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

Abstract

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 µg/ml pre-infusion; 100.95 µg/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.

Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects

“…The Step-up infusion protocol was initially tested in a total of 42 patients and recently reported ( 40 ). The G3 adverse events occurrence rate was significantly reduced from 8.1% (23 out of 284 infusions) with standard administration to 2.5% (5 out of 202 infusions) with the Step-Up regimen (p=0.037).…”

“…The G3 adverse events occurrence rate was significantly reduced from 8.1% (23 out of 284 infusions) with standard administration to 2.5% (5 out of 202 infusions) with the Step-Up regimen (p=0.037). The odds of a G3 adverse event occurring were reduced by 70% with the Step-Up protocol ( 40 ). Using the Step-up infusion procedure, naxitamab serum levels were collected before antibody (Ctrough) and after its completion (Cmax) for 12 patients over their multiple treatment cycles as previously reported ( 24 ).…”

“…Using the Step-up infusion procedure, naxitamab serum levels were collected before antibody (Ctrough) and after its completion (Cmax) for 12 patients over their multiple treatment cycles as previously reported (24). Drug exposure did not appear to be negatively affected by the Step-Up infusion procedure (40). Since the Step-Up was implemented, over 150 patients have been infused and no CTCAE grade 4 toxicities have been observed and thus all patients have been able to complete planned infusions.…”

Global Impact of Monoclonal Antibodies (mAbs) in Children: A Focus on Anti-GD2

“…In addition, prolonged infusions that require inpatient admission may not be cost-effective in the absence of home hospitalization units. To reduce autonomic side effects, desensitization strategies using a step-up infusion protocol were shown to reduce hemodynamic side effects, whereas alternative pharmacologic interventions (e.g., ketamine) reduced pain complications [164,167].…”