Dinutuximab (Unituxin)

Number: 0895

Policy

Aetna considers dinutuximab (Unituxin) medically necessary, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim (Leukine)), interleukin-2 (IL-2) (aldesleukin (Proleukin)), and isotretinoin (13-cis-retinoic acid (RA)), for the treatment of children and adolescents less than 18 years of age with high-risk neuroblastoma who meet the following criteria:

• member has achieved at least a partial response to prior first-line multiagent, multimodality therapy that includes induction combination chemotherapy and maximum feasible surgical resection; and
• member has had the previous procedure/therapy:
  
  
  • myeloablative consolidation chemotherapy followed by autologous stem cell transplantation; and
  • radiation therapy to residual soft tissue disease.

Aetn considers dinutuximab not medicallly necessary for persons who have experienced disease progression on dinutuximab.

Aetna considers dinutuximab experimental and investigational for all other indications including the following (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Lung cancer (e.g., small cell lung cancer)
• Osteosarcoma.

Background

Neuroblastoma is a tumor derived from primitive cells of the sympathetic nervous system and is the most common extracranial tumor in childhood, the second most common solid tumor in childhood, the most common cancer in infancy, Neuroblastoma makes up approximately 8% of the total number of children's cancers (NIHR HSC, 2014)with an annual incidence in the United States of approximately 700 patients, of whom 50% are diagnosed as having high-risk disease (United Therapeutics, 2015)..

Treatment of neuroblastoma depends on risk category, which is determined according to the age of the child, the size and position of the tumor, stage, the tumor biology and whether the neuroblastoma has spread (NIHR HSC, 2014). Based on various prognostic factors and the International Neuroblastoma Staging System (INSS), children are classified into 3 different risk groups: low, intermediate, and high. High-risk neuroblastoma is characterized by age (>1 year), disseminated disease, MYCN oncogene amplification, and/or unfavourable histopathologic findings; approximately 40% of children with neuroblastoma are classified as high-risk.

Unituxin (dinutuximab) is a disialoganglioside, GD2-binding chimeric monoclonal antibody (formerly ch14.18), composed of a combination of mouse and human DNA, which binds to the glycolipid GD2. This glycolipid is expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including the central nervous system and peripheral nerves. Unituxin (dinutuximab) binds to cell surface GD2 and induces cell lysis of GD2‐expressing cells through antibody‐dependent cell‐mediated cytotoxicity and complement‐dependent cytotoxicity and is part of an immunotherapeutic regimen to treat pediatric high-risk neuroblastoma (United Therapeutics, 2015).

Dinutuximab (Unituxin) has been approved by the U.S. Food and Drug Administration (FDA) for use, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy (FDA, 2015). In clinical trials for FDA approval, dinutuximab was used in pediatric patients with high‐risk neuroblastoma who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and autologous stem cell transplantation (ASCT). 

The FDA approval was based on demonstration of improved event-free survival (EFS) and overall survival (OS) in a multicenter, open-label, randomized trial (ANBL0032) in pediatric patients with high-risk neuroblastoma, conducted by the Children's Oncology Group (COG) (United Therapeutics, 2015).  All patients had received prior therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy to residual soft tissue disease. Patients were required to have achieved at least a partial response prior to autologous stem cell transplantation, have no evidence of disease progression following completion of front-line multi-modality therapy, have adequate pulmonary function (no dyspnea at rest and peripheral arterial oxygen saturation of at least 94% on room air), adequate hepatic function (total bilirubin < 1.5 x the upper limit of normal and ALT < 5 x the upper limit of normal), adequate cardiac function (shortening fraction of > 30% by echocardiogram, or if shortening fraction abnormal, ejection fraction of 55% by gated radionuclide study), and adequate renal function (glomerular filtration rate at least 70 mL/min/1.73 m2). Patients with systemic infections or a requirement for concomitant systemic corticosteroids or immunosuppressant usage were not eligible for enrollment.

The trial randomized (1:1) 226 patients to either the dinutuximab/13-cis-retinoic acid (RA) arm or the RA alone arm.  Patients in each arm received six cycles of treatment.  The dinutuximab/RA arm consisted of dinutuximab in combination with granulocyte macrophage-colony stimulating factor and RA (cycles 1, 3, and 5), dinutuximab in combination with interleukin-2 and RA (cycles 2 and 4), and RA (cycle 6).  Patients were 11 months to 15 years of age (median age 3.8 years). 

