AUTHOR=Varo Amalia , Castañeda Alicia , Chamorro Saray , Muñoz Juan Pablo , Gorostegui Maite , Celma Mónica S. , Lopez Sandra , Simao Margarida , Perez-Jaume Sara , Mora Jaume 

TITLE=Novel infusion strategy reduces severe adverse events caused by the anti-GD2 monoclonal antibody naxitamab

JOURNAL=Frontiers in Oncology

VOLUME=Volume 13 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1164949

DOI=10.3389/fonc.2023.1164949

ISSN=2234-943X

ABSTRACT=Introduction: Anti-disialoganglioside 2 (anti-GD2) monoclonal antibodies (mAbs) are associated with Grade ≥3 (≥G3) adverse events (AEs) such as severe pain, hypotension, and bronchospasm. We developed a novel method of administering the GD2-binding mAb naxitamab, termed “Step-Up” infusion (STU), to reduce the risk of the AEs of severe pain (G3: reported to be experienced by 54% of patients), hypotension (G3: experienced by 59% of patients), and bronchospasm (G3: experienced by 18% of patients). 
Methods: Forty-two patients with GD2-positive tumors received naxitamab under “compassionate use” protocols and administered via either the standard infusion regimen (SIR) or the STU regimen. The SIR comprises a 60-minute infusion of 3 mg/kg/day on Day 1 of cycle 1 and a 30–60-minute infusion on Day 3 and Day 5, as tolerated. The STU regimen uses a 2-hour infusion on Day 1, initiated at a rate of 0.06 mg/kg/hour during 15 minutes (0.015 mg/kg) and which increases gradually to a cumulative dose of 3 mg/kg; on Days 3 and 5 the 3 mg/kg dose is initiated at 0.24 mg/kg/hour (0.06 mg/kg) and delivered in 90 minutes according to the same gradual-increase same strategy. AEs were graded according to Common Terminology Criteria for Adverse Events version 4.0. 
Results: The frequency of infusions with an associated G3 AE was reduced from 8.1% (23/284 infusions) with SIR to 2.5% (5/202 infusions) with STU. The odds of an infusion being associated with a G3 AE reduced by 70.3% with STU vs SIR (odds ratio: 0.297; p=0.037). Mean serum naxitamab levels pre- and post-STU (11.46 µg/mL pre-infusion; 100.95 µg/mL post-infusion) were within the range reported for SIR. 
Discussion: The comparable pharmacokinetics of naxitamab during SIR and STU may indicate that switching to STU reduces G3 AEs without impact on efficacy.