The U.S. Food and Drug Administration (FDA) approved mirdametinib (Gomekli, SpringWorks Therapeutics, Inc.), a kinase inhibitor, for adults and children aged 2 years and older with inoperable neurofibromatosis type 1–associated plexiform neurofibromas based on data from the phase III ReNeu trial.
Researchers evaluated 114 patients with inoperable, symptomatic neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas (PN) causing morbidity, including 58 adults and 56 pediatric patients. Inoperable PN was defined as a lesion that could not be surgically removed without substantial morbidity due to encasement of or proximity to vital structures, invasiveness, or high vascularity. The primary efficacy endpoint was confirmed overall response rate (ORR), assessed by blinded independent central review using volumetric magnetic resonance imaging per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria, with modifications requiring confirmation within 2 to 6 months during the 24-cycle treatment period.
The ORR was 41% (95% confidence interval [CI] = 29%–55%) in adult patients and 52% (95% CI = 38%–65%) in pediatric patients, with all responses being partial (≥ 20% reduction in PN volume) and no complete responses observed.
Among adults, the most common treatment-related adverse events (occurring in > 25% of patients) included rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue; grade 3 or 4 laboratory abnormalities (occurring in > 2%) included increased creatine phosphokinase levels. In pediatric patients, frequent adverse events (occurring in > 25%) included rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea; grade 3 or 4 laboratory abnormalities (occurring in > 2%) included decreased neutrophil count and increased creatine phosphokinase levels.
Mirdametinib has been associated with left ventricular dysfunction and ocular toxicity, including retinal vein occlusion, retinal pigment epithelial detachment, and blurred vision. Treatment modifications, including dose adjustments or discontinuation, are recommended based on adverse event severity. The prescribing information includes dosing recommendations based on body surface area.
