FDA Approves Mirdametinib for Neurofibromatosis Type 1

The US Food and Drug Administration (FDA) has approved mirdametinib (Gomekli) for adults and children aged 2 and older with neurofibromatosis type 1 (NF1). The approval specifically applies to patients with symptomatic plexiform neurofibromas that cannot be completely removed through surgery.

Efficacy and Safety

Efficacy was evaluated in ReNeu (NCT03962543), a multicenter, single-arm trial in 114 patients ≥2 years of age (58 adults, 56 pediatric patients) with symptomatic, inoperable NF1-associated PN causing significant morbidity. An inoperable PN was defined as a PN that could not be completely surgically removed without risk for substantial morbidity due to encasement or close proximity to vital structures, invasiveness, or high vascularity.

The major efficacy outcome measure was confirmed overall response rate (ORR), defined as the percentage of patients with complete response (disappearance of the target PN) or partial response (≥20% reduction in PN volume). Responses were assessed by blinded independent central review using volumetric MRI analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria, modified to require confirmation of responses within 2 to 6 months during the 24-cycle treatment phase. Confirmed ORR was 41% for adults (95% CI: 29, 55) and 52% in the pediatric cohort (95% CI: 38, 65).

The most common adverse reactions (>25%) in adult patients were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. The most common Grade 3 or 4 laboratory abnormality (>2%) was increased creatine phosphokinase.

The most common adverse reactions (>25%) in pediatric patients were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea. The most common Grade 3 or 4 laboratory abnormalities (>2%) were decreased neutrophil count and increased creatine phosphokinase.

Mirdametinib can also cause left ventricular dysfunction and ocular toxicity including retinal vein occlusion, retinal pigment epithelial detachment and blurred vision. Mirdametinib should be withheld, dosage reduced or permanently discontinued based on the severity of adverse reactions.