions (octreoscan uptake ≥ normal liver) and creatinine clearance of 50 mL/min or greater were included. Randomization was stratified by octreoscan tumor uptake score (grade 2, 3, or 4) and the length of time that patients had been on the most recent constant dose of octreotide prior to randomization (≤6 or >6 months). The major efficacy outcome measure was PFS as determined by a blinded independent radiology committee per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Additional efficacy outcome measures were overall response rate assessed by an independent review committee, duration of response, and OS. The result showed a consistent statistically significant and clinically meaningful effect on overall response rate, PFS, and OS among patients given Lu 177 dotatate compared with those given high-dose long-acting octreotide.

Inclusion criteria for the NETTER-2 trial were similar to NETTER-1 except that both grade 2 (Ki-67 ≥10% and ≤20%) and grade 3 (Ki-67 >20% and ≤55%) were included, and patients with a creatinine clearance <40 mL/min were excluded.^35, Randomization was stratified by tumor grade and origin. The primary outcome was PFS per the RECIST version 1.1 criteria. Other efficacy outcomes were objective response rate, time to deterioration in quality of life, disease control rate, duration of response, and OS.

Table 1. Summary of Key Randomized Controlled Trial Characteristics

Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
NETTER-2^35,	9 countries in North America, Europe, and Asia	45	2020-2022	Patients with newly-diagnosed, locally advanced or metastatic, inoperable, higher grade 2 to 3, well-differentiated GEP-NETs	151 patients given Lu 177 dotatate 7.4 GBq (200 mCi) every 8 wk for 4 cycles plus long-acting octreotide 30 mg every 8 wk until completion of Lu 177 dotatate treatment, then every 4 wk until disease progression or treatment discontinuation for another reason	75 patients given long-acting octreotide (60 mg every 4 wk)
NETTER-1^31,^32,	Belgium, France, Germany, Italy, Portugal, Spain, U.S.	41	2012-2016	Adults with metastasized or locally advanced, inoperable, histologically confirmed, progressive midgut NETs	116 patients given Lu 177 dotatate 7.4 GBq (200 mCi) every 8 wk for up to 4 administrations plus long-acting octreotide 30 mg 4-24 h after each Lu 177 dotatate dose and every 4 wk after completion of Lu 177 dotatate treatment until disease progression or week 76 of the trial	113 patients given long-acting octreotide (60 mg every 4 wk)

GEP-NET: gastroenteropancreatic neuroendocrine tumor; Lu 177: lutetium 177; NET: neuroendocrine tumor.

Table 2. Summary of Key Randomized Controlled Trial Results

Trial	Median PFS (95% CI), months	Median OS (95% CI), months	ORR (95% CI), %	CR (95% CI), %	PR (95% CI), %	Median DOR (95% CI), months
NETTER-2^35,
N	226		226	226	226
Lu 177 dotatate	22.8 (9.4 to NE)	NR	43 (35 to 51.3)	5	38	Not reported
Control	8.5 (7.7 to 13.8)	NR	9.3 (3.8 to 18.3)	0	9	Not reported
OR or HR (95% CI) or p	0.276 (0.182 to 0.418)	NR	7.81 (3.32 to 18.40)	Not reported	Not reported	Not reported
NETTER-1^31,^32,
N	229	229	229	229	229
Lu 177 dotatate	NR (NE)^a	NR (31.0 to NE)	13 (7 to 19)	1 (1%)	14 (12%)	NR (2.8 to NE)
Control	8.5 (5.8 to 9.1)	27.4 (22.2 to NE)	4 (0.1 to 7)	0	4 (4%)	1.9 (1.9 to NE)
HR (95% CI) or p	0.21 (0.13 to 0.32)	0.52 (0.32 to 0.84)^b	.015	Not reported	Not reported	Not reported

CI: confidence interval; CR: complete response; DOR: duration of response; HR: hazard ratio; Lu 177: lutetium 177; NE: not evaluable; NR: not reached; OR: odds ratio; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; PR: partial response.
^a Median follow-up 10.5 mo at time of primary analysis of PFS (range, 0 to 29 mo).
^b Interim analysis of OS not statistically significant based on prespecified significance criteria.

The purpose of the study limitations tables (see Tables 3 and 4) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 3. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Duration of Follow-up^e
NETTER-2^35,					1. OS data was immature at the time of publication
NETTER-1^31,^32,

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
OS: overall survival.
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 4. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
NETTER-2^35,		1. Not blinded to treatment assessment
NETTER-1^31,^32,	1. Participants not randomly allocated because design was a retrospective single cohort study	1. Not blinded to treatment assignment 2. Not blinded outcome assessment 3. Outcome assessed by treating physician		1. Baseline tumor assessments obtained for only 578/1214 (48%) of patients	2. FDA noted that protocol along with a statistical analysis plan was retrospectively generated

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
FDA: U.S. Food and Drug Administration.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^fStatistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Retrospective Studies
In the ERASMUS study, 1214 patients with heterogeneous etiologies in terms of primary tumor site received Lu 177 dotatate as part of expanded access protocol at a single center in the Netherlands. Most patients had gastroenteropancreatic neuroendocrine tumors of the foregut, midgut, and hindgut, as well as the digestive tract, bronchus, and pancreatic neuroendocrine tumors. Other neuroendocrine tumors were also included in the trial, specifically medullary thyroid cancer, pheochromocytoma, paraganglioma, neuroblastoma, and Merkel cell carcinoma. Non-neuroendocrine somatostatin receptor-positive tumors including melanoma, nondifferentiated thyroid cancers, non-small-cell lung cancer, breast cancer, lymphoma, and malignant meningioma were also treated. From this heterogeneous cohort, 601 patients were assessed per RECIST criteria of whom 360 with foregut, midgut, or hindgut gastroenteropancreatic neuroendocrine tumors were retrospectively identified and analyzed. The major efficacy outcome was investigator-assessed overall response rate. Fifty-five percent of patients received a concomitant somatostatin analogue. Study characteristics and results are summarized in Tables 5 and 6.

In this cohort of 360 patients, the investigator-assessed overall response rate was 16% and the median duration of response was 35 months among 58 responders. The FDA did not view time to event analyses such as time to progression, PFS, and OS to be interpretable in the context of the single-arm ERASMUS study because of missing data at baseline, high dropout rates, and the open-label design of the study. However, the FDA considered that "these data provide statistically conservative estimates that were verifiable and are clinically meaningful for patients with gastroenteropancreatic neuroendocrine tumors. The results provide additional support for the indicated population that are consistent with the observed benefit in other populations of patients with the disease (ie, in NETTER-1), the biology of the disease itself, the mechanism of action of Lu 177 dotatate, and the limited treatment options available for these patients."

The SEPTRALU registry sought to elucidate the safety and efficacy of Lu 177 dotatate in the treatment of neuroendocrine tumors of various etiologies.^36, Results from the registry were published by Mitjavila et al (2023) for 522 patients across 24 centers in Spain which included stratified outcomes for pancreatic (n=182), midgut (n=148), and other gastroenteropancreatic neuroendocrine tumors (n=60). Study characteristics and results are summarized in Tables 5 and 6. The disease control rate, defined as the sum of complete response, partial response, and stable disease, was 84.8%, 93.5%, and 85.4%, respectively. After a median follow-up of 21.2 months, median PFS was 19.8 months, 31.3 months, and 24.3 months, respectively. Median OS was 34.2 months and 50.8 months for pancreatic and midgut tumors and was not reached for other gastroenteropancreatic tumors.

Table 5. Summary of Key Nonrandomized Trials Characteristics

Trial	Study Type	Country	Dates	Participants	Treatment	Follow-Up
ERASMUS Study^31,^32,	Retrospective cohort	Netherlands	2000-2012	Patients with somatostatin-positive GEP-NETs with a life expectancy of >12 wk and Karnofsky Performance Scale score ≥50	360 patients given Lu 177 dotatate 7.4 GBq (200 mCi) every 6-13 wk for up to 4 doses	34.8 months
SEPTRALU Registry^36,	Registry	Spain	2014-2022	Patients with somatostatin-positive GEP-NETs and unresectable, metastatic, or progressive disease	522 patients give Lu 177 dotatate 7.4 GBq (200 mCi) every 8-10 wk for up to 4 doses	21.2 months

GEP-NET: gastroenteropancreatic neuroendocrine tumor; Lu 177: lutetium 177.

Table 6. Summary of Key Nonrandomized Trial Results

Study	Median Duration of Response (95% CI), months	Overall Response Rate (95% CI), %	Median PFS (95% CI), months	Median OS (95% CI), months
ERASMUS Study^31,^32,
N	360	360	NA	NA
Lu 177 dotatate	35 (17 to 38)	16 (13 to 21)	NA	NA
SEPTRALU Registry^36,
Pancreatic NETs (N)	NA	182	182	182
Lu 177 dotatate	NA	84.8 (NR)	19.8 (16.8 to 28.1)	34.2 (30.4 to not reached)
Midgut NETs (N)	NA	148	148	148
Lu 177 dotatate	NA	93.5 (NR)	31.3 (25.7 to not reached)	50.8 (39.1 to not reached)
Other GEP-NETs (N)	NA	60	60	60
Lu 177 dotatate	NA	85.4 (NR)	24.3 (18.0 to not reached)	Not reached (35.1 to not reached)

CI: confidence interval; GEP: gastroenteropancreatic; Lu 177: lutetium 177; NA: not applicable; NET: neuroendocrine tumor; NR: not reported; PFS: progression-free survival; OS: overall survival.

The purpose of the limitations tables (see Tables 7 and 8) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 7. Study Relevance Limitations

Trial	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
ERASMUS Study^31,^32,			2. This was a single cohort study. There was no comparator.	2. Investigator-assessed ORR not a validated surrogate outcome measure
SEPTRALU Registry^36,			2. This was a single-arm registry with no comparator.

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
ORR: overall response rate.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 8. Study Design and Conduct Limitations

Trial	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness ^d	Power^e	Statistical^f
ERASMUS Study^31,^32,
SEPTRALU Registry^36,	1. Participants not randomly allocated because design was retrospective registry.	1-3. Blinding unclear.