The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy, or death (United Therapeutics, 2015).  At the seventh interim analysis, an improvement in EFS [HR 0.57 (95% CI: 0.37, 0.89); p = 0.01, log-rank test] was demonstrated and four remaining patients undergoing treatment on the RA arm crossed over to receive dinutuximab/RA.  The median EFS was not reached (3.4 years, NR) in the dinutuximab/RA arm and was 1.9 years (1.3, NR) in the RA arm.  An analysis of overall survival (OS) conducted three years later documented an improvement in OS in the dinutuximab/RA arm compared to the RA arm [HR 0.58 (95% CI: 0.37, 0.91)].  At the time of this survival analysis, median OS had not been reached in either arm. 

The most common serious adverse reactions (greater than or equal to 5%) are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome (United Therapeutics, 2015). 

The most common adverse drug reactions (greater than or equal to 25%) in dinutuximab/RA compared with RA alone are pain (85% vs. 16%), pyrexia (72% vs. 27%), thrombocytopenia (66% vs. 43%), lymphopenia (62% vs. 36%), infusion reactions (60% vs. 9%), hypotension (60% vs. 3%), hyponatremia (58% vs. 12%), increased alanine aminotransferase (56% vs. 31%), anemia (51% vs. 22%), vomiting (46% vs. 19%), diarrhea (43% vs. 15%), hypokalemia (43% vs. 4%), capillary leak syndrome (40% vs. 1%), neutropenia (39% vs. 16%), urticaria (37% vs. 3%), hypoalbuminemia (33% vs. 3%), increased aspartate aminotransferase (28% vs. 7%), and hypocalcemia (27% vs. 0%) (United Therapeutics, 2015).

Other Cancers

Ploessi and colleagues (2016) reviewed the pharmacology, pharmacokinetics, safety, effectiveness, dosage and administration, and formulary considerations for dinutuximab.  Medline was searched (1964 to January 2016) using the terms ch14.18, dinutuximab, immunotherapy, and neuroblastoma.  Other information was identified from package insert, Biologics License Application, abstracts, news releases, and ClinicalTrials.gov.  Identified English-language articles were reviewed.  Selected studies included phase I through III.  High-risk neuroblastoma is primarily a childhood cancer with 5-year survival rates of 40 % to 50 %.  Treatment for high-risk neuroblastoma includes induction chemotherapy, surgery, myeloablative chemotherapy with autologous hematopoietic stem cell transplant, and radiation therapy.  For patients achieving clinical remission, limited treatments exist for preventing relapse.  Dinutuximab is approved in combination with GM-CSF, aldesleukin, and isotretinoin for maintenance treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response (PR) to 1st-line multi-agent, multi-modality therapy.  In phase III clinical trials, dinutuximab increased 2-year EFS and OS when compared to standard treatment.  Severe adverse effects of dinutuximab include pain, hypersensitivity reactions, capillary leak syndrome, and hypotension.  The authors concluded that dinutuximab is the 1st anti-GD2 monoclonal antibody (MAb) approved in combination with GM-CSF, IL-2, and RA for maintenance treatment of pediatric patients with high-risk neuroblastoma who achieve at least a PR to 1st-line multi-agent, multi-modality therapy.  They stated that ongoing research will determine if dinutuximab could be used earlier in treatment, in non-responders to initial therapies, in combination with chemotherapy, or in other cancers.

1. a phase-II trial: “Dinutuximab in Combination With Sargramostim in Treating Patients With Recurrent Osteosarcoma” (last verified September 2017), and
2. a phase II/III trial: “Dinutuximab and Irinotecan Versus Irinotecan to Treat Subjects With Relapsed or Refractory Small Cell Lung Cancer” (last verified August 2017). 

Both trials are currently recruiting subjects.

The National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2017) does not list dinutuximab (Unituxin) as a cancer treatment indication.

Appendix

Dinutuximab is available as Unituxin in a 17.5mg/5mL solution for injection, single‐use vial. The recommended dose and schedule for dinutuximab is 17.5 mg/m2/day as a diluted intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles (United Therapeutics, 2015).  Patients require intravenous treatment with opioids prior to, during, and for 2 hours following the dinutuximab infusion to mitigate neuropathic pain.  Prior to each dinutuximab dose, intravenous hydration should be administered and the patient premedicated with antihistamines, analgesics, and antipyretics. The management of symptomatic adverse drug reactions, such as peripheral neuropathy and infusion reactions, may require infusion rate reduction, or treatment discontinuation of Unituxin (dinutuximab).

Unituxin (dinutuximab) should be prescribed by an oncologist.

Dinutuximab is contraindicated in patients with a history of anaphylaxis to dinutuximab (United Therapeutics, 2015). 

In connection with the Unituxin approval, United Therapeutics agreed to certain postmarketing requirements (PMRs) and certain postmarketing commitments (PMCs) (United Therapeutics, 2015). 

