FDA Approves Mirdametinib in Adult/Pediatric NF1-PN

The FDA based its decision on findings from the phase 2b ReNeu trial (NCT03962543) assessing treatment with the investigational MEK1/2 inhibitor among patients with NF1-PN.

The News

The FDA has approved mirdametinib (Gomekli) as a treatment for pediatric and adult patients 2 years and older with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) not amenable to complete resection, according to a news release from the agency.¹

Supporting Data

The FDA based its decision on findings from the phase 2b ReNeu trial (NCT03962543) assessing treatment with the investigational MEK1/2 inhibitor among patients with NF1-PN. Findings were previously published in The Journal of Clinical Oncology.²

At the time of analysis, treatment with mirdametinib produced a confirmed objective response rate (ORR) of 41% (n = 24; 95% CI, 29%-55%) in adult patients, significantly exceeding the trial’s predefined minimum clinically relevant response threshold of 23% (P <.001). Among pediatric patients, the confirmed ORR was 52% (n = 29; 95% CI, 38%-65%), which significantly exceeded the clinically relevant rate of 20% in this group (P <.001).

The median best percentage change in PN volume was –41% (range, –90% to 13%) among adult patients and –42% (range, –91% to 48%) for pediatric patients. Among patients with a confirmed response, a maximum reduction from baseline of more than 50% occurred in 62% (n = 15/24) and 52% (n = 15/29) of the adult and pediatric groups, respectively.

Expert Perspective

"This [approval] would open up a new route to FDA-approved, on-label therapy for adults [and children] with NF1-PNs. That's very important," lead study author Christopher L. Moertel, MD, a professor in the Department of Pediatrics, director of the Pediatric Neuro-Oncology Fellowship Program in the Division of Pediatric Hematology/Oncology, and medical director of the Pediatric Neuro-Oncology and Neurofibromatosis Programs at the University of Minnesota, stated in an interview with CancerNetwork^® ahead of the approval.

"In addition, mirdametinib is available as a dispersible tablet, so for our patients who have difficulty swallowing pills, that preparation is extremely important," he added.

ReNeu Trial Design

Investigators of the open-label, multi-center ReNeu trial included 58 adult patients and 56 children between the ages of 2 and 17 years old with NF1-PN. All patients were assigned to receive mirdametinib capsules or tablets at 2 mg/m² twice daily, orally, for up to 4 mg twice daily for 3 weeks on and 1 week off as part of each 28-day cycle.

The trial’s primary end point was confirmed ORR based on blinded independent central review. Secondary end points included duration of response and patient-reported changes from baseline in worst tumor pain severity, pain interference, and health-related quality of life.

Patients 2 years and older with a documented NF1 mutation or a diagnosis of NF1 per National Institute of Health Consensus Conference criteria were eligible for enrollment on the trial.³ Other requirements for study entry included having a PN that was causing significant morbidity or could not be surgically resected, a target tumor amenable to volumetric MRI analysis, and adequate organ and bone marrow function.

Safety Data

All adult patients (n = 58) had at least 1 adverse effect (AE), and 98% reported toxicities that were related to study treatment. The most common treatment-related AEs (TRAEs) in this cohort included dermatitis acneiform (78%), diarrhea (48%), nausea (36%), vomiting (28%), and fatigue (21%). AEs leading to dose interruptions, reductions, and discontinuations occurred in 31%, 17%, and 22% of patients, respectively. Investigators noted that no cases of PN transformed to malignant peripheral nerve sheath tumors.

All pediatric patients (n = 56) experienced at least 1 AE, and 95% had an AE that was related to study treatment. The most common TRAEs in this group included dermatitis acneiform (43%), diarrhea (38%), paronychia (30%), nausea (21%), ejection fraction decreases (20%), and blood creatinine phosphokinase elevations (20%). Additionally, 30%, 12%, and 9% of patients required dose interruptions, reductions, and discontinuations due to AEs, respectively. No cases of PN transformed to malignant peripheral nerve sheath tumors in this cohort.

The FDA previously granted priority review to mirdametinib for patients with NF1-PN in August 2024 based on data from the ReNeu trial.⁴

References

1. FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection. News release. FDA. February 11, 2025. Accessed February 11, 2025. https://tinyurl.com/ymr3ft29
2. Moertel CL, Hirbe AC, Shuhaiber HH, et al. ReNeu: a pivotal, phase IIb trial of mirdametinib in adults and children with symptomatic neurofibromatosis type 1-associated plexiform neurofibroma. J Clin Oncol. Published online November 8, 2024. doi:10.1200/JCO.24.01034
3. MEK inhibitor mirdametinib (PD-0325901) in patients with neurofibromatosis type 1 associated plexiform neurofibromas (ReNeu). ClinicalTrials.gov. Updated October 17, 2024. Accessed January 14, 2025. https://tinyurl.com/vykfjbr7
4. FDA Grants priority review to SpringWorks Therapeutics’ new drug application for mirdametinib for the treatment of adults and children with NF1-PN. News release. SpringWorks Therapeutics. August 28, 2024. Accessed November 12, 2024. https://shorturl.at/aTRMO