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Gastroenteropancreatic Neuroendocrine Tumors Including Foregut, Midgut, and Hindgut Tumors
The evidence for use of Lu 177 dotatate consists of 2 open-labeled RCTs, a multicenter registry, and a retrospective cohort study. The RCT results showed a consistent statistically significant and clinically meaningful effect on overall response rate, PFS, and OS (only available for one trial) among patients treated with Lu 177 dotatate compared to those treated with long-acting octreotide. The results of the retrospective studies were consistent with the treatment effect observed in the RCT and provide additional support for a clinical benefit of Lu 177 dotatate in patients with gastroenteropancreatic neuroendocrine tumors.

Bronchopulmonary or Thymus Neuroendocrine Tumors
Clinical Context and Therapy Purpose
The purpose of Lu 177 dotatate in individuals with a bronchopulmonary or thymus somatostatin receptor-positive neuroendocrine tumor who have progressed on first-line somatostatin analogues is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with locally advanced or metastatic somatostatin receptor-positive bronchopulmonary or thymus neuroendocrine tumor who have progressed on first-line somatostatin analogues. Bronchopulmonary neuroendocrine tumors comprise approximately 20% of all lung cancers.^2, Neuroendocrine tumors of the thymus account for only 5% of all tumors in the thymus and mediastinum.^3,

Interventions
The therapy being considered is Lu 177 dotatate.

Outcomes
The general outcomes of interest are OS, median PFS, and adverse events. In general, acute short-term safety outcomes occurring as a consequence of radiation include monitoring for lymphopenia, vomiting, nausea, increased aspartate aminotransferase, increased alanine aminotransferase, hyperglycemia, and hypokalemia; long-term chronic toxicities that require monitoring include myelodysplastic syndrome, renal failure, and leukemia.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Retrospective Studies
The evidence for use of Lu 177 dotatate in patients with bronchopulmonary or thymus neuroendocrine tumors consists of the retrospective ERASMUS cohort study and a bicenter, retrospective case series.^34,37, The ERASMUS study design and characteristics are described in the previous section. Unlike the previous indication, where the FDA considered a subset of 360 patients with gastroenteropancreatic neuroendocrine tumors as supportive evidence, the FDA identified multiple problems with ERASMUS data that precluded drawing conclusions about treatment efficacy in patients with bronchopulmonary or thymus neuroendocrine tumors. The FDA concluded that time to event analyses such as time to progression, PFS, and OS were not interpretable in the context of the single-arm ERASMUS study because of missing data at baseline, high dropout rates, and the open-label design of the study.

The ERASMUS study included 23 patients with bronchopulmonary and 2 patients with thymus neuroendocrine tumors.^34, Among the 23 patients with bronchopulmonary neuroendocrine tumor, the median PFS was 20 months, the median time to progression was 25 months, and median OS was 52 months. Stratified results of 2 patients with thymus neuroendocrine tumors were not reported.

Zidan et al (2022) published data from a retrospective case series assessing the efficacy of Lu 177 dotatate in 48 patients with somatostatin receptor-positive lung neuroendocrine tumors treated between 2006 and 2019 at 2 centers in Australia and Israel.^37, Median patient age was 64 years. The series included 13 (27%) women and 43 (90%) atypical carcinoid tumors. The majority of patients (98%) were treated for radiographic disease progression, with 1 individual receiving treatment for uncontrolled symptoms. Of 40 patients with RECIST-measurable disease at 3 months, 8 (20%) had a partial response, 27 (68%) had stable disease, and 5 (12%) had disease progression. In 26 patients with RECIST-measurable stable disease, 10 patients were classified as partial response and 1 patient as progressive disease by Gallium 68 (Ga 68) dotatate positron emission tomography (PET)/computed tomography (CT). At a median follow-up of 42 months, the median PFS and OS were 23 months (95% confidence interval [CI], 18 to 28) and 59 months (95% CI, 50 to not reached), respectively.

The SEPTRALU registry (see Table 5) sought to elucidate the safety and efficacy of Lu 177 dotatate in the treatment of neuroendocrine tumors of various etiologies.^36, Results from the registry were published by Mitjavila et al (2023) for 522 patients across 24 centers in Spain which included stratified outcomes for bronchopulmonary tumors (n=56). The disease control rate was 77.6% with 0 complete responses, 14 (28.6%) partial responses, and 24 (49.0%) patients with stable disease. After a median follow up of 21.2 months, median PFS was 17.6 months (95% CI, 14.4 to 33.1) and median OS was 44.8 months (95% CI, 19.9 to not reached).

The purpose of the limitations tables (see Tables 9 and 10) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 9. Study Relevance Limitations

Trial	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
ERASMUS Study^34,			2. This was a single cohort study without a comparator	2. Investigator-assessed ORR not a validated surrogate outcome measure
Zidan et al (2022)^37,		1. Patients received variable cycles of therapy, with or without radiosensitizing chemotherapy	2. This was a retrospective case series without a comparator	2. Investigator-assessed DCR not a validated surrogate outcome measure
SEPTRALU Registry^36,			2. This was a single-arm registry with no comparator.