Serious and potentially life threatening infusion reactions (facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension) occurred in 26% of patients treated with dinutuximab (United Therapeutics, 2015). The labeling requires prehydration and premedication including antihistamines prior to each dinutixmab infusion. Patients should be monitored closely for signs and symptoms of an infusion reaction during and for at least four hours following completion of each dinutuximab infusion. Dinutuximab should be immediately interrupted for severe infusion reactions and permanently discontinued for anaphylaxis. 

Dinutuximab causes severe neuropathic pain in the majority of patients (United Therapeutics, 2015). Intravenous opioid should be administered prior to, during, and for 2 hours following completion of the dinutuximab infusion. Severe (Grade 3) peripheral sensory neuropathy ranged from 2% to 9% in patients with neuroblastoma. In clinical studies of dinutuximab and related GD2-binding antibodies, severe motor neuropathy was observed in adults.  Resolution of motor neuropathy was not documented in all cases. Dinutuximab should be discontinued for severe unresponsive pain, severe sensory neuropathy, or moderate to severe peripheral motor neuropathy. 

Serious infusion reactions requiring urgent intervention including blood pressure support, bronchodilator therapy, corticosteroids, infusion rate reduction, infusion interruption, or permanent discontinuation of dinutuximab included facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension (United Therapeutics, 2015).  Infusion reactions generally occurred during or within 24 hours of completing the dinutuximab infusion.  Due to overlapping signs and symptoms, it was not possible to distinguish between infusion reactions and hypersensitivity reactions in some cases.  Severe (Grade 3 or 4) infusion reactions occurred in 35 (26%) patients in the dinutuximab/13-cis-retinoic acid (RA) group compared to 1 (1%) patient receiving RA alone. 

Eighty-five percent (114) of patients treated in the dinutuximab/RA group experienced pain despite pre-treatment with analgesics including morphine sulfate infusion (United Therapeutics, 2015).  Severe (Grade 3) pain occurred in 68 (51%) patients in the dinutuximab/RA group compared to 5 (5%) patients in the RA group. 

Severe (Grade 3) peripheral sensory neuropathy occurred in 2 (1%) patients and severe peripheral motor neuropathy occurred in 2 (1%) patients in the dinutuximab/RA group (United Therapeutics, 2015). 

Severe (Grade 3 to 5) capillary leak syndrome occurred in 31 (23%) patients in the dinutuximab/RA group and in no patients treated with RA alone (United Therapeutics, 2015). 

Depending on severity, adverse events should be managed by immediate interruption, infusion rate reduction or permanent discontinuation of dinutuximab (United Therapeutics, 2015). 

Severe (Grade 3 or 4) hypotension occurred in 22 (16%) patients in the dinutuximab/RA group compared to no patients in the RA group (United Therapeutics, 2015). The labeling recommends that intravenous hydration be administered prior to each dinutuximab infusion. Blood pressure should be closely monitored during dinutuximab treatment. Depending on severity, adverse reactions should be managed by immediate interruption, infusion rate reduction or permanent discontinuation of dinutuximab. 

Severe (Grade 3 or 4) bacteremia requiring intravenous antibiotics or other urgent intervention occurred in 17 (13%) patients in the dinutuximab/RA group compared to 5 (5%) patients treated with RA alone (United Therapeutics, 2015).  Sepsis occurred in 24 (18%) of patients in the dinutuximab/RA group and in 10 (9%) patients in the RA group. Patients should be monitored closely for signs and symptoms of systemic infection and dinutuximab should be temporarily discontinued in patients who develop systemic infection until resolution of the infection. 

Neurological disorders of the eye experienced by two or more patients treated with dinutuximab included blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema (United Therapeutics, 2015). The labeling recommends interrupting dinutuximab in patients experiencing dilated pupil with sluggish light reflex or other visual disturbances that do not cause visual loss. Upon resolution and if continued treatment with dinutuximab is warranted, the labeling recommends decreasing the dose of dinutuximab by 50%. Dinutuximab should be permanently discontinued in patients with recurrent eye disorder following dose reduction and in patients who experience loss of vision. 

Severe (Grade 3 or 4) thrombocytopenia (39% vs. 25%), anemia (34% vs. 16%), neutropenia (34% vs. 13%) and febrile neutropenia (4% vs. 0 patients) occurred more commonly in patients in the dinutuximab/RA group compared to patients treated with RA alone (United Therapeutics, 2015). Peripheral blood counts should be closely monitored during dinutuximab therapy. 

