Coverage Policy Manual
Policy #: 2021017
Category: Pharmacy
Initiated: June 2021
Last Review: February 2025
  Naxitamab-gqgk (e.g., Danyelza)
Description:
Naxitamab-gqgk is a monoclonal antibody that targets GD2 to induce complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity.
 
Naxitamab-gqgk binds to the glycolipid GD2. GD2 is a disialoganglioside that is overexpressed on neuroblastoma cells and other cells of neuroectodermal origin, including the central nervous system and peripheral nerves. In vitro, naxitamab-gqgk was able to bind to cell surface GD2 and induce complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC).
 
Regulatory Status
 
On 11/25/2020, the Food and Drug Administration approved Naxitamab-gqgk (e.g., Danyelza) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of pediatric individuals 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy. ­This indication was approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
 
Naxitamab has a black box warning for serious infusion-related reactions and neurotoxicity. Serious infusion reactions including cardiac arrest, anaphylaxis, hypotension, bronchospasm, and stridor can occur. The following warnings are described:
 
Neurotoxicity: Peripheral neuropathy, neurological disorders of the eye, including severe neuropathic pain, transverse myelitis, and reversible posterior leukoencephalopathy syndrome, and prolonged urinary retention have also occurred. Permanently discontinue.
 
Hypertension: Do not initiate in individuals with uncontrolled hypertension. Monitor blood pressure during and after infusion as recommended. Withhold, reduce infusion rate, or discontinue based on severity.
 
Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception.
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
Prior approval is required for naxitamab (e.g., Danyelza).
 
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
 
Approval timeframes may differ for members/participants of Self-Insured plans.
 
Effective February 28, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
  
Naxitamab-gqgk (e.g., Danyelza) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met (FDA, 2020):
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
 
1. Individual has a diagnosis of relapsed or refractory high-risk neuroblastoma (FDA, 2020); AND
2. Individual is age 1 year of age or older; AND
3. Individual has disease in the bone or bone marrow (FDA, 2020); AND
4. Individual has demonstrated a partial response, minor response, or stable disease with prior therapy (FDA, 2020); AND
5. Naxitamab is administered in combination with a granulocyte-macrophage colony-stimulating factor (GM-CSF) (e.g., sargramostim) (FDA, 2020); AND
6. It is recommended that Naxitamab-gqgk be prescribed by or in consultation with a physician experienced in treating high-risk neuroblastoma; AND
7. Must be dosed in accordance with the FDA label..
 
CONTINUED APPROVAL for up to 12 months:
 
1. Individual continues to meet initial criteria; AND
2. Individual continues to have clinical benefit on naxitamab-gqgk as demonstrated by tumor response or lack of disease progression; AND
3. Must be dosed in accordance with the FDA label.
 
Policy Guidelines
 
Defining “high-risk” neuroblastoma: The Children’s Oncology Group (COG) risk group system was initially based on the International Neuroblastoma Staging System (INSS) staging system but is now transitioning to using the International Neuroblastoma Risk Group Staging System (INRGSS), along with the major prognostic factors to place children into 3 different risk groups: low, intermediate, and high. High-risk neuroblastoma patients, per COG, are:
    • Stage 2A or 2B disease and MYCN gene amplification
    • Stage 3 disease and MYCN gene amplification
    • Stage 3 disease in children aged 18 months or older, no MYCN gene amplification, and unfavorable histopathology
    • Stage 4 disease in children younger than 12 months and MYCN gene amplification
    • Stage 4 disease in children between 12 months and 18 months with MYCN gene amplification, and/or diploidy, and/or unfavorable histology
    • Stage 4 disease in children 18 months or older
    • Stage 4S disease and MYCN gene amplification
 
Examples of medications used as prior therapies and therapeutic alternatives (used in various combinations in variable dosing regimens):
    • Cisplatin
    • Etoposide
    • Vincristine
    • Cyclophosphamide
    • Doxorubicin
    • Topotecan
    • Dinutuximab (e.g., Unituxin)
    • Isotretinoin
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (see policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dosage of naxitamab-gqgk is 3 mg/kg/day (up to 150 mg/day), administered as an intravenous infusion after dilution on Days 1, 3, and 5 of each treatment cycle. Treatment cycles are repeated every 4 weeks until complete response or partial response, followed by 5 additional cycles every 4 weeks. Subsequent cycles may be repeated every 8 weeks.
 
Discontinue Naxitamab-gqgk and GM-CSF for disease progression or unacceptable toxicity. Administer GM-CSF subcutaneously prior to and during each treatment cycle as recommended.
 
