On 11 February 2025, the US Food and Drug Administration (FDA) approved mirdametinib (Gomekli, SpringWorks Therapeutics, Inc.), a kinase inhibitor, for adult and paediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas not amenable to complete resection.
Efficacy was evaluated in ReNeu (NCT03962543), a multicentre, single-arm study conducted in 114 patients ≥2 years of age (58 adults, 56 paediatric patients) with symptomatic, inoperable NF1-associated plexiform neurofibromas causing significant morbidity. An inoperable plexiform neurofibroma was defined as a plexiform neurofibroma 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 plexiform neurofibromas) or partial response (≥20% reduction in plexiform neurofibromas 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% confidence interval [CI] 29, 55) and 52% in the paediatric cohort (95% CI 38, 65).
The most common adverse reactions (>25%) in adult patients were rash, diarrhoea, 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 paediatric patients were rash, diarrhoea, 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.
See the prescribing information for the recommended dose based on body surface area.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. submission from the applicant to facilitate the FDA’s assessment.
This application was granted priority review, fast track designation, and orphan drug designation. A priority review voucher was issued for this rare paediatric disease product application.
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