The FDA's Oncologic Drugs Advisory Committee (ODAC) has voted in favor of eflornithine (difluoromethylornithine; DFMO) for reducing the risk of relapse in pediatric patients with high-risk neuroblastoma who have completed multi-agent, multimodality therapy and are in remission. The vote, decided on October 4, 2023, was 14-6, signaling the committee's belief that sufficient evidence supports the drug's efficacy in this setting.
Trial Data and Efficacy
The recommendation is based primarily on data from the phase 2 Study 3b trial (NCT02395666), which compared 90 patients receiving eflornithine to an external control arm of 270 patients from the phase 3 ANBL0032 trial (NCT00026312) who received no further therapy. Both groups consisted of patients aged 0-21 years with histologically verified high-risk neuroblastoma who achieved at least a partial response prior to transplant and were in remission at the end of immunotherapy.
The primary endpoint of Study 3b was event-free survival (EFS). Results indicated a significant benefit in the eflornithine arm, with a hazard ratio (HR) of 0.48 (95% CI, 0.27-0.85). Overall survival (OS), a secondary endpoint, also favored eflornithine (HR, 0.32; 95% CI, 0.15-0.70). These findings remained consistent across various sensitivity analyses, including those accounting for index dates, excluding controls with early events, and focusing on US patients only.
Safety Profile and Considerations
The proposed warnings for eflornithine include myelosuppression, hepatotoxicity, and hearing loss. The most common adverse effects (AEs) reported in at least 5% of patients were hearing loss, otitis media, pyrexia, pneumonia, and diarrhea. Grade 3 or 4 AEs occurred in 42% of patients, with 7% discontinuing treatment due to AEs. No deaths were attributed to AEs.
Kristen Gullo, vice president of development and regulatory affairs for US WorldMeds, noted that DFMO was generally well-tolerated, with few patients requiring dose modification and even fewer requiring discontinuation. Researchers reported that 12.9% of patients experienced hearing loss that worsened at least 1 grade from baseline, and 12.2% experienced hearing loss that worsened to grade 3.
Panel Discussion and Concerns
During the ODAC meeting, potential limitations of non-randomized comparisons were discussed, particularly concerns about bias. Despite these concerns, the committee acknowledged that sensitivity analyses supported the effectiveness of eflornithine and were unlikely to be fully attributable to potential sources of bias.
Several panel members voiced concerns about setting a precedent for approving drugs based on single-arm trials with external controls. However, others argued that the unique circumstances of this rare disease and the strength of the available data justified a flexible approach.
Shahab Asgharzadeh, MD, director of the Neuroblastoma Basic and Translational Program at Children’s Hospital of Los Angeles, emphasized the importance of considering the long-term impact on children and the compelling preclinical data supporting eflornithine's efficacy.
Regulatory Implications
The FDA will consider the ODAC's recommendation when making its final decision on the approval of eflornithine. While the FDA is not bound by the advisory committee's vote, it typically follows their recommendations. If approved, eflornithine would provide a new treatment option for pediatric patients with high-risk neuroblastoma in remission, addressing a critical unmet need in this population.
