On February 11, the U.S. Food and Drug Administration approved mirdametinib (Gomekli), a kinase inhibitor, for adult and pediatric patients aged 2 years and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection.
ReNeu Trial
Efficacy was evaluated in ReNeu (ClinicalTrials.gov identifier 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, 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 magnetic resonance imaging 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 overall response rate was 41% for adults (95% confidence interval [CI] = 29%–55%) and 52% in the pediatric cohort (95% CI = 38%–65%).
The most common adverse reactions (occurring in > 25% of participants) in adult patients were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. The most common Grade 3 or 4 laboratory abnormality (occurring in > 2%) was increased creatine phosphokinase.
The most common adverse reactions (occurring in > 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 (occurring in > 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.
Recommended dose is based on body surface area.
This review used the Assessment Aid, a voluntary 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 pediatric disease product application.
