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 high-risk neuroblastoma who meet all of the following criteria:

• Member is less than 21 years of age; and
• 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.

Aetna considers continuation of dinutuximab (Unituxin) medicallly necessary for members meeting initial selection criteria, and when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

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:

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

Dosing Recommendations

Dinutuximab is available as Unituxin in a 17.5 mg/5 mL (3.5 mg/mL) solution for injection, single-use vial. 

The recommended dose of Unituxin is 17.5 mg/m² /day administered as an intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles. Consult the Prescribing Information for dosing administration schedule and required pre-treatment and guidelines for pain management.

Source: United Therapeutics Corp., 2017

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Unituxin is a GD2-binding monoclonal antibody indicated, 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 (United Therapeutics, 2017).

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).

In 2015, dinutuximab (Unituxin) was approved by the 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).

Dinutuximab causes severe neuropathic pain in the majority of patients (United Therapeutics, 2017). 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.

Black Box Warnings

• Infusion Reactions: Life‐threatening infusion adverse reactions occurred in 26% of patients treated with Unituxin. Administer required prehydration and premedication including antihistamines prior to each Unituxin infusion. Immediately interrupt for severe infusion reactions and permanently discontinue for anaphylaxis.
• Neurotoxicity: Unituxin causes serious neurologic adverse reactions including neuropathic pain and peripheral neuropathy. Administer intravenous opioid prior to, during, and for 2 hours following completion of the Unituxin infusion. In clinical studies of patients with high-risk neuroblastoma, Grade 3 peripheral sensory neuropathy occurred in 2% to 9% of patients. In clinical studies of Unituxin and related GD2-binding antibodies, severe motor neuropathy has occurred. Resolution of motor neuropathy did not occur in all cases. Discontinue Unituxin for severe unresponsive pain, severe sensory neuropathy, and moderate to severe peripheral motor neuropathy.

Warnings and Precautions

• Neurological Disorders of the Eye: Interrupt Unituxin for dilated pupil with sluggish light reflex or other visual disturbances and permanently discontinue Unituxin for recurrent eye disorders or loss of vision.
• Prolonged Urinary Retention and Transverse Myelitis: Permanently discontinue Unituxin and institute supportive care.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Permanently discontinue Unituxin and institute supportive care for signs and symptoms of RPLS.
• Capillary Leak Syndrome and Hypotension: Cases of severe (Grade 3 to 5) capillary leak syndrome occurred in the Unituxin/RA group. Grade 3 or 4 hypotension occurred in 16% patients in the Unituxin/RA group compared to no patients in the RA group. Administer required prehydration and monitor patients closely during treatment. Depending upon severity, manage by interruption, infusion rate reduction, or permanent discontinuation.
• Infection: Sepsis occurred in 18% patients in the Unituxin/RA group and in 9% patients in the RA group. Interrupt until resolution of systemic infection.
• Bone Marrow Suppression: Severe (Grade 3 or 4) thrombocytopenia, anemia, neutropenia, and febrile neutropenia occurred more commonly in patients in the Unituxin/RA group. Monitor peripheral blood counts during Unituxin therapy. 
• 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. Permanently discontinue Unituxin and institute supportive management.
• Embryo-Fetal toxicity: May cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception.

Recommended Dose Adjustments

• In the event of mild to moderate adverse reactions such as transient rash, fever, rigors, and localized urticaria 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.

Unituxin has not been studied in patients with renal or hepatic impairment. The safety and effectiveness of Unituxin in geriatric patients have not been established (United Therapeutics, 2017).

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.

There are 2 clinical trials of dinutuximab in the treatment of other malignancies --

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.