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
DCR: disease control rate; ORR: overall response rate.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 10. Study Design and Conduct Limitations

Trial	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness ^d	Power^e	Statistical^f
ERASMUS Study^34,	1. Participants not randomly allocated because design was a retrospective single cohort study	1. Not blinded to treatment assignment 2. Not blinded outcome assessment 3. Outcome assessed by treating physician		1. Baseline tumor assessments obtained for only 578 (48%) of patients	2. FDA noted that protocol along with statistical analysis plan were retrospectively generated
Zidan et al (2022)^37,	1. Participants not randomly allocated because design was retrospective case series	1. Not blinded to treatment assignment 2. Not blinded outcome assessment 3. Outcome assessed by treating physician
SEPTRALU Registry^36,	1. Participants not randomly allocated because design was retrospective registry	1-3. Blinding unclear

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
FDA: U.S. Food and Drug Administration.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Bronchopulmonary or Thymus Neuroendocrine Tumor
The evidence for use of Lu 177 dotatate consists of the retrospective ERASMUS cohort study, a multicenter registry, and a bicenter, retrospective case series. The ERASMUS study included a small number of patients with bronchopulmonary (n=23) and thymus (n=2) neuroendocrine tumors. Results for the 2 patients with thymus neuroendocrine tumors were not reported separately. The multicenter registry included 58 patients with bronchopulmonary tumors and reported 0 complete responses, 14 partial responses, a median PFS of 17.6 months, and a median OS of 44.8 months. The case series evaluated 48 patients with predominantly atypical carcinoid bronchopulmonary tumors. Across studies, median PFS and OS ranged from 20 to 23 months and 52 to 59 months, respectively. No RCTs were identified.

Safety
In the safety analysis, exposure data from 922 patients who received at least 1 dose of Lu 177 dotatate treated in the NETTER-1 and ERASMUS studies were analyzed.31, Drug exposure in NETTER-1 was a total of 600 mCi or more of Lu 177 dotatate in 79.3% of patients treated, and 26% of patients received cumulative doses of 800 mCi or more. Seventy-six percent of patients received all 4 planned doses. Dose reductions were reported in 6% of patients and drug discontinuation in 13% of patients. The most common adverse events observed in patients treated with Lu 177 dotatate were nausea (65%), vomiting (53%), fatigue (38%), diarrhea (26%), abdominal pain (26%), and decreased appetite (21%). The most common grade 3 and 4 adverse events with Lu 177 dotatate were lymphopenia (44%), increased gamma-glutamyl transferase (20%), vomiting (7%), nausea and elevated aspartate aminotransferase (5% each), as well as increased alanine aminotransferase, hyperglycemia, and hypokalemia (4% each). In the ERASMUS study, with a median follow-up of more than 4 years, the most serious chronic toxicities reported were myelodysplastic syndrome (2%), renal failure (2%), cardiac failure (2%), acute leukemia (1%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%).

Pheochromocytoma and Paraganglioma
Clinical Context and Therapy Purpose
The purpose of Lu 177 dotatate in individuals with unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma.

Interventions
The therapy being considered is Lu 177 dotatate injection.

Comparators
The following practices are currently being used to treat unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma: external beam radiation therapy, ablation therapy, transarterial chemoembolization, and chemotherapeutic agents, including cyclophosphamide, dacarbazine, vincristine, doxorubicin, temozolomide, thalidomide, and sunitinib.

Outcomes
The general outcomes of interest are OS, disease-specific survival, and adverse events. In general, acute short-term safety outcomes occurring as a consequence of radiation include monitoring for lymphopenia, vomiting, nausea, increased aspartate aminotransferase, increased alanine aminotransferase, hyperglycemia, and hypokalemia; long-term chronic toxicities that require monitoring are myelodysplastic syndrome, renal failure, and leukemia.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Lu 177 Dotatate
The evidence for the use of Lu 177 dotatate in individuals with pheochromocytoma or paraganglioma consists of systematic reviews of single-arm studies, a multicenter registry, and a case series.

Systematic Reviews
Prado-Wohlwend et al (2022) published a systematic review and meta-analysis of therapy with iobenguane I 131 or Lu 177 dotatate in patients (N=1248) with metastatic pheochromocytoma and paranglioma.38, Twenty-seven studies were included in the analysis, 4 of which were prospective, 9 focused on Lu 177 dotatate, 17 focused on iobenguane I 131, and 1 compared the 2 agents. A regression model analysis found that treatment with iobenguane I 131 yielded a 10 months lower PFS compared to Lu 177 dotatate (95% CI, -11.7 to -8.5). A subsequent Bayesian linear regression model found that the mean difference in PFS was dependent on the proportion of pheochromocytomas in the study sample, with PFS decreasing by 1.9 months (95% CI, -2.01 to -1.78) for each 10% increase in the proportion of pheochromocytomas.

Satapathy et al (2019) published a systematic review and meta-analysis of peptide receptor radionuclide therapy with Lu 177 dotatate and/or Yttrium 90 (Y 90) dotatoc in patients with advanced pheochromocytoma and paraganglioma.39, Eleven nonrandomized studies were evaluable for objective response rate and disease control rate, representing 179 patients and 151 patients, respectively. For Lu 177 dotatate, the pooled objective response rate was 26% (95% CI, 18% to 35%) with a disease control rate of 83% (95% CI, 75% to 90%). In contrast, the pooled objective response rate and disease control rate for Y 90 dotatoc was 24% (95% CI, 15% to 35%) and 85% (95% CI, 71% to 93%), respectively. Included studies varied in response criteria used and concomitant use of other treatment modalities, such as iobenguane I 131 or radiosensitizing chemotherapy.

