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Clinical Trial
. 2021 Apr 15;27(8):2179-2189.
doi: 10.1158/1078-0432.CCR-20-3909. Epub 2021 Jan 27.

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

Alice L Yu  1   2 , Andrew L Gilman  3 , M Fevzi Ozkaynak  4 , Arlene Naranjo  5 , Mitchell B Diccianni  6 , Jacek Gan  7 , Jacquelyn A Hank  7 , Ayse Batova  6 , Wendy B London  8 , Sheena C Tenney  5 , Malcolm Smith  9 , Barry L Shulkin  10 , Marguerite Parisi  11 , Katherine K Matthay  12 , Susan L Cohn  13 , John M Maris  14 , Rochelle Bagatell  14 , Julie R Park  11 , Paul M Sondel  15
Affiliations
Clinical Trial

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

Alice L Yu et al. Clin Cancer Res. .

Abstract

Purpose: Previously our randomized phase III trial demonstrated that immunotherapy including dinutuximab, a chimeric anti-GD2 mAb, GM-CSF, and 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.

Patients and methods: Patients recieved six cycles of isotretinoin with or without five 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. Fcγ receptor 2A and 3A genotypes were determined by PCR and direct sequencing.

Results: For 226 eligible randomized patients, 5-year EFS was 56.6 ± 4.7% for patients randomized to immunotherapy (n = 114) versus 46.1 ± 5.1% for those randomized to isotretinoin only (n = 112; P = 0.042). Five-year overall survival (OS) was 73.2 ± 4.2% versus 56.6 ± 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. Fcγ 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.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest:

A.L.Yu reports grant support from United Therapeutics for immune correlative studies during the conduct of the study. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1A:
Figure 1A:
Kaplan-Meier curves of EFS by randomized treatment arm (n=226), with four patients censored at crossover, on COG study ANBL0032
Figure 1B:
Figure 1B:
Kaplan-Meier curves of OS by randomized treatment arm (n=226), with four patients censored at crossover, on COG study ANBL0032
Figure 2A:
Figure 2A:
Kaplan-Meier curves of EFS for patients who are ≥18 months old at diagnosis with INSS stage 4 disease (n=158), by randomized treatment arm on COG study ANBL0032
Figure 2B:
Figure 2B:
Kaplan-Meier curves of OS for patients who are ≥18 months old at diagnosis with INSS stage 4 disease (n=158), by randomized treatment arm on COG study ANBL0032
See this image and copyright information in PMC

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