On November 25, 2020, naxita­mab-gqgk (Danyelza) was granted accelerated approval for use in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) for pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow demonstrating a partial response, minor response, or stable disease to prior therapy.^1,2

Supporting Efficacy Data

Approval was based on findings in patients with relapsed or refractory neuroblastoma in the bone or bone marrow enrolled in two single-arm open-label trials: the multicenter Study 201 ­(ClinicalTrials.gov identifier NCT03363373) and the single-center Study 12-230 (NCT01757626).² Patients with progressive disease after their most recent therapy were excluded. Patients received naxitamab at 3 mg/kg via intravenous (IV) infusion on days 1, 3, and 5 of each 4-week cycle in combination with GM-CSF subcutaneously (SC) at 250 μg/m²/d on days –4 to 0 and at 500 μg/m²/d on days 1 to 5. Patients were permitted to receive preplanned radiation to the primary disease site in Study 201 and radiation therapy to nontarget bony lesions or soft-tissue disease in Study 12-230 at investigator discretion.

The main efficacy outcome measures were confirmed overall response rate on International Neuroblastoma Response Criteria (INRC) and duration of response. Among 22 evaluable patients (median age = 5 years, range = 3–10 years) in Study 201, an objective response was observed in 10 (45%, 95% confidence interval [CI] = 24%–68%), including a complete response in 8 (36%). The median duration of response was 6.2 months (95% CI = 4.9 months to not estimable), with 30% of responders having a response for at least 6 months. Among 38 evaluable patients (median age = 5 years, range = 2–23 years) in Study 12-230, an objective response was observed in 13 (34%, 95% CI = 20%–51%), with a complete response in 10 (26%); 23% of responders had a response for at least 6 months. In both trials, responses were observed in bone, bone marrow, or both.

How It Works

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 studies in vitro, naxitamab-gqgk was found to bind to cell surface GD2 and induce complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.

How It Is Used

The recommended dosage of naxitamab is 3 mg/kg/d (up to 150 mg/d) via IV infusion on days 1, 3, and 5 of each 4-week treatment cycle in combination with SC GM-CSF at 250 μg/m²/d on days –4 to 0 and 500 μg/m²/d on days 1 to 5; GM-CSF is to be given at least 1 hour prior to naxitamab on days 1, 3, and 5. Treatment cycles are repeated every 4 weeks until complete response or partial response, followed by five additional cycles every 4 weeks. Subsequent cycles may be repeated every 8 weeks. Treatment should be discontinued for disease progression or unacceptable toxicity.

As described in product labeling, patients must receive medications for pain management prior to and during naxitamab infusion, including prophylactic medication for neuropathic pain and oral opioids prior to initiation of each infusion and additional IV opioids as needed for breakthrough pain during infusion, with use of ketamine considered for pain not adequately controlled by opioids. Patients must receive premedication to reduce the risk of infusion-related reactions and nausea/vomiting.

Product labeling provides instructions on dosage modification, including reduction in the infusion rate, interruption and withholding of treatment, and permanent discontinuation for adverse reactions (eg, infusion-related reactions, pain, reversible posterior leukoencephalopathy syndrome [RPLS], transverse myelitis, peripheral neuropathy, neurologic disorders of the eye, prolonged urinary retention, and hypertension) and other grade 3 or 4 adverse reactions. Treatment should be permanently discontinued for grade 4 infusion-related reactions and grade 3 or 4 anaphylaxis; severe pain unresponsive to maximum supportive measures; any-grade RPLS; any-grade transverse myelitis; grade ≥ 2 motor neuropathy and grade ≥ 3 sensory neuropathy; subtotal or total vision loss; urinary retention persisting following discontinuation of opioids; grade 4 hypertension; and any other grade 4 adverse reactions.

Safety Profile

The most common adverse events of any grade (incidence ≥ 25% in either Study 201 or Study 12-230) in patients receiving naxitamab plus GM-CSF were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection-site reaction, edema, anxiety, localized edema, and irritability.

Among 25 patients treated in Study 201, the most common grade 3 or 4 adverse events were pain (72%), infusion-related reaction (62%), depressed level of consciousness (18%), and anaphylactic reaction (12%). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (39%) and decreased lymphocytes (30%). Serious adverse events occurred in 32% of patients, with the most common being anaphylactic reaction (12%) and pain (8%). Adverse events led to permanent discontinuation of treatment in 12% of patients, with causes including anaphylactic reaction (8%) and respiratory depression (4%).

Among 72 patients receiving treatment in Study 12-230, the most common grade 3 or 4 adverse events were infusion-related reaction (32%), diarrhea (4%), and decreased appetite (4%). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (56%), decreased neutrophils (46%), decreased hemoglobin (42%), decreased platelets (40%), and decreased potassium (32%). Serious adverse events occurred in 40% of patients, with the most common being hypertension (14%), hypotension (11%), and pyrexia (8%). Permanent discontinuation due to adverse events occurred in 8% of patients, with causes including hypertension (6%) and RPLS (1.4%).

Naxitamab has boxed warnings for serious infusion-related reactions and neurotoxicity. The drug also has warnings/precautions for neurotoxicity, including peripheral neuropathy, neurologic disorders of the eye, and prolonged urinary retention; hypertension; and embryofetal toxicity. Naxitamab is contraindicated in patients with a history of severe hypersensitivity reaction to naxitamab. Patients should be advised not to breastfeed while receiving naxitamab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to naxitamab for high-risk neuroblastoma in bone or bone marrow. Available at https://www.fda.gov/drug-approvals-and-databases/fda-grants-accelerated-approval-naxitamab-high-risk-neuroblastoma-bone-or-bone-marrow. Accessed December 10, 2020.

2. Danyelza (naxitamab-gqgk) prescribing information, Y-mAbs Therapeutics Inc, 2020. Available at https:/www.accessdata.fda.gov/drugsatfda_docs/label/2020/761171lbl.pdf. Accessed December 10, 2020.