The US Food and Drug Administration (FDA) has granted accelerated approval for a new drug for certain patients with neuroblastoma based on response rate results in small open-label trials.
The drug is naxitamab (Danyelza, Y-mAbs Therapeutics), a humanized monoclonal antibody that targets GD2 3F8, a disialoganglioside highly expressed on neuroblastomas.
The product was originally developed at the Memorial Sloan Kettering Cancer Center (MSK) in New York City and licensed exclusively to Y-mAbs. As a result of the licensing arrangement, MSK has institutional financial interests in the product, the company noted.
Naxitamab has been approved for use in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients (children over 1 year old as well as adults) 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.
The accelerated approval was based on results for overall response rate (ORR) and duration of response from two single-arm, open-label trials: Study 201 (NCT 03363373) in 22 patients and Study 12-230 (NCT 01757626) in 38 patients.
In both studies, patients received naxitamab 3 mg/kg administered as an intravenous infusion on days 1, 3, and 5 of each 4-week cycle in combination with GM-CSF subcutaneously at 250 µg/m2/day on days -4 to 0 and at 500 µg/m2/day on days 1 to 5.
Some patients also received radiotherapy. At the investigator’s discretion, patients were permitted to receive pre-planned radiation to the primary disease site in Study 201 and radiation therapy to nontarget bony lesions or soft tissue disease in Study 12-230.
The results showed an ORR of 45% (95% CI, 24% – 68%) in Study 201 and an ORR of 34% (95% CI, 20% – 51%) in Study 12-230.
Responses were observed in the bone and/or bone marrow, the FDA noted.
Less than a third of patients had a duration of response that lasted 6 months or more (30% of responders in Study 201 and 23% of patients in Study 12-230).
The FDA noted that continued approval of the drug may be contingent upon verification and description of clinical benefit in confirmatory trials.
It also noted that the drug was granted priority review, breakthrough therapy, and orphan drug designation. In addition, a priority review voucher was issued for the rare pediatric disease product application.
Boxed Warning and Adverse Events
Naxitamab has a boxed warning about serious infusion-related reactions and neurotoxicity.
The product information notes that in clinical studies, naxitamab has been shown to cause serious infusion reactions including anaphylaxis, cardiac arrest, bronchospasm, stridor, and hypotension. Infusion reactions generally occurred within 24 hours of completing an infusion, most often within 30 minutes of initiation. Infusion reactions are most frequent during the first infusion in each cycle.
In order to mitigate these risks, the company recommends premedication with an antihistamine, acetaminophen, an H2 antagonist and corticosteroid, and close monitoring of patients during and for at least 2 hours after each infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.
Based on its mechanism of action, naxitamab can cause severe pain, the company notes. It recommends premedication with gabapentin and, for example, oral oxycodone, and recommends treating break-through pain with intravenous hydromorphone or equivalent.
In addition, naxitamab may cause severe hypertension. The onset of hypertension may be delayed, so blood pressure should be monitored both during and after infusion.
The product insert also notes that one case of transverse myelitis (Grade 3) and two cases of posterior reversible encephalopathy syndrome (PRES) have been reported.
The most common adverse reactions (incidence ≥ 25% in either trial) 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.
The most common Grade 3 or 4 laboratory abnormalities (≥ 5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium, and decreased phosphate.