Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma

N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056/NEJMoa0911123.

Abstract

Background: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma.

Methods: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis.

Results: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses).

Conclusions: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents / therapeutic use
  • Child
  • Child, Preschool
  • Combined Modality Therapy
  • Drug Therapy, Combination
  • Gangliosides / immunology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / therapeutic use
  • Humans
  • Immunotherapy* / adverse effects
  • Infant
  • Intention to Treat Analysis
  • Interleukin-2 / therapeutic use
  • Isotretinoin / therapeutic use
  • Neuroblastoma / drug therapy
  • Neuroblastoma / mortality
  • Neuroblastoma / therapy*
  • Stem Cell Transplantation
  • Survival Analysis

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Gangliosides
  • Interleukin-2
  • ganglioside, GD2
  • dinutuximab
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Isotretinoin

Associated data

  • ClinicalTrials.gov/NCT00026312