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

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

Warnings and Precautions

Recommended Dose Adjustments

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).

Ewing Sarcoma/Ewing-Like Sarcoma

Spasov et al (2022) stated that despite multi-modal therapy, the prognosis of patients with metastatic Ewing sarcoma (ES) remains poor, with new treatments urgently needed. The disialoganglioside GD2, a well-established tumor-associated antigen, is expressed in 40 % to 90 % of ES cells, making it a suitable therapeutic target. In a retrospective, case-series study, these investigators reported the findings of 3 cases with newly diagnosed, metastatic, GD2-positive ES or Ewing-like sarcoma treated with dinutuximab beta in addition to standard chemotherapeutic regimens. Treatment was well-tolerated, and all patients achieved complete remission (CR), without evidence of relapse. The authors concluded that 1st-line anti-GD2 immunotherapy in patients with metastatic, GD2-positive ES or Ewing-like sarcoma represents a promising therapeutic option that warrants further clinical evaluation.

The authors stated that this case-series study had several drawbacks, including its retrospective design, the small patient number (n = 3), and the short follow-up duration (ranging from 14 to 19 months). These researchers stated that these findings, in addition to previous results achieved with anti-GD2 therapy in neuroblastoma, suggested that a treatment approach combining anti-GD2 immunotherapy and chemotherapy might be worth examining in a wider clinical study in patients with ES and/or ELS, especially those with metastatic disease.

Small Cell Lung Cancer

Edelman et al (2022) stated that topotecan is approved as 2nd-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior tolerability. Pre-clinical studies support disialoganglioside (GD2) as an SCLC target and the combination of dinutuximab, an anti-GD2 antibody, plus irinotecan in this setting. In a randomized, phase-III clinical trial, these researchers examined dinutuximab/irinotecan versus irinotecan or topotecan as 2nd-line therapy in relapsed/refractory (RR) SCLC. Patients with RR SCLC and Eastern Cooperative Oncology Group(ECOG) performance status (PS) 0 to 1 were randomized 2:2:1 to receive dinutuximab 16 to 17.5 mg/m2 intravenous (IV)/irinotecan 350 mg/m2 IV (day 1), irinotecan 350 mg/m2 IV (day 1), or topotecan 1.5 mg/m2 IV (days 1 to 5) in 21-day cycles. The primary endpoint was OS; secondary endpoints were progression-free survival (PFS), objective response rate (ORR; complete response [CR] + partial response [PR]), and clinical benefit rate (CBR; CR + PR + stable disease [SD]). Safety/tolerability were also evaluated. A total of 471 patients were randomized to dinutuximab/irinotecan (n = 187), irinotecan (n = 190), or topotecan (n = 94). Age, sex, PS, prior therapies, and metastatic disease sites were similar between groups. Survival and response rates were not improved for patients receiving dinutuximab/irinotecan versus those receiving irinotecan or topotecan (median OS of 6.9 versus 7.0 versus 7.4 months; p = 0.3132; median PFS of 3.5 versus 3.0 versus 3.4 months; p = 0.3482); ORR of 17.1 % versus 18.9 % versus 20.2 % (p = 0.8043); and CBR of 67.4 % versus 58.9 % versus 68.1 % (p = 0.0989), respectively. Grade 3/4 adverse events (AEs; 5 % or higher receiving dinutuximab/irinotecan) included neutropenia, anemia, diarrhea, and asthenia. The authors concluded that dinutuximab/irinotecan treatment did not result in improved OS in RR SCLC versus irinotecan alone. Irinotecan administered every 21 days demonstrated comparable activity to topotecan administered daily × 5 every 21 days.

Triple-Negative Breast Cancer

Ly et al (2021) noted that triple-negative breast cancer (TNBC) is the most aggressive BC subtype with no effective standard therapy. Breast cancer stem-like cells (BCSCs) in primary TNBCs are reported to be responsible for metastatic spread of the disease and resistance to chemotherapy; however, no available therapeutic tools target BCSCs. These researchers previously reported that the ganglioside GD2 is highly expressed on BCSCs and that inhibition of its expression hampers TNBC growth; thus, they hypothesized that the anti-GD2 antibody dinutuximab (ch14.18) targets GD2+ BCSCs and inhibits TNBC growth. These investigators tested their hypothesis – they first determined GD2 expression via immunohistochemistry in frozen primary tumor samples from patients with TNBC (n = 89). Then, they examined the effects of dinutuximab on TNBC cell adhesion, migration, and mammosphere formation in-vitro and on tumor growth in-vivo using TNBC cell-line and patient-derived xenograft (PDX) models. These researchers found that GD2 was expressed in approximately 60 % of primary TNBC tumors at variable levels and was associated with worse OS of patients with TNBC (p = 0.002). GD2 was found to be expressed in tumors and stroma, but normal ducts and lobules in adjacent tissues have shown low or no GD2 staining, indicating that GD2 is potentially a novel biomarker for tumor and its micro-environment. Treatment with dinutuximab significantly decreased adhesion and migration of MDA-MB-231 and SUM159 TNBC cells. Moreover, dinutuximab treatment inhibited mTOR signaling, which has been shown to be regulated by GD2 in BCSCs. Dinutuximab also reduced tumor growth in nude mice bearing TNBC cell-line xenografts. Finally, dinutuximab in combination with activated natural killer (NK) cells inhibited tumor growth in a TNBC PDX model and improved OS of tumor-bearing mice. The authors concluded that dinutuximab successfully eliminated GD2+ cells and reduced tumor growth in both in-vivo models. These researchers stated that these findings provided proof-of-concept for the criticality of GD2 in BCSCs and demonstrated the potential of dinutuximab as a novel therapeutic agent for the treatment of TNBC.

Shao et al (2022) stated that TNBC is a heterogeneous disease characterized by lack of hormone receptor expression and is known for high rates of recurrence, distant metastases, and poor clinical outcomes. TNBC cells lack targetable receptors; hence, there is an urgent need for targetable markers for the disease. BCSCs are a fraction of cells in primary tumors that are associated with tumorigenesis, metastasis, and resistance to chemotherapy; therefore, targeting BCSCs is an effective approach for preventing cancer metastatic spread and sensitizing tumors to chemotherapy. The CD44hi CD24lo phenotype is a well-established phenotype for identification of BCSCs; however, CD44 and CD24 are not targetable markers owing to their expression in normal tissues. The ganglioside GD2 has been shown to be up-regulated in primary TNBC tumors compared with normal breast tissue and has been shown to identify BCSCs. These investigators discussed GD2 as a BCSC- and tumor-specific marker in TNBC; epithelial-to-mesenchymal transition and the signaling pathways that are up-stream and down-stream of GD2 and the role of these pathways in tumorigenesis and metastasis in TNBC; direct and indirect approaches for targeting GD2; and ongoing clinical trials and treatments directed against GD2 as well as future directions for these strategies. Dinutuximab is one of the key words listed in this study.

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.

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.

Criteria for Initial Approval

Neuroblastoma

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 13-cis-retinoic acid (RA) (isotretinoin), for the treatment of high-risk neuroblastoma when

of the following criteria are met:

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

Continuation of Therapy

Aetna considers continuation of dinutuximab (Unituxin) therapy medicallly necessary for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

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

The recommended dosing is as follows:

Neuroblastoma

Dinutuximab (Unituxin) is administered as 17.5 mg/m

/day 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, 2020

Experimental and Investigational

Aetna considers dinutuximab (Unituxin) 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: