Ladenstein R, et al. - In children and young people with high-risk neuroblastoma, authors evaluated the event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous interleukin-2 (IL-2), compared with dinutuximab beta alone. Improved outcomes were not seen with the addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Findings demonstrated an association between subcutaneous IL-2 with dinutuximab beta and greater toxicity than dinutuximab beta alone. Until results of ongoing randomized trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available, they suggested the consideration of dinutuximab beta and isotretinoin without subcutaneous IL-2 as the standard of care.

Methods

• Experts conducted an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries.
• The age of the eligible patients was 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of anyMYCN status, according to the International Neuroblastoma Staging System.
• Eligibility criteria for the patients comprised enrollment at diagnosis in the HR-NBL1/SIOPEN trial, completion of the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), achievement of a disease response that fulfilled prespecified criteria, reception of high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and reception of radiotherapy to the primary tumour site.
• In this component of the trial, they randomly assigned the patients (1:1) to receive dinutuximab beta (20 mg/m² per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 × 10⁶IU/m²per 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.
• Oral isotretinoin (160 mg/m²per day for 2 weeks) was received by all participants before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles.
• A 3-year event-free survival, analysed by intention to treat was the primary endpoint.

Results

• As per data, 422 patients were eligible between Oct 22, 2009, and Aug 12, 2013 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).
• Findings suggested that 4·7 years (IQR 3·9–5·3) was the median follow-up.
• Results demonstrated that 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment because of toxicity, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p < 0·0001).
• The 3-year event-free survival was with dinutuximab beta was 56% (95% CI 49–63) (83 patients had an event) and it was 60% (53–66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76).
• Four deaths were reported due to the 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).
• 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 vs19 [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) were the most common grade 3-4 adverse events.