Nonrandomized Studies
The SEPTRALU registry (see Table 5) sought to elucidate the safety and efficacy of Lu 177 dotatate in the treatment of neuroendocrine tumors of various etiologies.36, Results from the registry were published by Mitjavila et al (2023) for 522 patients across 24 centers in Spain which included stratified outcomes for pheochromocytoma or paraganglioma (n=31). The disease control rate was 84.6% with 0 complete responses, 5 (19.2%) partial responses, and 17 (65.4%) patients with stable disease. After a median follow-up of 21.2 months, median PFS was 30.6 months (95% CI, 14.4 to not reached) and median OS was not reached (95% CI, 15.1 to not reached).

Severi et al (2021) assessed the efficacy of Y 90 dotatoc (n=12) or Lu 177 dotatate (n=34) in consecutive patients with somatostatin receptor-positive progressive locally advanced or metastatic pheochromocytoma or paraganglioma enrolled across multiple study protocols at a single center in Italy from 2008 to 2018.40, Lu 177 dotatate was administered at dosages of 3.7 or 5.5 GBq/cycle, with lower dosages used in patients with risk factors for bone marrow or renal toxicity. Disease control rate, defined as the sum of partial responses and stable disease, was 82.4% with Lu 177 dotatate and 75% with Y 90 dotatoc after a median follow-up of 73 months. For Lu 177 dotatate, median PFS was not reached and and median OS was 143.5 months (95% CI, 103.1 to 146.2). For Y 90 dotatoc, median PFS was 74.5 months (95% CI, 8.4 to not reached) and median OS was 92.1 months (95% CI, 57.1 to 92.1). A disease control rate of 92% was achieved in patients receiving a full dosage of Lu 177 dotate, compared to 55% in those receiving a reduced dosage. Corresponding median PFS was not reached versus 27.5 months, respectively. Study relevance, design, and conduct limitations are summarized in Tables 11 and 12.

Kong et al (2017) assessed the efficacy of 177 Lu dotatate in a retrospective analysis of 20 consecutive patients with unresectable paraganglioma or pheochromocytoma and high somatostatin receptor expression.41, Fourteen patients were treated for uncontrolled hypertension and 6 were treated for progressive or symptomatic metastatic disease or local recurrence. Nine patients received radiosensitizing chemotherapy. Of 16 patients who received iobenguane scans, 6 had concordant positive uptake, 6 had mild uptake, and 4 had negative scans. Overall, 5 patients had disease regression, with 4 partial RECIST responses and 1 minor morphologic regression observed on CT out of 14 evaluable patients. At 3 months post-treatment, 8/13 patients (62%) required reduced doses of antihypertensive medications compared with baseline. The remaining 5 patients had no change in medication dose but attained symptom control. During a median follow-up of 28 months (range, 5 to 74 months) median OS was not reached (5 deaths) and median PFS was 39 months. During follow-up, 2 patients had tumor progression, 5 patients had recurrence of hypertension, and 2 others were treated with further maintenance therapies for persistent disease with favorable response. The most common toxicity observed was grade 2 lymphopenia. One patient experienced catecholamine crisis following treatment and catecholamine crisis could not be excluded in 1 patient who died from cardiac arrest after a third cycle of treatment. The authors noted that given the favorable efficacy and potential logistic and radiation safety advantages of Lu 177 dotatate compared to iobenguane I 131, further prospective trials are warranted. Patient outcomes were not stratified by iobenguane uptake status. Study relevance, design, and conduct limitations are summarized in Tables 11 and 12.

Table 11. Study Relevance Limitations

Trial	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
Severi et al (2021)^40,		1. Patients received variable doses of therapy and concomitant use of other treatment modalities was not standardized	2. This was a case series without planned direct comparison to other agents, including Y 90 dotatoc	2. Investigator-assessed DCR not a validated surrogate outcome measure
Kong et al (2017)^41,	1. Patients had variable degrees of iobenguane uptake	1. Patients received variable doses of therapy and concomitant use of other treatment modalities was not standardized	2. This was a retrospective study without a comparator	1. Patients outcomes were not stratified by iobenguane uptake status
SEPTRALU Registry^36,			2. This was a single-arm registry with no comparator.

DCR: disease control rate; Y 90: Yttrium 90.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 12. Study Design and Conduct Limitations

Trial	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Severi et al (2021)^40,	1. Participants not randomly allocated and evaluated across multiple study protocols 4. Inadequate control for selection bias	1. Not blinded to treatment assignment
Kong et al (2017)^41,	1. Participants not randomly allocated	1. Not blinded to treatment assignment		1. High loss to follow-up or missing data		3. Confidence intervals and/or p values not reported
SEPTRALU Registry^36,	1. Participants not randomly allocated because design was retrospective registry	1-3. Blinding unclear

