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Clinical Trial
. 2025 Sep 2;31(17):3692-3701.
doi: 10.1158/1078-0432.CCR-25-0180.

Fcγ Receptor Polymorphism in Patients with Relapsed/Refractory High-Risk Neuroblastoma Correlates with Outcomes in the SIOPEN Dinutuximab Beta Long-Term Infusion Trial

Holger N Lode  1 , Nikolai Siebert  1 , Dominique Valteau-Couanet  2 , Alberto Garaventa  3 , Adela Canete  4 , John Anderson  5 , Isaac Yaniv  6 , Shifra Ash  7 , Juliet Gray  8 , Thomas Klingebiel  9 , Hans Loibner  10 , Roberto Luksch  11 , Carla Manzitti  3 , Jean Marie Michon  12 , Cormac Owens  13 , Ulrike Pötschger  14 , Sascha Troschke-Meurer  1 , Evgenia Glogova  14 , Ruth Ladenstein  15 ; SIOP Europe Neuroblastoma Group (SIOPEN)
Affiliations
Clinical Trial

Fcγ Receptor Polymorphism in Patients with Relapsed/Refractory High-Risk Neuroblastoma Correlates with Outcomes in the SIOPEN Dinutuximab Beta Long-Term Infusion Trial

Holger N Lode et al. Clin Cancer Res. .

Abstract

Purpose: To identify a tolerable dinutuximab beta long-term infusion (LTI) schedule with immunomodulatory activity for relapsed/refractory high-risk neuroblastoma (HRNBL).

Patients and methods: In this phase I/II trial, dinutuximab beta LTI (five 35-day cycles) with subcutaneous interleukin-2 (IL-2) was evaluated in HRNBL cohorts (1× exploratory and 2× confirmatory). The composite primary endpoint was >80% patients free of intravenous morphine by day 5/cycle 1 plus ≥100 natural killer (NK) cells/μL and ≥1 μg/mL dinutuximab beta concentration by day 15/cycle 1. Secondary endpoints included objective response rate, event-free survival (EFS), overall survival (OS), Fcγ receptor (FCYR) polymorphisms, and NK cells.

Results: Overall, 122 patients were treated. At 10 mg/m2/day dinutuximab beta LTI, 95% patients (22/24 exploratory cohort and 20/20 confirmatory cohort 1) achieved the composite primary endpoint, with ≥80% patients intravenous morphine-free by day 5/cycle 1. The end-of-treatment objective response rate was 45% in 78 evaluable patients. Two-year EFS and OS were 56% (±4%) and 73% (±4%) overall and 45% (±5%) and 65% (±5%) in relapsed/refractory disease, respectively. Two-year survival rates were greater in patients with high-affinity FCYR polymorphisms and high-level NK cells versus patients with low-affinity FCYR polymorphisms and low-level NK cells [EFS, 79% (±9%) vs. 35% (±11%), P = 0.009; OS, 84% (±8%) vs. 70% (±10%); P = 0.083]. Multivariate analysis identified age >5 years, low-affinity FCYR polymorphisms, and relapse/refractory disease as independent risk factors.

Conclusions: Dinutuximab beta LTI was well tolerated and clinically active in patients with relapsed/refractory HRNBL, with FCYR polymorphisms and NK cells identified as prognostic biomarkers.

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Conflict of interest statement

H.N. Lode reports personal fees from Recordati Rare Diseases during the conduct of the study. D. Valteau-Couanet reports grants from EUSA Pharma RRD outside the submitted work. A. Canete reports personal fees from Norgine and other support from Recordati Rare Diseases outside the submitted work. J. Gray reports grants, personal fees, and other support from Recordati Rare Diseases, personal fees from YmAbs Therapeutics, Servier, and Bristol Myers Squibb, and grants from Celgene outside the submitted work. S. Troschke-Meurer reports grants from EUSA Pharma during the conduct of the study and grants from EUSA Pharma/Recordati Rare Diseases outside the submitted work. R. Ladenstein reports personal fees and other support from APEIRON during the conduct of the study. In addition, R. Ladenstein reports that the antibody development of dinutuximab beta was related to the high-risk neuroblastoma 1/SIOPEN trial, of which R. Ladenstein was the responsible international investigator; the outcomes of the study presented in this article supported the integration of the LTI concept into the first-line HR-NBL1/SIOPEN study; and immunotherapy dinutuximab beta (drug) was provided for free first by APEIRON company and after EMA approval in 2017 and licensure to EUSA company by the latter thereafter. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Intravenous morphine use in each dinutuximab beta LTI cycle. LTI, long-term infusion.
Figure 2.
Figure 2.
EFS and OS in the entire cohort (A) and in first-line PRD patients and all relapsed patients versus first-line patients with MTD (B and C). EFS, event-free survival; HRNBL, high-risk neuroblastoma; MTD, major treatment deviations; NBL, neuroblastoma; PRD, primary refractory disease; SE, standard error.
Figure 3.
Figure 3.
EFS and OS by high-affinity versus low-affinity FCGR polymorphisms in first-line PRD patients and relapsed patients versus first-line patients with MTD (A and B) and by combination of FCGR (high/low) with NK cells (high/low) in the overall population (C and D). EFS, event-free survival; FCGR, Fc-gamma receptor polymorphisms; incr., increase; MTD, major treatment deviations; NBL, neuroblastoma; NK, natural killer; OS, overall survival; PRD, primary refractory disease; SE, standard error.
See this image and copyright information in PMC

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