FC gamma receptor polymorphism in relapsed/refractory high-risk neuroblastoma patients correlates with outcomes in the SIOPEN dinutuximab beta long-term infusion trial

Abstract

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

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

Results: overall, 122 patients were treated. At 10 mg/m2/day dinutuximab beta LTI, 95% patients (22/24 exploratory cohort; 20/20 confirmatory cohort 1) achieved the composite primary endpoint, with ≥80% patients intravenous morphine-free by day 5/cycle 1. End-of-treatment objective response rate was 45% in 78 evaluable patients. Two-year event-free survival and overall survival 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 Fc-gamma receptor polymorphisms and high-level natural killer cells versus patients with low-affinity Fc-gamma receptor polymorphisms and low-level natural killer cells (event-free survival, 79% [±9%] vs 35% [±11%], p=0.009; overall survival, 84% [±8%] vs 70% [±10%]; p=0.083). Multivariate analysis identified age >5 years, low-affinity Fc-gamma receptor polymorphisms, and relapse/refractory disease as independent risk factors.

Conclusion: dinutuximab beta LTI was well tolerated and clinically active in patients with relapsed/refractory high-risk neuroblastoma, with Fc-gamma receptor polymorphisms and natural killer cells identified as prognostic biomarkers.

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Identifiers

ORCID for Juliet Gray: orcid.org/0000-0002-5652-4722

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