Severe (Grade 3 or 4) hypokalemia and hyponatremia occurred in 37% and 23% of patients in the dinutuximab/RA group, respectively, compared to 2% and 4% of patients in the RA group (United Therapeutics, 2015). The labeling recommends monitoring serum electrolytes daily during therapy with dinutuximab. 

Hemolytic uremic syndrome in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension occurred in two patients following receipt of the first cycle of dinutuximab (United Therapeutics, 2015). The labeling recommends permanent discontinuation of dinutuximab and institution of supportive management. 

Dinutuximab may cause fetal harm (United Therapeutics, 2015). Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment, and for two months after the last dose of dinutuximab.

Unituxin (dinutuximab) should not be used in the following

• Patients with hypersensitivity to Unituxin (dinutuximab) or any of its components;
• Women who are pregnant or lactating and have not been apprised of the potential hazard to the fetus;
• Patients greater than 18 years of age (safety and efficacy have not been established);
• Patients with renal and hepatic impairment (safety and efficacy have not been established);
• Patients that have experienced severe or life‐threatening reactions while receiving Unituxin (dinutuximab), including severe infusion‐related reaction including anaphylaxis, and severe peripheral neuropathy.

Warnings and Precautions

• Serious Infusion Reactions: Severe (Grade 3 or 4) infusion reactions occurred in 26% patients in the Unituxin/13‐cis‐retinoic acid (RA) group compared to 1% patient receiving RA alone. Cases of severe urticaria also occurred in the Unituxin/RA group causing 2 discontinuations. Additionally, 1 patient had multiple cardiac arrests and died within 24 hours after having received Unituxin
• Pain: Severe (Grade 3) pain occurred in 68 (51%) patients in the Unituxin/RA group compared to 5 (5%) patients in the RA group. Pain typically occurred during the Unituxin infusion and was most commonly reported as abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal chest pain, and arthralgia.
• Peripheral Neuropathy: Severe (Grade 3) peripheral sensory neuropathy and severe peripheral motor neuropathy occurred in 1% patients in the Unituxin/RA group.
• Capillary Leak Syndrome: Cases of severe (Grade 3 to 5) capillary leak syndrome occurred in the Unituxin/RA group.
• Hypotension: Grade 3 or 4 hypotension occurred in 16% patients in the Unituxin/RA group compared to no patients in the RA group.
• Infection: Sepsis occurred in 18% patients in the Unituxin/RA group and in 9% patients in the RA group.
• Neurological Disorders of the Eye: Neurological disorders of the eye experienced by two or more patients treated with Unituxin in the clinical studies included blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema.
• Bone Marrow Suppression: Severe (Grade 3 or 4) thrombocytopenia, anemia, neutropenia, and febrile neutropenia occurred more commonly in patients in the Unituxin/RA group.
• Electrolyte Abnormalities: Cases of patients receiving Unituxin developed syndrome of inappropriate antidiuretic hormone secretion resulting in severe hyponatremia.
• Atypical Hemolytic Uremic Syndrome: Hemolytic uremic syndrome in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension occurred in 2 patients following receipt of the first cycle of Unituxin. Atypical hemolytic uremic syndrome recurred following rechallenge with Unituxin in one patient.

Black Box warnings

• Infusion Reactions: Life‐threatening infusion adverse reactions occur with Unituxin.
• Administer required prehydration and premedication. Immediately interrupt for severe infusion reactions and permanently discontinue for anaphylaxis.
• Neuropathy: Unituxin causes severe neuropathic pain. Administer intravenous opioid prior to, during, and for 2 hours following completion of the Unituxin infusion. Severe peripheral sensory neuropathy ranged from 2% to 9% in patients with neuroblastoma. Severe motor neuropathy was observed in adults. Discontinue for severe unresponsive pain, severe sensory neuropathy, or moderate to severe peripheral motor neuropathy.

Recommended Dose Adjustments

• In the event of mild to moderate adverse reactions such as transient rash, fever, rigors, and localized urticarial that respond promptly to symptomatic treatment.
   
  • Onset of reaction: Reduce Unituxin infusion rate to 50% of the previous rate and monitor closely.
  • After resolution: Gradually increase infusion rate up to a maximum rate of 1.75 mg/m2/hour.
     
• In the event of prolonged or severe adverse reactions such as mild bronchospasm without other symptoms, angioedema that does not affect the airway.
   
  • Onset of reaction: Immediately interrupt Unituxin.
  • After resolution: If signs and symptoms resolve rapidly, resume Unituxin at 50% of the previous rate and observe closely.
  • Second recurrence: Permanently discontinue Unituxin.
    
    

The above policy is based on the following references: