Long-term follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-risk Neuroblastoma: COG Study ANBL0032.

Purpose: Previously our randomized Phase III trial demonstrated that immunotherapy including dinutuximab, a chimeric anti-GD2 monoclonal antibody, granulocyte macrophage-colony stimulating factor (GM-CSF), and interleukin-2 (IL2) improved survival for children with high-risk neuroblastoma that had responded to induction and consolidation therapy. These results served as the basis for FDA approval of dinutuximab. We now present long-term follow-up results and evaluation of predictive biomarkers. Experimental Design: Patients recieved 6 cycles of isotretinoin with or without 5 cycles of immunotherapy which consists of dinutuximab with GM-CSF alternating with IL2. Accrual was discontinued early due to meeting the protocol-defined stopping rule for efficacy, as assessed by 2-year event-free survival (EFS). Plasma levels of dinutuximab, soluble IL2 receptor (sIL2R) and human anti-chimeric antibody (HACA) were assessed by ELISA. Fcg receptor 2A and 3A genotypes were determined by PCR and direct sequencing. Results: For 226 eligible randomized patients, 5-year EFS was 56.6{plus minus}4.7% for patients randomized to immunotherapy (n=114) versus 46.1{plus minus}5.1% for those randomized to isotretinoin only (n=112) (p=0.042). Five-year overall survival (OS) was 73.2{plus minus}4.2% versus 56.6{plus minus}5.1% for immunotherapy and isotretinoin only patients, respectively (p=0.045). Thirteen of 122 patients receiving dinutuximab developed HACA. Plasma levels of dinutuximab, HACA, and sIL2R did not correlate with EFS/OS, or clinically significant toxicity. Fcg receptor 2A and 3A genotypes did not correlate with EFS/OS. Conclusions: Immunotherapy with dinutuximab improved outcome for patients with high-risk neuroblastoma. Early stoppage for efficacy resulted in a smaller sample size than originally planned, yet clinically significant long-term differences in survival were observed.