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

IntroductionAnti-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 AEs of severe pain, hypotension, and bronchospasm. MethodsForty-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-min infusion of 3 mg/kg/day on Day 1 of cycle 1 and a 30- to 60-min infusion on Day 3 and Day 5, as tolerated. The STU regimen uses a 2-h infusion on Day 1, initiated at a rate of 0.06 mg/kg/h during 15 min (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/h (0.06 mg/kg) and delivered in 90 min according to the same gradual-increase strategy. AEs were graded according to Common Terminology Criteria for Adverse Events version 4.0. ResultsThe 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 mu g/ml pre-infusion; 100.95 mu g/ml post-infusion) were within the range reported for SIR. DiscussionThe comparable pharmacokinetics of naxitamab during SIR and STU may indicate that switching to STU reduces G3 AEs without impact on efficacy.

Automated summary

A novel method of administering the GD2-binding mAb naxitamab, termed Step-Up infusion (STU), was developed to reduce the risk of severe adverse events. The STU regimen showed a reduction in the frequency of infusions associated with Grade >= 3 adverse events.