Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1)

Ruth Ladenstein, Ulrike Pötschger, Dominique Valteau-Couanet, Roberto Luksch, Victoria Castel, Shifra Ash, Genevieve Laureys, Penelope Brock, Jean Marie Michon, Cormac Owens, Toby Trahair, Godfrey Chi Fung Chan, Ellen Ruud, Henrik Schroeder, Maja Beck-Popovic, Guenter Schreier, Hans Loibner, Peter Ambros, Keith Holmes, Maria Rita Castellani, Mark N Gaze, Alberto Garaventa, Andrew D J Pearson, Holger N Lode, Ruth Ladenstein, Ulrike Pötschger, Dominique Valteau-Couanet, Roberto Luksch, Victoria Castel, Shifra Ash, Genevieve Laureys, Penelope Brock, Jean Marie Michon, Cormac Owens, Toby Trahair, Godfrey Chi Fung Chan, Ellen Ruud, Henrik Schroeder, Maja Beck-Popovic, Guenter Schreier, Hans Loibner, Peter Ambros, Keith Holmes, Maria Rita Castellani, Mark N Gaze, Alberto Garaventa, Andrew D J Pearson, Holger N Lode

Abstract

To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR); the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients' eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2-8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN amplification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38-47%) and 50% (46-55%) but was 57% (51-62%) and 64% (59-69%) for 378 patients receiving immunotherapy (p < 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573); type of HDT (p = 0.0029, HR 1.431); less than complete response prior to maintenance therapy (p = 0.0043, HR 1.494) and >1 metastatic compartment at diagnosis (p < 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN.

Keywords: dinutuximab beta; high-risk neuroblastoma; immunotherapy.

Conflict of interest statement

The academic data supported APEIRON to obtain the dinutuximab beta product licensure in May 2017 in the European Union (EMA). SIOPEN and CCRI established a contract with APEIRON regarding the provision of academic data. Ruth Ladenstein and Holger Lode acted as consultants for APEIRON on behalf of SIOPEN for the ch14.18/CHO development. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow chart for the analysis cohort. HDT (high-dose chemotherapy); BuMel (high-dose chemotherapy with busulfan and melphalan; CEM (high-dose chemotherapy with carboplatin, etoposide and melphalan); R1 (high-dose chemotherapy randomisation); R2 (immunotherapy randomisation) and IL-2 (interleukin-2).
Figure 2
Figure 2
Analysis population comparing control population versus immunotherapy population. (A) Event-free survival, (B) overall survival and (C) cumulative incidence of progression/relapse. CP (control population), IP (immunotherapy population), CIR (cumulative incidence of relapse) and NRM (non-relapse mortality).
Figure 3
Figure 3
Influence of risk factors within the analysis population on event-free survival (EFS). (A) EFS and age; (B) EFS and stage; (C) EFS and metastatic compartments (MC) localised and 4s stage vs. stage 4 (one MC vs. multiple MC); (D) response status prior to maintenance phase: CR (complete remission), VGPR (very good partial remission) and PR (partial remission) and (E) EFS and TVD (topotecan, vincristine and doxorubicin). TVD added = yes and TVD not added = no. (F) Type of high-dose chemotherapy = BuMel (busulfan and melphalan) and CEM (carboplatin, etoposide and melphalan).
Figure 4
Figure 4
HR-NBL1/SIOPEN treatment overview.

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