Association of immunotherapy of high-risk neuroblastoma patients with long term infusion of dinutuximab beta with survival over short term infusion: Results from the HR-NBL1/SIOPEN trial.

Abstract

10000 Background: Dinutuximab beta (DB) delivered as long-term infusion is associated with a lower frequency and magnitude of side effects compared to short-term infusion (STI). Here, we evaluated the efficacy (event free survival- and cumulative incidence of relapse-rates at 5 years) of LTI compared to STI within the HR-NBL1/SIOPEN trial (EudraCT:2006-001489-17). Methods: High-risk patients as defined by metastatic disease (stage M) or local stage with MYC-N amplification received high intensity induction, surgery, high dose therapy with busulfan/melphalan followed by autologous stem cell transplantation (HDT/SCT) and local radiotherapy. Patients who achieved at least a partial response prior to HDT/SCT within equal or less than 9 months between diagnosis and HDT/SCT without progression were randomized to receive 5 cycles of 100 mg/m 2 DB per cycle either as STI (20 mg/m 2 per day as 8 h infusion; days 1-5) with or without subcutaneous interleukin-2 (scIL2) (6 × 10 6 IU/m 2 per day; days 1-5 and days 8-12) (R2 randomization) or as LTI (10 mg/m 2 per day as 24h infusion; days 1-10) (d8-17) ± 3x10 6 IU/m 2 scIL2 (d1-5; d8, d10, d12, d14, d16) (R4 randomization). All patients received 160 mg/m 2 oral isotretinoin (d19-32). Results: From 2009-2018, 705 patients (pts) from 18 countries were randomized and eligible for this analysis. The median follow-up time is7.7 years. Key patient characteristics were age 1.5-5yrs: 65% (460 pts), disease status before HDCT: CR 56% (396 pts) versus non-CR 38% (268 pts), MYC-N amplification (MNA): 43% (304 pts); > 1 metastatic compartment (MC): 78% (553 pts); time between diagnosis to DB treatment start: > 9 months 48% (302 pts). There were no significantly different patient characteristics between STI and LTI cohorts, except for time to DB start > 9 months: 59% in the LTI cohort vs. 37% in STI.The 5yr EFS was 0.65±0.03 for LTI vs. 0.56±0.03 for STI (p = 0.041). The cumulative incidence of relapse was 0.33±0.03 for LTI vs. 0.42±0.03 for STI (p = 0.034). Multivariable pseudovalue-regression analysis for 5-year EFS found a significantly worse outcome for stage 4 patients with > 1MC (p = 0.025; cHR = 1,97), < CR (p = 0.059; cHR = 1.32) and for STI (p = 0.044; cHR = 0.74). Conclusions: We previously reported that LTI of DB increased the safety profile (less pain and inflammation) (Lancet Oncol 2018;19(12):1617-1629; J Clin Oncol 37, 2019 (suppl; abstr 10013). Here we demonstrate that LTI is also associated with an improved outcome. Clinical trial information: 2006-001489-17 .