Section Summary: Pheochromocytoma and Paraganglioma
The evidence for the use of Lu 177 dotatate consists of a systematic reviews and meta-analyses of single-arm studies, a multicenter registry, and 2 case series. One meta-analysis reported a pooled overall tumor response rate of 26% (95% CI, 18% to 35%). Another meta-analysis found improved PFS with Lu 177 dotatate compared to iobenguane I 131 among studies enriched with pheochromocytomas. One retrospective case series reported that 8/13 patients were able to reduce dosages of antihypertensive treatment at 3 months. Disease regression was reported in 5/14 patients with available CT imaging. Out of 16 patients with available iobenguane scans, 10 patients had mild or negative uptake. However, patient outcomes were not stratified by iobenguane uptake status. No prospective studies directly comparing Lu 177 dotatate to iobenguane I 131 or assessing Lu 177 dotatate response in a fully non-iobenguane avid population were identified.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Radiology et al
In 2022, the American College of Radiology (ACR) issued a practice parameter for lutetium 177 dotatate therapy of gastroenteropancreatic tumors in collaboration with the American College of Nuclear Medicine (ACNM), the American Society of Radiation Oncology (ASTRO), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI).42, Regarding patient selection and clinical evaluation, the practice parameter recommends the following:

Verification of pathology and indication for therapy, including confirmation of somatostatin receptor expression;
Discontinuation of somatostatin analog therapy with baseline laboratory evaluation;
Discussion and mitigation of risks in special populations, including pregnant, lactating, and pediatric patients;
Administration in the context of a quality management program;
Documentation of informed consent;
Treatment according to an established system of procedural steps unique for lutetium 177 dotatate; and
Application of radiation precautions and patient release criteria in accordance with federal and/or local regulations.

National Comprehensive Cancer Network Guidelines
The National Comprehensive Cancer Network (NCCN) guidelines ( v.2.2024) for neuroendocrine and adrenal tumors have published key eligibility criteria for patients treated with lutetium 177 dotatate for neuroendocrine tumors. Eligibility criteria include well-differentiated neuroendocrine tumor , detection of somatostatin receptor expression using somatostatin-based receptor imaging, and adequate bone marrow, renal and hepatic function. Table 13 summarizes the NCCN guidelines for neuroendocrine and adrenal tumors.^43,

Table 13. Recommendations for Use of Lutetium 177 Dotatate for Neuroendocrine Tumors

Treatment Category	Recommendation Category
Mid-gut recurrent, locoregional advanced or distant metastases gastrointestinal neuroendocrine tumors after disease progression on somatostatin analogues	1
Bronchopulmonary/thymic distant metastases neuroendocrine tumors if there is clinically significant tumor burden and low grade (typical) tumor or evidence of progression or intermediate grade (atypical) tumor or symptomatic disease	2A
Locoregional or recurrent advanced or distant metastases gastrointestinal neuroendocrine tumors after disease progression on somatostatin analogues	2A
Locoregional or recurrent advanced or distant metastases pancreatic neuroendocrine tumors after disease progression on somatostatin analogues	2A
Locally unresectable or distant metastases paraganglioma/pheochromocytoma (consider use if somatostatin receptor-positive)	2A

The NCCN guidelines also provide a category 2A recommendation to consider the use of lutetium 177 dotatate for treatment of patients with locally unresectable bronchopulmonary or thymus neuroendocrine tumors and locally unresectable or distant metastatic pheochromocytoma or paraganglioma. For pheochromocytoma and paraganglioma, the guidelines additionally note that data are limited for use in this setting. Due to lack of randomized data, the NCCN encourages participation in clinical trials of lutetium 177 dotatate for rare groups of neuroendocrine tumors including pancreatic neuroendocrine tumors, pheochromocytomas, paragangliomas, and bronchopulmonary/thymic neuroendocrine tumors.

The NCCN guidelines ( v.2.2024) for neuroendocrine and adrenal tumors gives iobenguane I 131 category 2A recommendation for treatment of patients with locally unresectable or distant metastatic pheochromocytoma or paraganglioma with positive MIBG (iobenguane) scan.

North American Neuroendocrine Tumor Society
In 2021, the North American Neuroendocrine Tumor Society released a consensus guideline on management of metastatic and/or unresectable pheochromocytoma and paraganglioma.^44, The guideline states that there is some evidence to support using lutetium 177 dotatate in some patients, but the consensus recommendation was to limit use to a clinical trial.

Also in 2021, the North American Neuroendocrine Tumor Society (and several other organizations) released a consensus guideline on management of patients with lung neuroendocrine tumors.^45, The final consensus statement was that peptide receptor radionuclide therapy may be an option for patients with somatostatin receptor positive tumors (grade B recommendation).

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 14.

Table 14. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
*Ongoing*
NCT03206060	Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma	90	Jan 2027
NCT04665739	Testing Lutetium Lu 177 Dotatate in Patients With Somatostatin Receptor Positive Advanced Bronchial Neuroendocrine Tumors	108	Aug 2024
NCT04086485	Lu-177-DOTATATE (Lutathera) in Combination With Olaparib in Inoperable Gastroenteropancreatico Neuroendocrine Tumors (GEP-NET)	42	Jan 2026
NCT03691064	Post-Authorization Long-Term Safety Study of Lutathera (SALUS)	1014	Jun 2028
NCT03972488^a	A Phase III Multi-center, Randomized, Open-label Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET (NETTER-2)	226	Oct 2027
NCT04954820	A Prospective Randomized Phase II Study Assess the Schema of Retreatment With Lutathera® ([177LU]LU-DOTA-TATE) in Patients With New Progression of Intestinal Well-differenciated Neuroendocrine Tumor (ReLUTH)	146	Sep 2029
NCT01876771	An Open-label Phase II Study of Lutetium-177 [DOTA0, Tyr3] Octreotate (Lu-DOTA-TATE) Treatment in Patients With Somatostatin Receptor Positive Tumours	500	Dec 2033
NCT06121271	Trial of Lu-177 DOTATATE (Lutathera®) in Unlicensed Indications Including Bronchial and Thymic Neuroendocrine Tumour, Paraganglioma/Phaeochromocytoma, Medullary Thyroid Carcinoma, and Repeat Peptide Receptor Radionuclide Therapy	110	Nov 2027

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

References

Society of Nuclear Medicine and Molecular Imaging. Lantheus to Discontinue Production of Azedra. August 18, 2023; https://snmmi.org/Web/News/Articles/Lantheus-to-Discontinue-Production-of-Azedra.aspx. Accessed September 4, 2024.
Gustafsson BI, Kidd M, Chan A, et al. Bronchopulmonary neuroendocrine tumors. Cancer. Jul 01 2008; 113(1): 5-21. PMID 18473355
Bohnenberger H, Dinter H, König A, et al. Neuroendocrine tumors of the thymus and mediastinum. J Thorac Dis. Nov 2017; 9(Suppl 15): S1448-S1457. PMID 29201448
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. Oct 01 2017; 3(10): 1335-1342. PMID 28448665
Frilling A, Akerström G, Falconi M, et al. Neuroendocrine tumor disease: an evolving landscape. Endocr Relat Cancer. Oct 2012; 19(5): R163-85. PMID 22645227
Sorbye H, Strosberg J, Baudin E, et al. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer. Sep 15 2014; 120(18): 2814-23. PMID 24771552
Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis in patients with metastatic pancreatic endocrine carcinomas. Pancreas. Apr 2009; 38(3): 255-8. PMID 19066493
Ter-Minassian M, Chan JA, Hooshmand SM, et al. Clinical presentation, recurrence, and survival in patients with neuroendocrine tumors: results from a prospective institutional database. Endocr Relat Cancer. Apr 2013; 20(2): 187-96. PMID 23319495
Caplin ME, Baudin E, Ferolla P, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. Aug 2015; 26(8): 1604-20. PMID 25646366
Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. Jan 2012; 61(1): 6-32. PMID 22052063
Berg K, Leyden J, Goldstein G, et al. Neuroendocrine tumor European patient experience: results from the first global NET patient survey - a collaboration between the International Neuroendocrine Cancer Alliance and Novartis [abstract]. Endocrine Abstracts. 2015;37:EP1139.
O'Toole D, Ducreux M, Bommelaer G, et al. Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer. Feb 15 2000; 88(4): 770-6. PMID 10679645
Strosberg J. Advances in the Treatment of Pancreatic Neuroendocrine Tumors (pNETs). Gastrointest Cancer Res. Jul 2013; 6(4 Suppl 1): S10-2. PMID 24312683
Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. Feb 10 2011; 364(6): 514-23. PMID 21306238
Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. Mar 05 2016; 387(10022): 968-977. PMID 26703889
Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. Dec 10 2011; 378(9808): 2005-2012. PMID 22119496
Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. Feb 10 2011; 364(6): 501-13. PMID 21306237
Garcia-Carbonero R, Sorbye H, Baudin E, et al. ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. Neuroendocrinology. 2016; 103(2): 186-94. PMID 26731334
Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. Jun 2014; 99(6): 1915-42. PMID 24893135
Lefebvre M, Foulkes WD. Pheochromocytoma and paraganglioma syndromes: genetics and management update. Curr Oncol. Feb 2014; 21(1): e8-e17. PMID 24523625
Hamidi O, Young WF, Gruber L, et al. Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: A systematic review and meta-analysis. Clin Endocrinol (Oxf). Nov 2017; 87(5): 440-450. PMID 28746746
Hamidi O, Young WF, Iñiguez-Ariza NM, et al. Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years. J Clin Endocrinol Metab. Sep 01 2017; 102(9): 3296-3305. PMID 28605453
Pheochromocytoma and Paraganglioma Treatment. National Cancer Institute. August 25, 2022. https://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq. Accessed September 4, 2024.
Gunawardane PTK, Grossman A. Phaeochromocytoma and Paraganglioma. Adv Exp Med Biol. 2017; 956: 239-259. PMID 27888488
Ayala-Ramirez M, Feng L, Habra MA, et al. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer. Jun 01 2012; 118(11): 2804-12. PMID 22006217
Fliedner SM, Lehnert H, Pacak K. Metastatic paraganglioma. Semin Oncol. Dec 2010; 37(6): 627-37. PMID 21167381
Ayala-Ramirez M, Chougnet CN, Habra MA, et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab. Nov 2012; 97(11): 4040-50. PMID 22965939
Novartis. Novartis provides update on production of radioligand therapy medicines. May 5, 2022; https://www.novartis.com/news/media-releases/novartis-provides-update-production-radioligand-therapy-medicines. Accessed September 4, 2024.
Novartis. Novartis resumes production and delivery of radioligand therapy medicines ahead of schedule. June 30, 2022; https://www.novartis.com/news/media-releases/novartis-resumes-production-and-delivery-radioligand-therapy-medicines-ahead-schedule. Accessed September 4, 2024.
Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of 177 Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. Jan 12 2017; 376(2): 125-135. PMID 28076709
Food and Drug Administration, Center for Drug Evaluation and Research. Application Number: 208700Orig1s000 Multi-Disciplinary Review. Addendum to Review, NDA 208700. 2018; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/208700Orig1s000MultidisciplineR.pdf. Accessed September 4, 2024.
Novartis Inc. Lutathera (lutetium Lu 177 dotatate) injection, for intravenous use administration of Lutathera (Prescribing Label). 2024; https://www.novartis.com/us-en/sites/novartis_us/files/lutathera.pdf. Accessed September 4, 2024.
Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. May 01 2008; 26(13): 2124-30. PMID 18445841
Brabander T, van der Zwan WA, Teunissen JJM, et al. Long-Term Efficacy, Survival, and Safety of [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res. Aug 15 2017; 23(16): 4617-4624. PMID 28428192
Singh S, Halperin D, Myrehaug S, et al. [ 177 Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. Jun 29 2024; 403(10446): 2807-2817. PMID 38851203
Mitjavila M, Jimenez-Fonseca P, Belló P, et al. Efficacy of [ 177 Lu]Lu-DOTATATE in metastatic neuroendocrine neoplasms of different locations: data from the SEPTRALU study. Eur J Nucl Med Mol Imaging. Jul 2023; 50(8): 2486-2500. PMID 36877234
Zidan L, Iravani A, Oleinikov K, et al. Efficacy and Safety of 177 Lu-DOTATATE in Lung Neuroendocrine Tumors: A Bicenter study. J Nucl Med. Feb 2022; 63(2): 218-225. PMID 34049983
Prado-Wohlwend S, Del Olmo-García MI, Bello-Arques P, et al. Response to targeted radionuclide therapy with [ 131 I]MIBG AND [ 177 Lu]Lu-DOTA-TATE according to adrenal vs. extra-adrenal primary location in metastatic paragangliomas and pheochromocytomas: A systematic review. Front Endocrinol (Lausanne). 2022; 13: 957172. PMID 36339441
Satapathy S, Mittal BR, Bhansali A. 'Peptide receptor radionuclide therapy in the management of advanced pheochromocytoma and paraganglioma: A systematic review and meta-analysis'. Clin Endocrinol (Oxf). Dec 2019; 91(6): 718-727. PMID 31569282
Severi S, Bongiovanni A, Ferrara M, et al. Peptide receptor radionuclide therapy in patients with metastatic progressive pheochromocytoma and paraganglioma: long-term toxicity, efficacy and prognostic biomarker data of phase II clinical trials. ESMO Open. Aug 2021; 6(4): 100171. PMID 34139487
Kong G, Grozinsky-Glasberg S, Hofman MS, et al. Efficacy of Peptide Receptor Radionuclide Therapy for Functional Metastatic Paraganglioma and Pheochromocytoma. J Clin Endocrinol Metab. Sep 01 2017; 102(9): 3278-3287. PMID 28605448
Love C, Desai NB, Abraham T, et al. ACR-ACNM-ASTRO-SNMMI Practice Parameter for Lutetium-177 (Lu-177) DOTATATE Therapy. Clin Nucl Med. Jun 01 2022; 47(6): 503-511. PMID 35507433
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed September 4, 2024.
North American Neuroendocrine Tumor Society. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. 2021; https://nanets.net/images/2021/2021_NANETS_Consensus_Guidelines_for_Surveillance_and_Management_of_Metastatic_and_or_Unresectable_ Pheochromocytoma_and_Paraganglioma.pdf. Accessed September 4, 2024.
North American Neuroendocrine Tumor Society. Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines. 2021; https://nanets.net/images/guidelines/20021_COMMNETS_NANETS_Lung_Guidelines.pdf. Accessed September 3, 2024.

