In an international phase III trial (HR-NBL1/SIOPEN) reported in The Lancet Oncology, Ladenstein et al found that the addition of interleukin (IL)-2 to dinutuximab beta did not improve event-free survival in children and young people with high-risk neuroblastoma.
The current report is on an immunotherapy randomized component of the HR-NBL1/SIOPEN trial including patients aged 1–20 years who had completed a multidrug induction regimen, achieved disease response, received high-dose consolidation therapy, and received radiotherapy to the primary tumor site. In this component, patients were randomly assigned to receive dinutuximab beta (20 mg/m2 per day as an 8-hour infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous (SC) IL-2 (6 × 106 IU/m2 per day on days 1–5 and days 8–12 of each 35-day cycle). All participants received oral isotretinoin (160 mg/m2 per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle for 6 cycles. Between October 2009 and August 2013, 422 patients were eligible to participate in the immunotherapy randomization component of the trial. Of these, 406 (96%) were randomly assigned to dinutuximab beta plus IL-2 (n = 206) or dinutuximab beta alone (n = 200); of these, 188 and 183 were evaluable for completion of treatment.
The primary endpoint was 3-year event-free survival in the intent to treat population.
Median follow-up was 4.7 years. Due to toxicity, only 117 (62%) of 188 patients in the dinutuximab beta plus IL-2 group received all allocated treatment, compared with 160 (87%) of 183 in the dinutuximab beta group (P < .0001). Three-year event-free survival was 60% in the dinutuximab beta plus IL-2 group vs 56% in the dinutuximab beta group (P = .76).
Hematologic grade 3 or 4 toxicities were more common in the dinutuximab beta plus IL-2 group, including decreased hemoglobin (66% vs 42%) and decreased platelets (61% vs 35%). Grade 3 or 4 nonhematologic toxicities were also more common in the dinutuximab beta plus IL-2 group (87% vs 65%), with the most common including impaired general condition (41% vs 16%), fever (40% vs 14%), infection (33% vs 25%), immunotherapy-related pain (26% vs 16%), hypersensitivity reactions (20% vs 10%), and capillary leak (15% vs 4%).
The investigators concluded, “There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8-[hour] 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 randomized trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available.”
The study was funded by the European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, and Fondation ARC pour la recherche sur le Cancer.
Ruth Ladenstein, MD, of St. Anna Kinderkrebsforschung e.V. Children’s Cancer Research Institute, Vienna, is the corresponding author for The Lancet Oncology article.
Disclosure: See study authors’ full disclosures at thelancet.com.
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