Naxitamab-gqgk (e.g., Danyelza) is available as  40 mg/10 mL in a single-dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Naxitamab-gqgk (e.g., Danyelza), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Naxitamab-gqgk (e.g., Danyelza), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective March 2023 to February 27, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
  
The use of Naxitamab-gqgk meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of adult and pediatric individuals 1 year of age and older with neuroblastoma when the following criteria are met (FDA, 2020):
 
Initial Therapy (6 month approval)
 
    1.  The individual has a diagnosis of relapsed or refractory high-risk neuroblastoma (FDA, 2020); AND
2.  The individual has disease in the bone or bone marrow (FDA, 2020); AND
3.  The individual has demonstrated a partial response, minor response, or stable disease with prior therapy (FDA, 2020); AND
4.  Naxitamab is administered in combination with a granulocyte-macrophage colony-stimulating factor (GM-CSF) (e.g., sargramostim) (FDA, 2020); AND    
5.  Must be dosed in accordance with the FDA label; AND
6.  It is recommended that Naxitamab-gqgk be prescribed by or in consultation with a physician who specializes in the condition being treated.
 
Continuation Therapy
 
1.  Continues to meet initial criteria
2.  Continued clinical benefit on naxitamab-gqgk as demonstrated by tumor response or lack of disease progression.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (see policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dosage is 3 mg/kg/day (up to 150 mg/day), administered as an intravenous infusion after dilution on Days 1, 3, and 5 of each treatment cycle. Treatment cycles are repeated every 4 weeks until complete response or partial response, followed by 5 additional cycles every 4 weeks. Subsequent cycles may be repeated every 8 weeks.
 
Discontinue Naxitamab-gqgk and GM-CSF for disease progression or unacceptable toxicity. Administer GM-CSF subcutaneously prior to and during each treatment cycle as recommended.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Naxitamab-gqgk does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any indication or circumstance other than those outlined above.
 
For members with contracts without primary coverage criteria, the use of Naxitamab-gqgk is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective January 2022 to February 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
  
The use of Naxitamab-gqgk meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of adult and pediatric patients 1 year of age and older with neuroblastoma when the following criteria are met (FDA, 2020):
 
Initial Therapy (6 month approval)
 
1. The patient has a diagnosis of relapsed or refractory high-risk neuroblastoma (FDA, 2020); AND
2. The patient has disease in the bone or bone marrow (FDA, 2020); AND
3. The patient has demonstrated a partial response, minor response, or stable disease with prior therapy (FDA, 2020); AND
4. Naxitamab is administered in combination with a granulocyte-macrophage colony-stimulating factor (GM-CSF) (e.g., sargramostim) (FDA, 2020).
5. It is recommended that Naxitamab-gqgk be prescribed by or in consultation with a physician who specializes in the condition being treated.
 
Continuation Therapy
 
1. Continues to meet initial criteria
2. Continued clinical benefit on naxitamab-gqgk as demonstrated by tumor response or lack of disease progression.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (see policy #2000030).
 
Dosage and Administration
 
The recommended dosage is 3 mg/kg/day (up to 150 mg/day), administered as an intravenous infusion after dilution on Days 1, 3, and 5 of each treatment cycle. Treatment cycles are repeated every 4 weeks until complete response or partial response, followed by 5 additional cycles every 4 weeks. Subsequent cycles may be repeated every 8 weeks.
 
Discontinue Naxitamab-gqgk and GM-CSF for disease progression or unacceptable toxicity. Administer GM-CSF subcutaneously prior to and during each treatment cycle as recommended.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Naxitamab-gqgk does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than those outlined above.
 
For members with contracts without primary coverage criteria, the use of Naxitamab-gqgk is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to January 2022  
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
  
The use of Naxitamab-gqgk meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of adult and pediatric patients > 1 year of age and older with neuroblastoma when the following criteria are met:
 
Initial Therapy (6 month approval)
 
1. The patient has a diagnosis of relapsed or refractory high-risk neuroblastoma; AND
2. The patient has disease in the bone or bone marrow; AND
3. The patient has demonstrated a partial response, minor response, or stable disease with prior therapy; AND
4. Naxitamab is administered in combination with a granulocyte-macrophage colony-stimulating factor (GM-CSF)
 (e.g., sargramostim).
5. Naxitamab must be prescribed by or in consultation with a physician who specializes in the condition being treated.
 
Continuation Therapy
 
1. Continues to meet initial criteria
2. Continued clinical benefit on naxitamab-gqgk as demonstrated by tumor response or lack of disease progression.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (see policy #2000030).
 
Dosage and Administration
 
The recommended dosage is 3 mg/kg/day (up to 150 mg/day), administered as an intravenous infusion after dilution on Days 1, 3, and 5 of each treatment cycle. Treatment cycles are repeated every 4 weeks until complete response or partial response, followed by 5 additional cycles every 4 weeks. Subsequent cycles may be repeated every 8 weeks.
 
­Discontinue Naxitamab-gqgk and GM-CSF for disease progression or unacceptable toxicity. Administer GM-CSF subcutaneously prior to and during each treatment cycle as recommended.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of naxitamab-gqgk does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than those outlined above.
 
For members with contracts without primary coverage criteria, the use of Naxitamab-gqgk is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
The efficacy of Naxitamab-gqgk in combination with GM-CSF was evaluated in two open-label, single arm trials in patients with high-risk neuroblastoma with refractory or relapsed disease in the bone or bone marrow, Study 201 and Study 12-230.
 