Coding Section

Codes	Number	Description
CPT		No Codes
HCPCS	A9513	Lutetium Lu 177, dotatate, therapeutic, 1 millicurie
ICD-10-CM	C7A.00-C7A.8	Malignant neuroendocrine tumor code range
	C7B.00-C7B.09	Secondary neuroendocrine tumor code range
	C7B.8	Other secondary neuroendocrine tumors
ICD-10-PCS	No specific code
Type of service	Radiopharmaceuticals Oncology
Place of service	Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

History From 2019 Forward

06/09/2025	Annual review, removing all content related to iobenguane. Also updating summary of evidence, background, regulatory status, policy guidelines, rationale, key trials, and references. Removing code A9590.
06/04/2024	Annual review, no change to policy intent. Updating rationale and references.
06/01/2023	Annual review, updating policy to include statement regarding pheochromocytoma and paraganglioma. Also updating criteria 3,4,and 5 for initial Lutetium 177 use for clarity and specificity. Updating regulatory status.
11/10/2022	Interim review after adoption of CAM 50143 Which addresses Lutetium in regards to prostate cancer. Updating title, background, guidelines, rationale, references and coding. No change to policy intent.
06/15/2022	Annual review, no change to policy intent.
06/07/2021	Annual review, no change to policy intent. UPdating ratonale and references.
06/01/2020	Annual review, adding medical necessity coverage for lobenguane I 131. Updating background, description, guidelines, regulatory status, rationale and references.
07/30/2019	Interim review, updating HCPCS coding. No other changes.
06/17/2019	New Policy, replacing CAM 203

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Therapeutic Radiopharmaceuticals for Neuroendocrine Tumors - CAM 60160