On December 13, 2023, the FDA approved eflornithine (Iwilfin; US WorldMeds), an ornithine decarboxylase inhibitor, to reduce the risk for relapse in adults and pediatric patients with high-risk neuroblastoma who have had at least a partial response to previous multiagent, multimodality therapy including anti-GD2 immunotherapy. The FDA granted this approval priority review and breakthrough and orphan drug designations.
Eflornithine is the first FDA-approved therapy for the reduction of relapse risk in a pediatric population with high-risk neuroblastoma. According to the American Cancer Society, neuroblastoma, a rare cancer that begins in the nerve tissue, most often affects children aged <5 years, with between 700 and 800 cases diagnosed annually in the United States.
This approval was based on the results of an externally controlled trial that compared outcomes from 2 studies—Study 3b (NCT02395666; the investigational arm) and Study ANBL0032 (NCT00026312; the clinical trial–derived external control arm).
The phase 2 Study 3b was a multicenter, open-label, nonrandomized trial including 2 cohorts. In one cohort, 105 eligible patients with high-risk neuroblastoma received oral eflornithine twice daily, with the dose based on body surface area (BSA), until disease progression, until unacceptable adverse events, or for a maximum of 2 years. This study was prospectively designed to compare outcomes with Study ANBL0032’s historic benchmark event-free survival (EFS) rate.
The external control arm included 1241 patients from the experimental arm of Study ANBL0032. This phase 3, multicenter, open-label, randomized clinical trial compared dinutuximab, granulocyte-macrophage colony-stimulating factor, interleukin-2, and cis-retinoic acid with cis-retinoic acid alone in pediatric patients with high-risk neuroblastoma.
If the patients met the criteria for the comparative analysis of Study 3b and ANBL0032, with complete data for specified clinical covariates, they were matched in a 1:3 ratio using propensity scores; the resultant matched efficacy populations for the primary analysis comprised 90 patients who received eflornithine and 270 control patients from Study ANBL0032.
The efficacy measures included EFS (the main measure, which was defined as disease progression, relapse, secondary cancer, or death from any cause) and overall survival (OS; which was defined as death from any cause). The EFS hazard ratio (HR) in the protocol-specified primary analysis was 0.48 (95% confidence interval [CI], 0.27-0.85) and the OS HR was 0.32 (95% CI, 0.15-0.70). Because the externally controlled study design has associated uncertainty in treatment effect estimation, supplementary analyses in subpopulations or using alternative statistical methods were performed. The EFS HR in these analyses ranged from 0.43 (95% CI, 0.23-0.79) to 0.59 (95% CI, 0.28-1.27), and the OS HR ranged from 0.29 (95% CI, 0.11-0.72) to 0.45 (95% CI, 0.21-0.98).
“After diligent efforts for the past decade, I am both humbled and overjoyed to see this product that holds the potential to evolve the standard of care for high-risk neuroblastoma come to fruition,” said Giselle Saulnier Sholler, MD, Chair and Founder, Beat Childhood Cancer Research Consortium, and Division Chief of Pediatric Hematology and Oncology at Penn State Health Children’s Hospital, in a press release.
The most common (≥5%) adverse events 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 aminotransferase, increased aspartate aminotransferase, hearing loss, skin infection, and urinary tract infection.
The recommended dose of eflornithine is based on the patient’s BSA. For more information on dosing, consult the prescribing information for eflornithine.