FDA Approves Mirdametinib for NF1-Associated Plexiform Neurofibromas in Adults and Children

A version of this story originally appeared on our sister site, OncLive.

FDA logo

The FDA has granted approval to mirdametinib (Gomekli; SpringWorks Therapeutics) for the treatment of adult and pediatric patients aged 2 years and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) that are not amenable to complete surgical resection.¹

The approval was based on data from the phase 2 ReNeu trial (NCT03962543), in which mirdametinib demonstrated an overall response rate (ORR) of 41% (95% CI, 29-55) in adult patients (n = 58) and 52% (95% CI, 38-65) in pediatric patients (n = 56). The treatment, which is a highly selective MEK inhibitor, offers a new option for patients with NF1 with inoperable PN, marking a significant advancement, particularly for adults who have lacked an FDA-approved therapy.

“This approval is significant because mirdametinib provides a much-needed option for both adults and children with NF1 who have symptomatic plexiform neurofibromas that are not candidates for surgery and that severely impact quality of life,” Christopher L. Moertel, MD, of the University of Minnesota and principal investigator of the ReNeu trial, told NeurologyLive's sister site, OncLive. “For adults with NF1, this represents a major step forward.”

ReNeu Trial Findings

The multicenter, open-label ReNeu trial enrolled patients aged 2 years and older with inoperable NF1-associated PN causing significant comorbidities.² The study included 58 adult patients and 56 pediatric patients between 2 and 17 years of age, all of whom received mirdametinib at 2 mg/m² twice daily (maximum dose of 4 mg twice daily) on a 3-week-on, 1-week-off schedule.

The study’s primary end point was confirmed ORR, defined as at least a 20% reduction in target tumor volume on MRI per blinded independent central review. Secondary end points included duration of response (DOR), patient-reported outcomes, and safety.

At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, investigators presented additional data from ReNeu showing a median tumor volume reduction of –41% (range, –90 to 13) in adult patients. Among responders, 62% achieved a deep response, defined as a tumor-volume reduction of more than 50%. The median duration of treatment (DOT) was 22 months, with a median time to response (TTR) of 7.8 months (range, 4-19), and the median DOR was not reached.

In pediatric patients, the median best tumor volume change was –42% (range, –91 to 48), with 52% of responders achieving a deep response. The median DOT, TTR, and DOR were similar to those observed in adults, at 22 months, 7.9 months (range, 4-19), and not reached, respectively. Mirdametinib treatment was also associated with significant improvements in pain severity and health-related quality of life, further supporting its clinical benefit in this patient population.

Safety and Tolerability

The safety analysis showed that treatment-related adverse effects (TRAEs) occurred in 98% of adult patients and 95% of pediatric patients. Grade 3 or higher TRAEs were reported in 16% of adults and 25% of pediatric patients.

Serious TRAEs were rare, occurring in only 1 adult patient (2%) and none in the pediatric cohort. Treatment-related dose modifications included dose interruptions (9% of adults; 14% of pediatrics), dose reductions (17% of adults; 12% of pediatrics), and treatment discontinuations (21% of adults; 9% of pediatrics).

The most common adverse events (AEs) in adults (reported in >25% of patients) were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. The most common grade 3 or 4 laboratory abnormality observed in more than 2% of patients was an increase in creatine phosphokinase levels.

In pediatric patients, frequently reported AEs included rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea. Grade 3 or 4 laboratory abnormalities observed in more than 2% of pediatric patients included decreased neutrophil count and increased creatine phosphokinase levels.

Implications for NF1 Treatment

The approval of mirdametinib marks a significant milestone in treating NF1-associated PN, particularly for adult patients who have historically had limited therapeutic options. By providing a targeted, nonsurgical approach to reducing tumor burden and improving patient-reported outcomes, mirdametinib has the potential to significantly enhance the quality of life for individuals living with NF1.

REFERENCES
1. FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection. FDA. February 11, 2025. Accessed 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 adults and children with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN). J Clin Oncol. 2024;42(suppl 16):3016. doi:10.1200/JCO.2024.42.16_suppl.3016