Glioblastoma Multiforme

Marx and colleagues (2020) stated that disialoganglioside GD2 is expressed by glioblastoma multiforme (GBM) cells representing a promising target for anti-GD2 immunotherapeutic approaches. The investigators examined the anti-tumor efficacy of dinutuximab beta (DB) against GBM. Expression levels of GD2 and complement regulatory proteins (CRP; CD46, CD55 and CD59) on well-known and newly established primary tumor originated GBM cell lines were analyzed by flow cytometry. Ab-dependent cellular (ADCC) and complement-dependent cytotoxicity (CDC) mediated by DB against GBM cells were determined by a non-radioactive calcein-AM-based assay. Analysis of primary GBM cells revealed a heterogeneous GD2 expression that varied between the cell lines analyzed with higher expression levels in the tumor surface compared to the core originated cells. Both GD2-positive and -negative tumor cells were detected in every cell line analyzed. In contrast to CDC, ADCC mediated by DB was observed against the majority of GBM cells.  Importantly, CDC-resistant cells showed high expression of the CRP CD46, CD55 and CD59. The authors concluded that these findings showed anti-tumor effects mediated by DB against GBM cells providing a rationale for a GD2-directed immunotherapy against GBM. Due to high CRP expression, a combining of GD2-targeting with CRP blockade might be a further therapeutic option for GBM.

Nivolumab and Dinutuximab for the Treatment of Relapsed / Refractory Neuroblastoma

Ehlert and colleagues (2020) noted that in the past 10 years, immunotherapy approaches with checkpoint inhibitors were approved for patients with certain malignant diseases such as melanoma or Hodgkin lymphoma. In pre-clinical models, DB resulted in an up-regulation of the programmed cell death protein 1 (PD-1) checkpoint in neuroblastoma (NB) cell lines and a combined treatment of DB with a murine anti-PD-1 checkpoint inhibitor showed a synergistic effect in a NB mouse model.  These researchers presented the findings of 2 patients who were admitted with refractory metastatic NB.  In the 4-year old girl, NB was diagnosed in 2013.  She completed her 1st-line therapy with a 1st remission in 2015, but suffered a relapse in 2017.  Treatment with chemotherapy and DB resulted in progressive disease after transient improvement.  In the 17-year old young man, NB was first diagnosed in April 2010.  After 2 local relapses in 2011 and 2014, a metastatic relapse and a large abdominal tumor bulk were found in 2018.  Despite transient improvement with multi-modal therapy, progressive metastatic disease was observed in May 2019.  Both patients had a satisfactory quality of life (QOL).  Thus, treatment with DB and nivolumab was carried out – in the girl from October 2018 until August 2019; in the young man since June 2019.  Tolerance to treatment was excellent.  The girl continued to be in complete remission 6 months after therapy was stopped.  In the young man, the soft tissue lesions disappeared completely, the skeletal lesions regressed substantially after 9 months of his still ongoing treatment.  The authors concluded that the combination of DB with nivolumab resulted in complete and a very good PR in 2 patients and may be a promising strategy for relapsed/refractory NB.  Moreover, these researchers stated that prospective trials are needed to examine the role of this novel approach in a larger number of patients.

National Comprehensive Cancer Network (NCCN)

The NCCN Drugs & Biologics Compendium (2020) does not provide a recommendation for dinutuximab (Unituxin) as a treatment option for any cancer indication.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366	each additional hour (List separately in addition to code for primary procedure)
96401 - 96450	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
Dinutuximab (Unituxin) - no specific code:
Other HCPCS codes related to the CPB:
J2820	Injection, sargramostim (GM-CSF), 50 mcg
J9015	Injection, aldesleukin, per single use vial
ICD-10 codes covered if selection criteria are met:
C74.00 - C74.92	Malignant neoplasm of adrenal gland [neuroblastoma]
ICD-10 codes not covered if selection criteria are met:
C34.00 - C34.82	Malignant neoplasm of bronchus and lung [small cell lung cancer]
C40.00 - C41.9	Malignant neoplasm of bone and articular cartilage of limbs [osteosarcoma]
C71.0 - C71.9	Malignant neoplasm of brain [glioblastoma multiforme]

The above policy is based on the following references: