Data from the pivotal Phase 2b ReNeu trial of mirdametinib, an investigational MEK inhibitor, in adult and pediatric patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN), have been published in the Journal of Clinical Oncology (JCO). The multi-center, single-arm trial demonstrated significant confirmed objective response rates and a manageable safety profile.
ReNeu Trial Results
The ReNeu trial met its primary endpoint of confirmed objective response rate (ORR), as assessed by blinded independent central review. During the 24-cycle treatment phase, the ORR was 41% (95% CI, 29 to 55; n=24/58) in adults and 52% (95% CI, 38 to 65; n=29/56) in children receiving mirdametinib. An efficacy analysis that also included patients who achieved a confirmed objective response after 24 cycles of mirdametinib treatment resulted in an ORR of 45% in adults (n=26/58) and 54% in pediatric (n=30/56) patients. Of the patients who achieved a confirmed objective response during the treatment phase, 96% of adults and 100% of children had durable responses at the time of data cut-off, with 75% of adults and 76% of children having met or exceeded 12 months in response. The median time to onset of confirmed response was 7.8 months (range: 4 to 19) in adults and 7.9 months (range: 4.1 to 18.8) in children.
Tumor Volume Reduction and Quality of Life Improvements
Tumor volume reductions were deep and durable during the course of the study. The median best percentage change in target PN volume was –41% (range: –90 to 13%) in adults and –42% (range:–91 to 48%) in children. Among those with a confirmed objective response, 62% of adults and 52% of children achieved a best percent reduction in target tumor volume from baseline of >50%. From baseline to Cycle 13, both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported secondary endpoint outcome measures of worst tumor pain severity, pain interference, and health-related quality of life that began early and were sustained during treatment.
Safety and Tolerability
Mirdametinib was generally well tolerated in the ReNeu trial, with the majority of adverse events (AEs) being Grade 1 or 2. The most commonly reported treatment-related adverse events (TRAEs) occurring in >20% of adults were dermatitis acneiform (78%), diarrhea (48%), nausea (36%), vomiting (28%) and fatigue (21%). The most commonly reported TRAEs occurring in >20% of children were dermatitis acneiform (43%), diarrhea (38%), paronychia (30%), nausea (21%), ejection fraction decreased (20%), and increased blood creatine phosphokinase (20%). Among all study participants, 22% of adults and 9% of children discontinued treatment due to AEs.
Mirdametinib: A Potential New Treatment Option
"Plexiform neurofibromas can cause extreme pain, disfigurement, compression of internal organs, and impaired physical function. There is a substantial unmet need for a highly effective and well tolerated systemic therapy for these patients," said Christopher Moertel, M.D., Medical Director, Pediatric Neuro-Oncology and Neurofibromatosis Programs and Kenneth and Betty Jayne Dahlberg Professor of Pediatrics, University of Minnesota and lead author of the JCO publication. "The deep tumor volume reductions and significant improvements in pain and other quality of life measures that we saw in the ReNeu trial, as well as having a formulation option for young children or those who have difficulty swallowing, underscore the potential for mirdametinib to be a valuable new treatment option for adults and children with NF1-PN."
Regulatory Status
The U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for mirdametinib in adults and children with NF1-PN, granting it Priority Review designation and setting a Prescription Drug User Fee Act (PDUFA) action date of February 28, 2025. The European Medicines Agency (EMA) has validated the Marketing Authorization Application (MAA) for mirdametinib for the treatment of adult and pediatric patients with NF1-PN.
