FDA OKs Mirdametinib for Neurofibromatosis Type 1

The FDA on Tuesday approved mirdametinib (Gomekli) for adults and kids ages 2 and up with neurofibromatosis type 1 (NF1).

Approval of the MEK inhibitor is specifically for patients who have symptomatic plexiform neurofibromas that are not amenable to total resection.

The agency’s decision was supported by the pivotal ReNeu trial, a multicenter, single-arm phase IIb study of 114 patients with symptomatic, inoperable NF1-associated plexiform neurofibromas causing significant morbidity.

Mirdametinib yielded a confirmed overall response rate of 41% (95% CI 29-55) among the 58 adults enrolled and 52% (95% CI 38-65) among the 56 children enrolled, with responses defined as a 20% or greater reduction in target plexiform neurofibroma volume on consecutive MRI scans.

“It’s a breakthrough for our patients,” study investigator Christopher Moertel, MD, of the University of Minnesota in Minneapolis, told MedPage Today when the trial data were published last fall.

“The toxicity was acceptable and we really showed that people could remain on this therapy for a good long time,” he said, adding that “some patients had reductions in tumor size of well into 80%.” Median time to response with mirdametinib was about 8 months in both cohorts, and the median duration of response had not yet been reached.

An autosomal-dominant genetic condition, NF1 loss-of-function variants occur in about one per 2,500 births worldwide. The variants cause neurofibromin dysfunction and persistent MAP kinase (MEK) pathway activation. Plexiform neurofibromas are non-malignant nerve-sheath tumors that develop in 30-50% of patients, often causing pain, organ displacement/compression, impaired physical function, and disfigurement.

In ReNeu, patients were considered inoperable if their tumors could not be completely resected “without risk for substantial morbidity due to encasement or close proximity to vital structures, invasiveness, or high vascularity,” the FDA noted.

Common adverse events (AEs) among the adults included dermatitis acneiform (78%), diarrhea (48%), nausea (36%), vomiting (28%), and fatigue (21%). In kids, common AEs included dermatitis acneiform (43%), diarrhea (38%), paronychia (30%), nausea (21%), and decreased ejection fraction (20%).

Common grade 3/4 laboratory abnormalities (occurring in over 2%) included increased creatine phosphokinase in the adult cohort and decreased neutrophil count and increased creatine phosphokinase in the pediatric cohort.

Other warnings and precautions with mirdametinib noted by FDA included risks for left ventricular dysfunction and ocular toxicity, including retinal vein occlusion, retinal pigment epithelial detachment, and blurred vision. The drug should be paused or discontinued depending on the severity of AEs.

Senior Editor Charles Bankhead contributed to this report.

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