FDA Approves Mirdametinib for NF1-Associated Plexiform Neurofibromas

The FDA has approved mirdametinib (Gomekli) for adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection.1

The regulatory decision was supported by data from the phase 2 ReNeu (NCT03962543), which showed that mirdametinib generated a confirmed 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 approval of mirdametinib is significant because this a highly selective MEK inhibitor that will provide benefit to both adults and children with NF1 who have PN that are not amenable to surgery and are causing significant quality-of-life or pain issues. For this population, this is a big win. Adults with NF1 have been without an FDA-approved drug for quite some time," Christopher L. Moertel, MD, of the University of Minnesota and principal investigator of the ReNeu trial, said in an exclusive interview with OncLive®.

ReNeu was a multicenter, open-label study that enrolled patients at least 2 years of age with inoperable NF1-associated PN causing significant comorbidity.2 The study included 58 adult patients and 56 pediatric patients between 2 and 17 years of age.

All patients received mirdametinib at 2 mg/m2 twice per day with a maximum dose of 4 mg twice per day. Treatment was given on a 3-weeks-on/1-week-off schedule.

The study's primary end point was confirmed ORR, which was defined as a 20% or greater reduction in target tumor volume by MRI on consecutive scans per blinded independent central review. Secondary end points comprised duration of response (DOR), patient-reported outcomes, and safety/tolerability.

Additional data from the study presented at the 2024 ASCO Annual Meeting showed that the median tumor volume reduction was –41% (range, –90% to 13%) among adult patients, and 62% of adult responders experienced a deep response, defined as a tumor volume reduction of more than 50%. The median duration of treatment (DOT) among adult patients was 22 months, the median time to response (TTR) was 7.8 months (range, 4-19), and the median DOR was not reached (NR).

In pediatric patients, the median best change in tumor volume was –42% (range, –91% to 48%), and 52% of pediatric responders achieved a deep response. The median DOT, TTR, and DOR were 22 months, 7.9 months (range, 4-19), and NR, respectively.

Mirdametinib was also associated with improvements in pain severity and health-related quality of life.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) occurred in 98% of adult patients and 95% of evaluable pediatric patients. The rates of grade 3 or higher TRAEs were 16% and 25%, respectively.

Serious TRAEs were reported in 1 patient (2%) in the adult cohort and no patients in the pediatric cohort. In adult patients, TRAEs led to dose interruptions, dose reductions, and treatment discontinuation in 9%, 17%, and 21% of patients, respectively. In the pediatric cohort, these respective rates were 14%, 12%, and 9%.

The most common AEs reported in more than 25% of adult patients included rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue.1 The most common grade 3 or 4 laboratory abnormality that occurred in more than 2% of patients was increased creatine phosphokinase.

The most frequent AEs reported in more than 25% of pediatric patients comprised rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea. The most common grade 3 or 4 laboratory abnormalities reported in more than 2% of this population included decreased neutrophil count and increased creatine phosphokinase level.

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. Feburary 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