On December 13, the U.S. Food and Drug Administration approved eflornithine (Iwilfin), an irreversible inhibitor of ornithine decarboxylase, to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy, including anti-GD2 immunotherapy.
This represents the first FDA approval of a therapy intended to reduce the risk of relapse in pediatric patients with high-risk neuroblastoma.
Study 3b and Study ANBL0032: Comparative Analysis
Efficacy was evaluated in an externally controlled trial comparing outcomes from Study 3b (investigational arm) and Study ANBL0032 (clinical trial–derived external control arm). Study 3b (ClinicalTrials.gov identifier NCT02395666) was a multicenter, open-label, nonrandomized trial with two cohorts. A total of 105 eligible patients with high-risk neuroblastoma from one cohort (Stratum 1) received eflornithine orally twice daily at a dosage based on body surface area until disease progression, unacceptable toxicity, or for a maximum of 2 years. Study 3b was prospectively designed to compare outcomes to the historical benchmark event-free survival rate from Study ANBL0032 reported in published literature.
The external control arm was derived from 1,241 patients on the experimental arm of Study ANBL0032, a multicenter, open-label, randomized trial of dinutuximab, granulocyte-macrophage colony-stimulating factor, interleukin-2, and cis-retinoic acid compared to cis-retinoic acid alone in pediatric patients with high-risk neuroblastoma.
Patients who met the criteria for the comparative analysis of Study 3b and ANBL0032, with complete data for specified clinical covariates, were matched 1:3 using propensity scores; the matched efficacy populations for the primary analysis included 90 patients treated with eflornithine and 270 control patients from Study ANBL0032.
The major efficacy outcome measure was event-free survival, defined as disease progression, relapse, secondary cancer, or death due to any cause. An additional efficacy outcome measure was overall survival, defined as death due to any cause. In the protocol-specified primary analysis, the event-free survival hazard ratio was 0.48 (95% confidence interval [CI] = 0.27–0.85) and overall survival hazard ratio was 0.32 (95% CI = 0.15–0.70). Given the uncertainty in treatment effect estimation associated with the externally controlled study design, supplementary analyses in subpopulations or using alternative statistical methods were performed. In these analyses, the event-free survival hazard ratio ranged from 0.43 (95% CI = 0.23–0.79) to 0.59 (95% CI = 0.28–1.27), and the overall survival hazard ratio ranged from 0.29 (95% CI = 0.11–0.72) to 0.45 (95% CI = 0.21–0.98).
The most common adverse reactions (occurring in ≥ 5% of patients) in Study 3b, including laboratory abnormalities, were otitis media, diarrhea, cough, sinusitis, pneumonia, upper respiratory tract infection, conjunctivitis, vomiting, pyrexia, allergic rhinitis, decreased neutrophils, increased alanine transaminase, increased aspartate transaminase, hearing loss, skin infection, and urinary tract infection.
The recommended dose is based on body surface area; see the prescribing information for more information.
This review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Priority Review, Breakthrough Therapy designation, and Orphan Drug designation.
