Naxitamab-gqgk – Uses, Dosage, Side Effects, Interaction

The first anti-GD2-monoclonal IgG antibody to be approved by the FDA for the treatment of neuroblastoma was dinutuximab under the brand name Unituxin in 2015.^[rx] One stark disadvantage of this therapy is the requirement for concurrent use of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA?).^[rx]

Naxitamab-gqgk (Danyelza) was granted accelerated approval by the FDA in November 2020 for the treatment of high-risk relapsed/refractory neuroblastoma of the bone or bone marrow.^[rx] This approval requires naxitamab to be co-administered only with GM-CSF, a factor known to enhance the granulocyte-mediated antibody-dependent cytotoxicity of anti-GD2 therapies,^[rx] making the administration of naxitamab therapy markedly simpler than that of its predecessor.

Mechanism of action

Neuroblastomas are neuroendocrine tumors occurring in immature and developing cells of the nervous system and are the most common malignancy diagnosed in children <1 year of age.^[rx] The GD2 disialoganglioside is a glycolipid found highly expressed on the surface of neuroectodermal tumors,^[rx] including neuroblastomas. GD2 exhibits high density and homogeneity across neuroblastomas and a rare occurrence of antigen loss,^[rx] making it a desirable target in the treatment of these cancers.

Naxitamab is an IgG1 monoclonal antibody directed against GD2 disialogangliosides – it binds to GD2 on the surface of neuroblastoma cells and induces both complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC),^[rx] the latter of which is enhanced by co-administration with GM-CSF.^[rx]

or

In targeting cell surface glycoproteins (GD2) that occur on the surface of neuroendocrine tumors, naxitamab directs the immune system toward these cancerous cells and induces the activation of both complement-dependent and antibody-dependent cytotoxicity.^[rx] Naxitamab can cause serious infusion reactions – including hypotension?, hypoxia?, anaphylaxis?, and cardiac arrest? – that necessitate careful monitoring? during therapy. All patients should be pre-medicated with intravenous corticosteroids (e.g. methylprednisolone) as well as an antihistamine, H2 receptor antagonist, acetaminophen, and an antiemetic prior to therapy to mitigate the risk and severity of infusion-related reactions. Naxitamab may also cause severe? neurotoxicity, including significant neuropathic pain, transverse myelitis, reversible posterior leukoencephalopathy syndrome? (RPLS), and ocular toxicities. Pain management should be implemented prior to and during therapy – patients should take a 12-day course of neuropathic pain prophylaxis (e.g. gabapentin) starting 4 days prior to infusion and should receive oral opioids 45-60 minutes prior to infusion and intravenous opioids and/or ketamine as needed thereafter.^[rx]

Indications

• Naxitamab-gqgk is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of patients 1 year of age and older 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.^[rx]
• High-risk, refractory Neuroblastomas of the bone or bone marrow
• High-risk, relapsed Neuroblastomas of the bone or bone marrow
• In combination with granulocyte-macrophage colony-stimulating factor (GMCSF) for 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.

Use in Cancer

Naxitamab-gqgk is approved to be used with granulocyte-macrophage colony-stimulating factor (GM-CSF) to treat:

• Neuroblastoma in the bone or bone marrow that is high risk and has relapsed (come back) or is refractory (does not respond to treatment). It is used in children aged 1 year and older and adults who had at least a partial response to other types of treatment.

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that naxitamab-gqgk provides a clinical? benefit in these patients.

Contraindications

• inflammation? of the spinal cord?
• a painful condition that affects the nerves in the legs and arms called peripheral neuropathy?
• a decrease in sharpness of vision called reduced visual acuity?
• high blood pressure
• an inability to completely empty the bladder?
• pregnancy
• a patient who is producing milk and breastfeeding
• a type of brain disorder called posterior reversible encephalopathy syndrome

Dosage?

Strengths: gqgk 4 mg/mL

Neuroblastoma

• 3 mg/kg/day (up to 150 mg/day) IV on Days 1, 3, and 5 of each cycle in combination with GM-CSF subcutaneously
  NOTE: For the first infusion (Cycle 1, Day 1), administer over 60 minutes; for subsequent infusions, administered over 30 to 60 minutes, as tolerated.

RECOMMENDED DOSE REGIMEN FOR EACH TREATMENT CYCLE:

• DAYS -4 to 0: Administer GM-CSF 250 mcg/m2 subcutaneously daily beginning 5 days prior to naxitamab infusion
• DAYS 1 to 5: Administer GM-CSF 500 mcg/m2 subcutaneously daily at least 1 hour prior to naxitamab on Days 1, 3, and 5
• DAYS 1, 3, and 5: Administer naxitamab 3 mg/kg/day (up to 150 mg/day) IV
• Duration of therapy: 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 this drug and GM-CSF for disease progression? or unacceptable toxicity.

PREMEDICATIONS AND SUPPORTIVE MEDICATIONS PAIN MANAGEMENT PRIOR TO AND DURING INFUSION:

• Five days prior to the first infusion of naxitamab in each cycle, initiate a 12-day course (Day -4 through Day 7) of prophylactic medication for neuropathic pain, such as gabapentin.
• Administer oral opioids 45 to 60 minutes prior to initiation of each naxitamab infusion and additional IV opioids as needed for breakthrough pain during the infusion. Consider the use of ketamine for pain that is not adequately controlled by opioids.

PREMEDICATION: REDUCE RISK OF INFUSION-RELATED REACTIONS AND NAUSEA?/VOMITING?:

• Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg with maximum dose of 80 mg or equivalent corticosteroid dose) 30 minutes to 2 hours prior to the first infusion of naxitamab.
• Administer corticosteroid premedication for subsequent infusions if a severe infusion reaction occurred with the previous infusion or during the previous cycle.
• Administer an antihistamine, an H2 antagonist, acetaminophen and an antiemetic 30 minutes prior to each infusion.
• Refer to the GM-CSF Prescribing Information for recommended dosing information.
• Administer pre-infusion medications and supportive treatment, if needed, during infusion.

Usual Pediatric Dose

Neuroblastoma

1 year and older:

• 3 mg/kg/day (up to 150 mg/day) IV on Days 1, 3, and 5 of each cycle in combination with GM-CSF subcutaneously
• For the first infusion (Cycle 1, Day 1), administer over 60 minutes; for subsequent infusions, administer over 30 to 60 minutes, as tolerated.

RECOMMENDED DOSE REGIMEN FOR EACH TREATMENT CYCLE:

• DAYS -4 to 0: Administer GM-CSF 250 mcg/m2 subcutaneously daily beginning 5 days prior to naxitamab infusion
• DAYS 1 to 5: Administer GM-CSF 500 mcg/m2 subcutaneously daily at least 1 hour prior to naxitamab on Days 1, 3, and 5
• DAYS 1, 3, and 5: Administer naxitamab 3 mg/kg/day (up to 150 mg/day) IV
• Duration of therapy: 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 this drug and GM-CSF for disease progression? or unacceptable toxicity.

PREMEDICATIONS AND SUPPORTIVE MEDICATIONS PAIN MANAGEMENT PRIOR TO AND DURING INFUSION:

• Five days prior to the first infusion of naxitamab in each cycle, initiate a 12-day course (Day -4 through Day 7) of prophylactic medication for neuropathic pain, such as gabapentin.
• Administer oral opioids 45 to 60 minutes prior to initiation of each naxitamab infusion and additional IV opioids as needed for breakthrough pain during the infusion.
• Consider use of ketamine for pain that is not adequately controlled by opioids.

PREMEDICATION: REDUCE RISK OF INFUSION-RELATED REACTIONS AND NAUSEA/VOMITING:

• Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg with maximum dose of 80 mg or equivalent corticosteroid dose) 30 minutes to 2 hours prior to the first infusion of naxitamab.
• Administer corticosteroid premedication for subsequent infusions if a severe infusion reaction occurred with the previous infusion or during the previous cycle.
• Administer an antihistamine, an H2 antagonist, acetaminophen and an antiemetic 30 minutes prior to each infusion.
• Refer to the GM-CSF Prescribing Information for recommended dosing information.
• Administer pre-infusion medications and supportive treatment, if needed, during infusion.

Dose Adjustments

MISSED DOSE:

• If a naxitamab dose is missed, administer the missed dose the following week by Day 10. Administer GM-CSF 500 mcg /m2 /day on the first day of the naxitamab infusion, and on the day before and on the day of the second and third infusion, respectively (i.e., a total of 5 days with 500 mcg /m2 /day).

DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
INFUSION-RELATED REACTIONS:

• GRADE 2 (therapy or infusion interruption indicated but responds promptly to symptomatic treatment [e.g., antihistamines, NSAIDS, narcotics, IV fluids]; prophylactic medications indicated for 24 hours or less): Reduce naxitamab infusion rate to 50% of previous rate and monitor closely until recovery to Grade 1 or less; increase infusion rate gradually to rate prior to the event as tolerated.
• GRADE 3 (prolonged [e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion]; recurrence? of symptoms following initial improvement; hospitalization indicated for clinical sequelae?): Immediately interrupt naxitamab infusion and monitor until recovery to Grade 2 or less; resume infusion at 50% of the rate prior to the event and increase infusion rate gradually to infusion rate prior to the event as tolerated; permanently discontinue therapy in patients not responding to medical intervention.
• GRADE 4 (e.g., life-threatening consequences: urgent intervention indicated or Grade 3 or 4 anaphylaxis): Permanently discontinue therapy.

PAIN:

• GRADE 3 (e.g., unresponsive to maximum supportive measures): Permanently discontinue therapy.

REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME (RPLS):

• ALL GRADES: Permanently discontinue therapy.

TRANSVERSE MYELITIS:

• ALL GRADES: Permanently discontinue therapy.

PERIPHERAL NEUROPATHY?:

• Motor neuropathy (GRADE 2 or greater OR sensory neuropathy (GRADE 3 or 4): Permanently discontinue therapy.

NEUROLOGICAL DISORDERS OF THE EYE:

• GRADE 2 to 4 resulting in decreased visual acuity or limiting activities of daily living: Withhold therapy until resolution; if resolved resume therapy at 50% of the prior dose; if tolerated without recurrence of symptoms, gradually increase to dose prior to onset? of symptoms; permanently discontinue naxitamab if not resolved within 2 weeks or upon recurrence.
• Subtotal or total vision loss: Permanently discontinue therapy.

PROLONGED URINARY RETENTION?:

• Persisting following discontinuation of opioids: Permanently discontinue therapy.

HYPERTENSION?:

• GRADE 3: Withhold therapy or pause infusion until recovery to Grade 2 or less; resume infusion at 50% of prior rate; if tolerated without recurrence of symptoms, gradually increase to rate prior to onset of symptoms; permanently discontinue therapy in patients not responding to medical intervention.
• GRADE 4: Permanently discontinue therapy.

OTHER ADVERSE REACTIONS:

• GRADE 3: Withhold therapy or pause infusion until recovery to Grade 2 or less; If resolved to Grade 2 or less resume at same rate; permanently discontinue therapy if not resolved to Grade 2 or less within 2 weeks.
• GRADE 4: Permanently discontinue therapy.

Administration advice:

• Administer this drug as a diluted IV infusion.
• Do not administer as an IV push or bolus.
• Observe patients for a minimum of 2 hours following each infusion.

Side Effects

The Most Common

• vomiting
• nausea
• diarrhea
• loss of appetite
• anxiety
• tiredness
• cough, runny nose, fever, or other signs of infection
• severe headache, racing or irregular heartbeat, chest pain, dizziness, shortness of breath, nose bleeds, or fatigue
• severe pain anywhere in your body;
• numbness, tingling, or burning pain in your hands or feet;
• severe headache, confusion, thinking problems, weakness, and vision loss;
• a seizure;
• painful or difficult urination;
• cold symptoms–such as runny or stuffy nose, sneezing, sore throat, cough, low fever, and not feeling well;
• eye problems–blurred vision, trouble focusing, dilated pupils, unequal pupil size, being more sensitive to light;
• high blood pressure–headache, nausea, vomiting, dizziness, vision changes, nosebleeds, chest pain, fast or pounding heartbeats, pounding in your neck or ears; or
• low blood cell counts, or other abnormal lab tests;
• skin rash or hives;
• swelling; headache, fever, feeling tired;
• fast heart rate; feeling anxious or irritable; cough; or
• pain, bruising, swelling, or irritation where the medicine was injected.low blood cell counts–fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet, feeling light-headed or short of breath.

More common

• Back pain, sudden and severe
• bigger, dilated, or enlarged pupils (black part of eye)
• blurred vision
• bone pain
• burning, numbness, tingling, or painful sensations
• change in color vision
• chest tightness
• confusion
• decrease in frequency of urination
• decrease in urine volume
• difficulty in passing urine
• difficulty seeing at night
• dizziness
• drowsiness
• fever
• flushing
• headache
• increased sensitivity of the eyes to light
• muscle weakness, sudden and progressing
• nausea and vomiting
• nervousness
• painful urination
• pounding in the ears
• seizures
• slow or fast heartbeat
• stomach pain
• swelling
• trouble breathing
• unsteadiness or awkwardness
• unusual tiredness or weakness
• weakness in the arms, hands, legs, or feet

Rare

• Constipation
• diarrhea
• Blistering, peeling, loosening of the skin
• chills
• cough
• decreased appetite
• fast heartbeat
• flushing, redness of the skin
• increased sweating
• itching
• joint or muscle pain
• red, irritated eyes
• runny nose
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• unusual drowsiness, dullness, tiredness, weakness or feeling of sluggishness
• unusually warm skin

Naxitamab-gqgk may cause other side effects. Call your doctor if you have any unusual problems while receiving this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration’s (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Drug interaction

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Based on its mechanism of action, Naxitamab-gqgk may cause fetal harm when administered to pregnant women. There are no available data on the use of Naxitamab-gqgk in pregnant women and no animal reproduction studies have been conducted with Naxitamab-gqgk. IgG1 monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Advise pregnant women of the potential risk to a fetus.

Lactation

There are no data on the presence of naxitamab-gqgk in human milk or its effects on the breastfed child, or on milk production, however, human IgG is present in human milk. Because of the potential for serious adverse reactions in a breastfed child from DANYELZA, advise women not to breastfeed during treatment and for 2 months after the final dose.

References