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The Lancet. Oncology Dec 2018Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma.
METHODS
We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 × 10 IU/m per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed.
FINDINGS
Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0·0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192).
INTERPRETATION
There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available.
FUNDING
European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer.
Topics: Adolescent; Age Factors; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Infant; Interleukin-2; Isotretinoin; Male; Neuroblastoma; Progression-Free Survival; Risk Factors; Time Factors; Young Adult
PubMed: 30442501
DOI: 10.1016/S1470-2045(18)30578-3 -
Hospital Pharmacy Jul 2015Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The...
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, call The Formulary at 800-322-4349. The July 2015 monograph topics are ivabradine, dinutuximab, glycopyrronium bromide/indacaterol, patriromer, and idarucizumab. The Safety MUE is on ivabradine.
PubMed: 26445907
DOI: 10.1310/hpj5007-619 -
Hospital Pharmacy Oct 2015The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues...
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: [email protected]; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: [email protected].
PubMed: 26912916
DOI: 10.1310/hpj5009-767 -
American Journal of Health-system... Apr 2017The pharmacology, clinical efficacy, safety, dosage and administration, and role in therapy of dinutuximab for the treatment of high-risk pediatric neuroblastoma are... (Review)
Review
PURPOSE
The pharmacology, clinical efficacy, safety, dosage and administration, and role in therapy of dinutuximab for the treatment of high-risk pediatric neuroblastoma are reviewed.
SUMMARY
Dinutuximab (Unituxin, United Therapeutics) is a novel monoclonal antibody recently approved for use in combination with granulocyte- macrophage colony-stimulating factor, interleukin-2, and isotretinoin for the treatment of pediatric patients with high-risk neuroblastoma. Its approval has led to the first major change in standard recommended first-line maintenance therapy for high-risk pediatric neuroblastoma in over a decade. Dinutuximab causes antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity by binding to GD2, a tumor-associated antigen. The recommended dosage of dinutuximab is 17.5 mg/m/day for 4 consecutive days of each 24- or 32-day cycle, for a maximum of 5 cycles. In a Phase III trial, patients who received dinutuximab as part of combination immunotherapy in addition to standard maintenance therapy had significantly improved 2-year event-free survival relative to those who received standard maintenance therapy alone (66% versus 46%, < 0.01). Dinutuximab has a unique adverse-effect profile that includes infusion reactions, neuropathic pain, and electrolyte abnormalities; the most common adverse effects observed with dinutuximab use in clinical trials were pain, pyrexia, myelosuppression, infusion reactions, and electrolyte abnormalities.
CONCLUSION
Dinutuximab is a novel monoclonal antibody that is efficacious as part of combination immunotherapy in pediatric patients with high-risk neuroblastoma.
Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Child; Disease-Free Survival; Gangliosides; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunotherapy; Interleukin-2; Isotretinoin; Maintenance Chemotherapy; Neuroblastoma
PubMed: 28389455
DOI: 10.2146/ajhp160228 -
Journal of Research in Medical Sciences... 2023Dinutuximab, which is a monoclonal antibody targeting GD2 expressed in neuroblasts, improves survival when included in the therapy regimen. This article reviews the... (Review)
Review
Dinutuximab, which is a monoclonal antibody targeting GD2 expressed in neuroblasts, improves survival when included in the therapy regimen. This article reviews the importance of dinutuximab in managing neuroblastoma (NB). Dinutuximab targets high levels of GD2 expression in NB cells, thus increasing event-free survival when used in the maintenance therapy of high-risk patients with NB. Although several collaborative studies have set the standard of care for maintenance therapy, the long-term follow-up and continuous evaluation of the use of antibodies and the co-administration of other pharmacological or immunomodulatory drugs remain to be studied. Trials have shown that the use of dinutuximab for maintenance therapy can prolong the time before the first relapse and improve overall survival. However, there is uncertainty in the function of cytokines co-administered with dinutuximab, which may lead to increased toxicity without additional benefits. Recent studies on relapsed and refractory NB have shown the potential efficacy of dinutuximab. Further research is required to properly incorporate Dinutuximab in current treatment modalities.
