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Eflornithine Approved for Reduction of Risk of Relapse in High-Risk Neuroblastoma

Neuroblastoma metastases.

The FDA has granted approval to eflornithine (Iwilfin™, US World Meds, LLC) for reduction of the risk of relapse in adult and pediatric patients with high-risk neuroblastoma (HRNB) who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. This marks the first approval of a therapy intended to reduce the risk of relapse in pediatric patients with HRNB.  

Why it matters: "Long-term survival in HRNB is approximately 50%, with mortality primarily driven by relapse," wrote Javier Oesterheld, MD, Specialty Medical Director of Pediatric Hematology/Oncology/Bone Marrow Transplantation (BMT) at Atrium Health Levine Children's Hospital, of Carolinas Medical Center, and colleagues, in their comparative analysis of Study 3b (NCT02395666) and Study ANBL0032 (NCT00026312), on which approval was based. "Using patient-level data from ANBL0032 as an external control, we present new analyses to further evaluate eflornithine as HRNB post–immunotherapy maintenance."

What they studied: Efficacy was measured through an externally controlled pooled analysis of two trials: Study 3b, which was the investigational arm, and Study ANBL0032, which was the clinical trial–derived external control arm.

Study 3b was a multicenter, open-label, non-randomized trial consisting of two cohorts. The Stratum 1 cohort enrolled 105 patients with HRNB to receive eflornithine orally, twice daily at a dosage based on body surface area (BSA) until disease progression, unacceptable toxicity, or for a maximum of 2 years. The study was prospectively designed to compare outcomes with the historical benchmark event-free survival rate observed in Study ANBL0032.

Study ANBL0032, which served as the external control arm, was a multicenter, open-label trial in which 1,241 pediatric patients with HRNB were enrolled in the experimental arm to receive dinutuximab, granulocyte-macrophage colony-stimulating factor, interleukin-2, and cis-retinoic acid or cis-retinoic acid alone.

Those who met the criteria to be included in the comparative analysis of the two studies, with complete data for specified clinical covariates, were matched 1:3 using propensity scores. The matched efficacy population included 90 patients who were treated with eflornithine from Study 3b and 270 control patients from Study ANBL0032.

The major efficacy outcome measured was event-free survival, with events defined as disease progression, relapse, secondary cancer, or death from any cause. Overall survival was an additional outcome measure.

What they found: In the protocol-specified primary analysis, the event-free survival hazard ratio was 0.48 (95% CI: 0.27, 0.85) and the overall survival hazard ratio was 0.32 (95% CI: 0.15, 0.70). Supplementary analyses in subpopulations or alternative statistical methods were performed due to the uncertainty in treatment effect estimation associated with the externally controlled study design. 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).

Adverse events: The most common adverse events experienced by ≥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 aminotransferase (ALT), increased aspartate aminotransferase (AST), hearing loss, skin infection, and urinary tract infection.

Conclusion: "The externally controlled analyses presented show a relapse risk reduction in patients with HRNB treated with post-immunotherapy eflornithine," concluded Dr. Oesterheld and colleagues.

Instructions: The recommended dosage of eflornithine is based on BSA. Please see the prescribing information for more information.

For More Information

Oesterheld J, Ferguson W, Kraveka JM, et al (2023). Eflornithine as postimmunotherapy maintenance in high-risk neuroblastoma: externally controlled, propensity score-matched survival outcome comparisons. J Clin Oncol. [Epub ahead of print] JCO2202875. DOI:10.1200/JCO.22.02875

Yu AL, Gilman AL, Ozkaynak MF, et al (2021). Long-term follow-up of a phase III study of ch14.18 (dinutuximab) + cytokine immunotherapy in children with high-risk neuroblastoma: COG Study ANBL0032. Clin Cancer Res, 27(8):2179-2189. DOI:10.1158/1078-0432.CCR-20-3909

Clinicaltrials.gov (2023). Preventative trial of difluoromethylornithine (DFMO) in high risk patients with neuroblastoma that is in remission. NLM identifier: NCT02395666.

Clinicaltrials.gov (2023). Isotretinoin with or without dinutuximab, aldesleukin, and sargramostim following stem cell transplant in treating patients with neuroblastoma. NLM identifier: NCT00026312.

Iwilfin™ (eflornithine) prescribing information (2023). US World Meds, LLC. Available at: https://www.iwilfin.com/wp-content/uploads/2023/12/iwilfin_PI-and-PPI_letter.pdf

US Food and Drug Administration (2023). FDA approves eflornithine for adult and pediatric patients with high-risk neuroblastoma. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-eflornithine-adult-and-pediatric-patients-high-risk-neuroblastoma

Image credit: Animalcultist. Licensed under CC BY-SA 4.0

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