Study 201  
The efficacy of Naxitamab-gqgk in combination with GM-CSF was evaluated in Study 201 (NCT03363373), a multicenter open-label, single arm trial, in a subpopulation of patients who had refractory or relapsed high-risk neuroblastoma in the bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. Patients received Naxitamab-gqgk 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg on Days 1, 3 and 5 of each cycle. Patients received GM-CSF subcutaneously at 250 µg/m2/day on Days -4 to 0 and at 500 µg/m2/day on Days 1 to 5. Preplanned radiation to the primary site was allowed.
 
The major efficacy outcome measure was overall response rate (ORR) according to the revised International Neuroblastoma Response Criteria (INRC), as determined by independent pathology and imaging review and confirmed by at least one subsequent assessment. An additional efficacy outcome measure was duration of response (DOR).
 
Of the 22 patients included in the efficacy analysis, 64% had refractory disease and 36% had relapsed disease; the median age was 5 years (range 3 to 10 years), 59% were male; 45% were White, 50% were Asian and 5% were Black. MYCN amplification was present in 14% of patients and 86% of patients were International Neuroblastoma Staging System (INSS) stage 4 at time of diagnosis. Disease sites included 59% in the bone only, 9% in bone marrow only, and 32% in both. Prior therapies included surgery (91%), chemotherapy (95%), radiation (36%), autologous stem cell transplant (ASCT) (18%), and anti-GD2 antibody treatment (18%).
 
Results demonstrated an ORR 45% (CR 36% and PR of 9% with a duration of response (DOR) of 6.2 months and 30% responders > 6 months.
 
In an exploratory analysis in the subset of patients previously treated with an anti-GD2 antibody (n=4), one patient demonstrated a confirmed complete response and no patients demonstrated a partial response.
 
Study 12-230
The efficacy of Naxitamab-gqgk in combination with GM-CSF was evaluated in Study 12-230 (NCT01757626), a single center, open-label, single arm trial, in a subpopulation of patients who had relapsed or refractory high-risk neuroblastoma in bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. Patients were required to have received at least one dose of Naxitamab-gqgk at a dose of 3 mg/kg or greater per infusion and have evaluable disease at baseline according to independent review per the revised INRC.
 
Patients received Naxitamab-gqgk 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg (on Days 1, 3 and 5) in the first week of each cycle. Patients received GM-CSF subcutaneously at 250 µg/m2/day on Days -4 to 0 and at 500 µg/m2/day on Days 1 to 5. Radiation to non-target bony lesions and soft tissue lesions was permitted at the investigator’s discretion; assessment of response excluded sites that received radiation. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by independent pathology and imaging review according to the revised INRC and confirmed by at least one subsequent assessment.   
 
Of the 38 patients included in the efficacy analysis, 55% had relapsed neuroblastoma and 45% had refractory disease; 50% were male, the median age was 5 years (range 2 to 23 years), 74% were White, 8% Asian and 5% were Black, 5% Native American/American Indian/Alaska Native, 3% other races and 5% was not available. MYCN-amplification was present in 16% of patients and most patients were International Neuroblastoma Staging System (INSS) stage 4 (95%). Fifty percent (50%) of patients had disease involvement in the bone only, 11% only in bone marrow, and 39% in both. Prior therapies included surgery (100%), chemotherapy (100%), radiation (47%), autologous stem cell transplant (ASCT) (42%), and anti-GD2 antibody treatment (58%).
 
Results demonstrated an ORR 34% (CR 26% and PR of 8%) with a duration of response (DOR) of > 6 months in 23%.
 
In an exploratory analysis in the subset of patients previously treated with an anti-GD2 antibody (n=22), the ORR was 18% (95% CI 5%, 40%), with no patients having a documented response of 6 months or greater.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2024. No new literature was identified that would prompt a change in the coverage statement.
 
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2025. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
C9399Unclassified drugs or biologicals
J3490Unclassified drugs
J3590Unclassified biologics
J9348Injection, naxitamab-gqgk, 1 mg
J9999Not otherwise classified, antineoplastic drugs
References: American Cancer Society.(2023) Treating neuroblastoma. Last revised December 19, 2023. Available at https://www.cancer.org/cotent/dam/CRC/PDF/Public/8761.00.pdf. Accessed February 23, 2024

DANYELZA®(2020) (naxitamab-gqgk) [package insert]. New York, NY: Y-mAbs Therapeutics, Inc..; 2020

FDA. 2020.(2020) Danyelza (naxitamab-gqgk). Accessed at https://www.fda.gov. Accessed 2/18/2021.

Micromedex Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed February 23, 2024

Mora , Castaneda A. Gorostegui M, Varo A, Perez-Jaume S, Simao M, Munoz JP, Garraus M, Larrosa C, Salvador N, Lavarino C.(2023) Naxitamab Combined with Granulocyte-Macrophage Colony-Stimulating Factor as Consolidation for High-Risk Neuroblastoma Patients in First Complete Remission under Compassionate Use- Updated Outcome Report Cancers. 2023 Apr 28; 15(9):2535.

Shohet JM, Lowas SR, Nuchtern JG.(2021) Treatment and prognosis of neuroblastoma. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2021.
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.
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