PubMed: 38116487
DOI: 10.4103/jrms.jrms_727_22 -
Expert Opinion on Drug Safety Dec 2018Dinutuximab, an anti-GD2 antibody, specifically targets the high-expression of GD2 on neuroblastoma cells, and its incorporation into maintenance high-risk neuroblastoma... (Review)
Review
Dinutuximab, an anti-GD2 antibody, specifically targets the high-expression of GD2 on neuroblastoma cells, and its incorporation into maintenance high-risk neuroblastoma therapy has increased event-free survival for this devastating disease. Efficacy of dinutuximab during other phases of therapy or in relapsed and refractory patients remains under investigation. Areas covered: This review looked at available publications (via PubMed search and online abstract catalogs of recent scientific meetings) on pre-clinical safety studies of dinutuximab as well as results and current impressions of pending trials including dinutuximab and other anti-GD2 antibodies. While dinutuximab has become the standard of care for maintenance therapy in many cooperative trials, long-term follow-ups as well as ongoing assessment about timing of antibody use and co-administration of other pharmacologic or immune-modulatory agents remains under study. Expert opinion: Results of these and ongoing trials demonstrate prolonged time to first relapse and potentially overall survival benefit when dinutuximab is used during maintenance therapy. The role cytokines administered in conjunction with dinutuximab remains unclear and may increase toxicity without additional benefit. Current also investigations demonstrate promising efficacy in relapsed and refractory neuroblastoma. Further study is warranted in order to appropriately incorporate dinutuximab into current treatment strategies.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Child; Cytokines; Disease-Free Survival; Gangliosides; Humans; Neuroblastoma; Risk
PubMed: 30433831
DOI: 10.1080/14740338.2018.1549221 -
FEBS Letters Nov 2020Aberrant expression of glycosphingolipids (GSLs) is a unique feature of cancer and stromal cells in tumor microenvironments. Although the impact of GSLs on tumor... (Review)
Review
Aberrant expression of glycosphingolipids (GSLs) is a unique feature of cancer and stromal cells in tumor microenvironments. Although the impact of GSLs on tumor progression remains largely unclear, anticancer immunotherapies directed against GSLs are attracting growing attention. Here, we focus on GD2, a disialoganglioside expressed in tumors of neuroectodermal origin, and Globo H ceramide (GHCer), the most prevalent cancer-associated GSL overexpressed in a variety of epithelial cancers. We first summarize recent advances on our understanding of GD2 and GHCer biology and then discuss the clinical development of the first immunotherapeutic agent targeting a glycolipid, the GD2-specific antibody dinutuximab, its approved indications, and new strategies to improve its efficacy for neuroblastoma. Next, we review ongoing clinical trials on Globo H-targeted immunotherapeutics. We end with highlighting how these studies provide sound scientific rationales for targeting GSLs in cancer and may facilitate a rational design of new GSL-targeted anticancer therapeutics.
Topics: Antibodies, Monoclonal; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Agents, Immunological; Clinical Trials as Topic; Gangliosides; Gene Expression Regulation, Neoplastic; Glycosphingolipids; Humans; Immunotherapy; Neoplasms, Glandular and Epithelial; Neuroectodermal Tumors; Tumor Microenvironment
PubMed: 32860713
DOI: 10.1002/1873-3468.13917 -
International Journal of Molecular... Nov 2021Prognosis of metastatic neuroblastoma is very poor. Its treatment includes induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance with... (Review)
Review
Prognosis of metastatic neuroblastoma is very poor. Its treatment includes induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance with retinoic acid, associated with the anti-GD2 monoclonal antibody (ch14.18) dinutuximab. Immunotherapy determined a significant improvement in survival rate and is also utilized in relapsed and resistant neuroblastoma patients. Five courses of dinutuximab 100 mg/m are usually administered as a 10-day continuous infusion or over 5 consecutive days every 5 weeks. Dinutuximab targets the disialoganglioside GD2, which is highly expressed on neuroblastoma cells and minimally present on the surface of normal human neurons, peripheral pain fibers, and skin melanocytes. Anti GD2 antibodies bind to surface GD2 and determine the lysis of neuroblastoma cells induced by immune response via the antibody-dependent cellular cytotoxicity and the complement-dependent cytotoxicity. Dinutuximab has significant side effects, including neuropathic pain, peripheral neuropathy, hypersensitivity reactions, capillary leak syndrome, photophobia, and hypotension. The most important side effect is neuropathic pain, which is triggered by the same antibody-antigen immune response, but generates ectopic activity in axons, which results in hyperalgesia and spontaneous pain. Pain can be severe especially in the first courses of dinutuximab infusion, and requires the administration of gabapentin and continuous morphine infusion. This paper will focus on the incidence, mechanisms, characteristics, and treatment of neuropathic pain and peripheral neuropathy due to dinutuximab administration in neuroblastoma patients.
Topics: Analgesics; Antibodies, Monoclonal; Gabapentin; Gangliosides; Humans; Morphine; Neoplasm Metastasis; Neuralgia; Neuroblastoma; Peripheral Nervous System Diseases
PubMed: 34884452
DOI: 10.3390/ijms222312648 -
The Annals of Pharmacotherapy May 2016To review the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, and formulary considerations for dinutuximab. (Review)
Review
OBJECTIVE
To review the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, and formulary considerations for dinutuximab.
DATA SOURCES
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.
STUDY SELECTION AND DATA EXTRACTION
Identified English-language articles were reviewed. Selected studies included phase I through III.
DATA SYNTHESIS
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 a chimeric, human-murine, anti-GD2 monoclonal antibody approved in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), aldesleukin (interleukin-2 [IL-2]), and isotretinoin (13-cis-retinoic acid [RA]) for maintenance treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to first-line multiagent, multimodality therapy. In phase III trials, dinutuximab increased 2-year event-free survival and overall survival when compared to standard treatment. Severe adverse effects of dinutuximab include pain, hypersensitivity reactions, capillary leak syndrome, and hypotension.
CONCLUSIONS
Dinutuximab is the first anti-GD2 monoclonal antibody 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 partial response to first-line multiagent, multimodality therapy. Ongoing research will determine if dinutuximab could be used earlier in treatment, in nonresponders to initial therapies, in combination with chemotherapy, or in other cancers.
Topics: Antibodies, Monoclonal; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Immunotherapy; Maintenance Chemotherapy; Neuroblastoma
PubMed: 26917818
DOI: 10.1177/1060028016632013 -
MAbs 2015The commercial pipeline of recombinant antibody therapeutics is robust and dynamic. As of early December 2014, a total of 6 such products (vedolizumab, siltuximab,... (Review)
Review
The commercial pipeline of recombinant antibody therapeutics is robust and dynamic. As of early December 2014, a total of 6 such products (vedolizumab, siltuximab, ramucirumab, pembrolizumab, nivolumab, blinatumomab) were granted first marketing approvals in 2014. As discussed in this perspective on antibodies in late-stage development, the outlook for additional approvals, potentially still in 2014 and certainly in 2015, is excellent as marketing applications for 7 antibody therapeutics (secukinumab, evolocumab, mepolizumab, dinutuximab, nivolumab, blinatumomab, necitumumab) are undergoing a first regulatory review in the EU or US. Of the 39 novel mAbs currently in Phase 3 studies, a marketing application for one (alirocumab) may be submitted in late 2014, and marketing application submissions for at least 4 (reslizumab, ixekizumab, ocrelizumab, obiltoxaximab) are expected in 2015. Other 'antibodies to watch' are those in Phase 3 studies with estimated primary completion dates in late 2014 or 2015, which includes 13 for non-cancer indications (brodalumab, bimagrumab, bococizumab, MABp1, gevokizumab, dupilumab, sirukumab, sarilumab, tildrakizumab, guselkumab, epratuzumab, combination of actoxumab + bezlotoxumab, romosozumab) and 2 (racotumomab and clivatuzumab tetraxetan) undergoing evaluation as treatments for cancer. In addition to the novel antibody therapeutics mentioned, biosimilar infliximab and biosimilar trastuzumab are 'antibodies to watch' in 2015 because of their potential for entry into the US market and regulatory review, respectively.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Humans; United States
PubMed: 25484055
DOI: 10.4161/19420862.2015.988944