Dinutuximab (Unituxin)

Unituxin: Yoo-nee-TUX-in

Dinutuximab: Dee-noo-TUX-uh-mab

Neuroblastoma

Unituxin is approved for:

• Pediatric patients with high-risk neuroblastoma, who have had at least a partial response to prior treatment with multiple agents. Unituxin is used in combination with the cytokine drug granulocyte-macrophage colony-stimulating factor (GM-CSF), the cytokine drug interleukin-2 (IL-2), and 13-cis-retinoic acid (RA).

Limitations of Use

Age: Unituxin is approved for use in pediatric patients based on clinical trials in patients aged 11 months to 15 years. The safety and efficacy of Unituxin in patients outside this age range have not been established.
Pregnancy/Breastfeeding: The risks associated with Unituxin during pregnancy are not known and cannot be ruled out. Due to the potential for harm to the fetus, Unituxin is not recommended for use during pregnancy. Patients who could become pregnant are advised to use contraception during treatment and for at least 2 months after the last dose of Unituxin. The risks associated with Unituxin during breastfeeding are not known and cannot be ruled out. Due to the potential for negative reactions in the breastfed child, women are advised not to breastfeed during treatment with Unituxin.

Antibody therapy

• Cell-killing antibody

Target:

• GD2

Unituxin is an antibody that was made in a laboratory and designed to attach to a protein molecule called GD2. GD2 is present on the surface of nerve cells, but is present in much higher quantities on the surface of neuroblastoma cells. Higher-than-normal amounts of GD2 on neuroblastoma cells make these cells the main targets of Unituxin.

Unituxin and other antibody molecules have an overall “Y” shape. The two tips of the upper arms of the “Y” shape are the parts of the antibody that can very precisely bind to their targets. For Unituxin, the tips of the upper arms bind to GD2. The stem of Unituxin “Y” shape has binding sites for immune cells or other parts of the immune system.

Unituxin works to kill cancer cells in at least two ways:

Complement-dependent cytotoxicity (CDC)

When bound to GD2 on the surface of neuroblastoma cells, the stem of Unituxin can attract and bind molecules of the immune system called “complement” that freely flow in the blood or tissues. Activation of the complement system causes the formation of the “membrane attack complex”, which can puncture and destroy the cell that Unituxin is bound to.

Antibody-dependent cell-mediated cytotoxicity (ADCC)

When bound to GD2 on the surface of neuroblastoma cells, the stem of Unituxin can also attract and bind immune cells (like NK cells). This allows Unituxin to act as a bridge between the target cell and the immune cell. The immune cell then releases molecules that can kill the cell Unituxin is bound to.

Unituxin is given over the course of 5 treatment cycles. Treatment cycles 1, 3, and 5 are each 24 days long, with Unituxin administered slowly through a tube in the vein (intravenous infusion, or i.v.) over the course of 10-20 hours on days 4, 5, 6, and 7. During these treatment cycles, granulocyte-macrophage colony-stimulating factor (GM-CSF) is also given via an injection under the skin or by i.v. infusion on days 1-14, and RA is given by mouth twice a day on days 11-24. Treatment cycles 2 and 4 are each 32 days long, with Unituxin administered over the course of 10-20 hours on days 8, 9, 10, and 11. During these treatment cycles, IL-2 is given continuously via i.v. infusion on days 1-4 and 8-11, and RA is given by mouth twice a day on days 15-18. Starting an hour prior to each infusion of Unituxin, patients receive i.v. hydration (to prevent dehydration), an antihistamine (to prevent allergic reactions), and acetaminophen (to prevent fever and pain). These medications are also given periodically throughout the infusion. Further, a morphine sulfate is administered during the entire infusion process and for 2 hours after the infusion is complete for pain management. If morphine sulfate is not tolerated, other drugs may be used for pain management. 

During treatment with Unituxin, patients are closely monitored for reactions to the infusion. If symptoms of an infusion-related reaction occur, the infusion may be slowed or entirely stopped, depending on the severity of the reaction. Treatment with Unituxin requires a hospital stay.

It is important to keep in mind that each patient’s actual outcome is individual and may be different from the results found in the clinical studies. In addition, with immunotherapy, sometimes it takes several months for responses to be observed.

Neuroblastoma (previously treated)

In a clinical trial, 226 pediatric patients (11 months to 15 years old) with neuroblastoma who had at least a partial response to previous treatment with multiple agents and modalities (chemotherapy, surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy), were treated with Unituxin in combination with GM-CSF, IL-2, and 13-cis-retinoic acid (RA) or with RA alone. After 5 years:

The most common side effects of Unituxin include pain, fever, abnormal blood counts, reactions related to the infusion, low blood pressure, low sodium levels, increased molecules in the blood related to liver or muscle damage, anemia, vomiting, diarrhea, low potassium, capillary leak syndrome, hives, low albumin, and low calcium. Some side effects, such as infections, fevers, infusion-related reactions, low blood potassium, low blood pressure, pain, peripheral neuropathy (nerve pain), neurological disorders of the eye, prolonged urinary retention, inflammation of the spinal cord, Reversible Posterior Leukoencephalopathy Syndrome, bone marrow suppression, electrolyte abnormalities, Atypical Hemolytic Uremic Syndrome (causing blood clots), and capillary leak syndrome can be severe or life-threatening. Patients are monitored for signs and symptoms related to these conditions throughout treatment. These conditions are managed by the healthcare provider.

Infusion-related reactions

Infusion-related reactions are an adverse response to receiving an infusion. Almost all patients treated with Unituxin experience infusion-related reactions with some level of severity. Most of these reactions typically occur within 24 hours of the first or second infusion. Symptoms include hives (itchy red welts) or rash, itchiness (pruritus), and swelling of the tongue, lips, face, or throat. Coughing, shortness of breath, wheezing, difficulty breathing, weakness, low blood pressure, dizziness, or faintness can also occur. Palpitations (feeling as if your heart is fluttering or racing) and chest pain can also be symptoms of a reaction. Serious reactions include anaphylactic shock and cardiac arrest (the heart stops pumping blood around the body).

Nerve damage

Because Unituxin can also target the GD2 molecule on nerve cells, treatment with Unituxin may result in damage to the nervous system, resulting in:

• Pain - most patients treated with Unituxin experienced bodily pain with some degree of severity, including pain in the stomach region, bones, neck, arms, and legs.
• Transverse myelitis - an inflammation of the spinal cord. Symptoms include pain, weakness, sensory problems (numbness, tingling, burning, or aversion to light, sound, touch, taste, or smell), and bladder or bowel problems.
• Reversible posterior leukoencephalopathy syndrome - caused by swelling in the brain that does not compromise blood flow. Symptoms of RPLS include high blood pressure, headache, seizures, visual disturbances, and altered consciousness.
• Peripheral neuropathy - caused by damage to nerves that are responsible for relaying sensory and motor information. Symptoms of peripheral neuropathy include pain, a persistent “pins and needles” sensation, tingling, chilling, burning, numbness, and weakness.
• Neurological disorders of the eye - Symptoms include unequal pupils, blurred or bad vision, difficulty focusing vision, dilated pupils, and extreme light sensitivity.
• Prolonged urinary retention - a condition in which patients cannot completely empty the bladder when peeing. If this condition does not resolve after the administration of opioids has been stopped, then treatment with Unituxin should be permanently stopped.

Low blood pressure

Low blood pressure is a common side effect of treatment with Unituxin, however in rare cases, the condition can become serious. Patients receive iv, hydration and have their blood pressure monitored during each infusion with Unituxin to monitor for any signs and symptoms of low blood pressure.

Patients should report any symptoms to their healthcare provider, who can then initiate actions to limit or reverse the side effects. Treatment with Unituxin may be interrupted and later resumed at a lower dose, or discontinued entirely depending on the severity of the condition. For a more complete list of possible side effects, see the full prescribing information.

Manufacturer

United Therapeutics Corp.

Approval

FDA and EMA (European product name: Qarziba)

Links to drug websites

• US: https://www.unituxin.com/
• EU: https://www.ema.europa.eu/en/medicines/human/EPAR/qarziba-previously-dinutuximab-beta-eusa-dinutuximab-beta-apeiron

Other references

• Long-term follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-risk Neuroblastoma: Children’s Oncology Group Study ANBL0032. Yu AL, et al. Clinical Cancer Research (2021)

Last updated: December 22, 2023

The European product name for Unituxin is Qarziba.