FDA Approves Mirdametinib for Neurofibromatosis Type 1 with Plexiform Neurofibromas

Mirdametinib (Gomekli; SpringWorks Therapeutics), a kinase inhibitor, for the treatment of adult and pediatric patients aged 2 years and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) and are not seeking complete surgical resection, received FDA approval.¹

The trial showed improvements in PN volume, pain severity, and quality of life.

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The approval was based on the findings from the ReNeu (NCT03962543) trial, which is the largest multicenter study of NF1 PN conducted to date.² Mirdametinib demonstrated a statistically significant overall response rate (ORR) according to blinded independent central review. The trial showed durable reductions in PN volume, along with significant improvements in pain severity, pain interference, and health-related quality of life (HRQOL). Additionally, the safety profile of mirdametinib was manageable in both adults and children.

“We know that plexiform neurofibroma can impact QOL in a number of different ways,” study author Christopher L. Moertel, MD, medical director of the Pediatric Neuro-Oncology and Neurofibromatosis Programs at the University of Minnesota, said in an interview with CancerNetwork^®.³ “Seeing that in a statistically significant [way] was quite gratifying. Likewise, [for] pain relief—one of the main reasons people present with plexiform neurofibroma and desire treatment is because of the pain it causes—we saw statistically significant relief of pain. Those things, all together, are great.”

The multicenter, single-arm study evaluated the efficacy and safety of mirdametinib in 114 patients (58 adults and 56 pediatric patients) with symptomatic, inoperable NF1-associated PN.² These tumors, often deeply embedded within critical structures, pose significant challenges for complete surgical removal without substantial risk.

The primary efficacy measure was the confirmed ORR, defined as the percentage of patients experiencing a complete or partial response (≥ 20% reduction in PN volume). Results showed a confirmed ORR of 41% in adult patients (95% CI, 29-55) and 52% in pediatric patients (95% CI, 38-65), using volumetric MRI analysis (P < .001).

Common adverse effects reported in adult patients included rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue, with increased creatine phosphokinase levels being the most frequently observed grade 3 or 4 laboratory abnormality.¹ Pediatric patients experienced similar adverse effects, along with additional concerns such as abdominal pain, headache, and left ventricular dysfunction. Notably, serious risks associated with mirdametinib include left ventricular dysfunction and ocular toxicity, which may require dosage adjustments or discontinuation.

The FDA granted mirdametinib several designations, including priority review, fast track designation, and orphan drug designation, in response to the urgent need for treatments targeting rare pediatric diseases. The approval process was further expedited by the use of the Assessment Aid, a voluntary submission tool designed to streamline FDA evaluations. Additionally, a priority review voucher was issued as part of the regulatory incentives aimed at encouraging the development of treatments for rare pediatric conditions.

The FDA approval of mirdametinib for the management of NF1-associated plexiform neurofibromas offers another treatment option to patients who previously had limited alternatives. While safety considerations remain important, the drug's profile and regulatory support show its potential to provide meaningful pain relief, improvements in quality of life, and durable tumor reductions.

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. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirdametinib-adult-and-pediatric-patients-neurofibromatosis-type-1-who-have-symptomatic

2. Moertel CL, Hirbe AC, Shuhaiber HH, et al. ReNeu: A pivotal phase 2b trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN). JCO 42, 3016-3016(2024). doi:10.1200/JCO.2024.42.16_suppl.3016

3. Moertel CL. Objective data highlight substantial benefits with mirdametinib in NF1-PN. Cancer Network. February 12, 2025. Accessed February 12, 2025. https://www.cancernetwork.com/view/objective-data-highlight-substantial-benefits-with-mirdametinib-in-nf1-pn