Naxitamab-gqgk (Danyelza)

Number: 0984

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses naxitamab-gqgk (Danyelza) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification.

Precertification of naxitamab-gqgk (Danyelza) is required of all Aetna participating providers and members in applicable plan designs. For precertification of Danyelza, call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   High-risk neuroblastoma

   Aetna considers naxitamab-gqgk (Danyelza) medically necessary for treatment of high-risk neuroblastoma when all of the following criteria are met:

   1. The member is 1 year of age or older with relapsed or refractory disease in the bone or bone marrow; and
   2. The member has demonstrated a partial or minor response or stable disease with prior therapy; and
   3. The requested medication will be used in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF).

   Aetna considers all other indications as experimental, investigational, or unproven. 

2. Continuation of Therapy

   Aetna considers continuation of naxitamab-gqgk (Danyelza) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

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Dosage and Administration

Danyelza (naxitamab-gqgk) is supplied in 40 mg/10 mL (4 mg/mL) single-dose vials for intravenous infusion. 

High-Risk Neuroblastoma: The recommended dosage of Danyelza 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, in combination with GM-CSF administered as a subcutaneous injection as per below:

• Days -4 to 0: administer GM-CSF 250 µg/m² /day by subcutaneous injection, beginning 5 days prior to Danyelza infusion.
• Days 1 to 5: administer GM-CSF 500 µg/m² /day by subcutaneous injection. Administer at least 1 hour prior to Danyelza administration on Days 1, 3, and 5.
• Days, 1, 3, and 5: administer Danyelza 3 mg/kg/day (up to 150 mg/day) by intravenous infusion.

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.

Source: Y-mAbs Therapeutics, 2024

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96413 - 96417	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J9348	Injection, naxitamab-gqgk, 1 mg
Other HCPCS codes related to the CPB:
J2820	Injection, sargramostim (GM-CSF), 50 mcg
ICD-10 codes covered if selection criteria are met:
C74.00 - C74.92	Malignant neoplasm of adrenal gland [neuroblastoma]

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Background

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

• Danyelza is a GD2-binding monoclonal antibody indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of pediatric patients 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.

Danyelza (naxitamab-gqgk) is a humanized, monoclonal antibody that targets the ganglioside GD2, which is highly expressed in various neuroectoderm-derived tumors and sarcomas. 

Danyelza carries a black box warning for risk of serious infusion-related reactions and neurotoxicity. Serious infusion reactions, including cardiac arrest, anaphylaxis, hypotension, bronchospasm, and stridor may occur. Infusion reactions of any Grade occurred in 94-100% of patients. Severe infusion reactions occurred in 32-68% and serious infusion reactions occurred in 4-18% of patients in Danyelza clinical studies. Per the prescribing information, premedicate prior to each Danyelza infusion as recommended and monitor patients for at least 2 hours following completion of each infusion. Reduce the rate, interrupt infusion, or permanently discontinue Danyelza based on severity. Danyelza may also cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis and reversible posterior leukoencephalopathy syndrome (RPLS). Pain of any Grade occurred in 94-100% of patients in the Danyelza clinical studies. The prescribing information recommends to premedicate to treat neuropathic pain. Permanently discontinue Danyelza based on the adverse reaction and severity.

Refer to the Full Prescribing Information on Danyelza for additional information regarding contraindications, adverse reactions, other warnings and precautions, dosing administration, and dosing modifications.

High-Risk Neuroblastoma

Neuroblastoma is a solid tumor that arises in the nervous system, outside of the brain, and occurs most often in infants and young children. Neuroblastoma tumors develop from immature nerve cells, neuroblasts, which are usually located in the adrenal glands; however, tumors may also begin in the neck, chest or spinal cord. The clinical behavior of neuroblastoma is highly variable. Some tumors are easily treatable; however, the majority are very aggressive and are resistant to treament.

There are two methods of neuroblastoma staging, one that is based on post-operative patients, International Neuroblastoma Staging System (INSS), and one developed for pre-treatment patients, International Neuroblastoma Risk Group Staging System (INRGSS), which is based on imaging. INRGSS is now being used to determine staging for most Children's Oncology Group studies, but some studies have results that are being published that used INSS. Based on INSS, which ranges from stage 1 through stage 4S, all patients with stage 4 disease diagnosed after one year of age are classified in the high-risk category, where the neuroblastoma tumor cells have already metastasized to other sites in the body, such as the bone or bone marrow. Essentially all patients who have tumors with many copies, or amplification, of the MYCN oncogene also have high-risk disease, even if they do not have evidence of the tumor having spread (American Cancer Society, 2018; ASCO, 2018; Y-mAbs, 2020).

Therapy for high-risk neuroblastoma has consisted of a regimen of chemotherapy, surgery, tandem cycles of myeloablative therapy, and dinutuximab, with interleukin-2/granulocyte-macrophage colony-stimulating factor (GM-CSF) and isotretinoin (NIH, 2020). In November 2020, the U.S. Food and Drug Administration (FDA) approved Danyelza (naxitamab-gqgk; Y-mAbs, New York, NY), in combination with GM-CSF, for the treatment of pediatric patients 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 regulation based on overall response rate and duration of response. Danyelza is a humanized, monoclonal antibody that targets the ganglioside GD2, which is highly expressed in various neuroectoderm-derived tumors and sarcomas. Danyelza is administered to patients three times in a week in an outpatient setting and the treatment is repeated every four weeks (Y-mAbs, 2020). FDA approval of Danyelza is based on clinical evidence from two pivotal studies (Study 201, NCT03363373; Study 12-230, NCT01757626) in patients with high-risk neuroblastoma with refractory or relapsed disease. 

The efficacy of Danyelza in combination with GM-CSF was evaluated in Study 201, which was a multicenter, open-label, single arm trial, in a subpopulation of patients (n=22; median age 5 years, range 3 to 10 years) 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 Danyelza 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, 64% had refractory disease and 36% had relapsed disease. 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%). Efficacy results include an ORR of 45% (95% CI), complete response rate of 36%, and 9% partial response rate (Y-mAbs, 2024).

The efficacy of Danyelza in combination with GM-CSF was also evaluated in Study 12-230, which was a  a single center, open-label, single arm trial, in a subpopulation of patients (n=38; median age 5 years, range 2 to 23 years) 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 Danyelza 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 Danyelza 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. Efficacy results include an ORR of 34% (95% CI), complete response rate of 26%, and 8% partial response rate. Responders with DOR greater than or equal to 6 months was 23% (Y-mAbs, 2024).

Danyelza appears to be well-tolerated with few discontinuations of treatment in the clinical trials and adverse events were clinically manageable.

Serious infusion-related reactions occurred in 4% of patients in Study 201 and in 18% of patients in Study 12-230. Infusion-related reactions of any Grade occurred in 100% of patients in Study 201 and 94% of patients in Study 12-230. Hypotension of any grade occurred in 100% of patients in Study 201 and 89% of patients in Study 12-230. In Study 201, 68% of patients experienced Grade 3 or 4 infusion reactions; and in Study 12-230, 32% of patients experienced Grade 3 or 4 infusion reactions. Anaphylaxis occurred in 12% of patients and 2 patients (8%) permanently discontinued DANYELZA due to anaphylaxis in Study 201. One patient in Study 12-230 (1.4%) experienced a Grade 4 cardiac arrest 1.5 hours following completion of Danyelza infusion. In Study 201, infusion reactions generally occurred within 24 hours of completing a Danyelza infusion, most often within 30 minutes of initiation. Infusion reactions were most frequent during the first infusion of Danyelza in each cycle. Eighty percent of patients required reduction in infusion rate and 80% of patients had an infusion interrupted for at least one infusion-related reaction (Y-mAbs, 2024).

Pain, including abdominal pain, bone pain, neck pain, and extremity pain, occurred in 100% of patients in Study 201 and 94% of patients in Study 12-230. Grade 3 pain occurred in 72% of patients in Study 201. One patient in Study 201 (4%) required interruption of an infusion due to pain. Pain typically began during the infusion of Danyelza and lasted a median of less than one day in Study 201 (range less than one day and up to 62 days) (Y-mAbs, 2024).

Danyelza can cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis, and reversible posterior leukoencephalopathy syndrome. For patients who develop transverse myelitis, the label states to permanently discontinue Danyelza. Reversible posterior leukoencephalopathy syndrome (RPLS) (also known as posterior reversible encephalopathy syndrome or PRES) occurred in 2 (2.8%) patients in Study 12-230. Events occurred 2 and 7 days following completion of the first cycle of Danyelza. Per the label, monitor blood pressure during and following Danyelza infusion and assess for neurologic symptoms. Permanently discontinue Danyelza in case of symptomatic RPLS (Y-mAbs, 2024).

Study 201 is the ongoing post-marketing clinical trial required by the FDA to verify and to further characterize the clinical benefit, which will enroll a minimum of 80 patients and report ORR, DOR, progression free survival (PFS) and overall survival (OS). The ORR is the primary endpoint for the study, DOR is the secondary endpoint, PFS and OS are secondary endpoints in long-term follow up (Y-mAbs, 2020).

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References