Mirdametinib, an investigational MEK1/2 inhibitor, has demonstrated significant clinical benefits in both adult and pediatric patients with neurofibromatosis type 1-associated plexiform neurofibroma (NF1-PN). Data from the phase 2b ReNeu trial, published in The Journal of Clinical Oncology, reveal substantial tumor volume reductions and improvements in patient-reported outcomes, including pain and health-related quality of life (HRQOL).
ReNeu Trial: Mirdametinib Efficacy and Safety
The ReNeu trial (NCT03962543) was an open-label, multi-center study that enrolled 58 adult patients and 56 children (ages 2-17) with NF1-PN. Participants received mirdametinib capsules or tablets at a dose of 2 mg/m² twice daily, administered in 28-day cycles (3 weeks on, 1 week off). The primary endpoint was the confirmed objective response rate (ORR) assessed by blinded independent central review. Secondary endpoints included duration of response and changes from baseline in patient-reported outcomes.
Significant Response Rates and Tumor Volume Reduction
In adult patients, mirdametinib achieved a confirmed ORR of 41% (95% CI, 29%-55%), significantly exceeding the predefined minimum clinically relevant response threshold of 23% (P < .001). Among pediatric patients, the confirmed ORR was 52% (95% CI, 38%-65%), also surpassing the clinically relevant response rate of 20% (P < .001). The median best percentage change in PN volume was -41% (range, -90% to 13%) in adults and -42% (range, -91% to 48%) in children.
Improvements in Pain and Quality of Life
Adults treated with mirdametinib reported significant improvements in worst tumor pain severity (P < .001), pain interference (P < .001), and HRQOL (P = .02). At cycle 13, 71% of adult patients reported an improvement in overall status. Similarly, pediatric patients experienced significant improvements in worst tumor pain severity (P = .003), patient-reported pain interference (P = .02), parent-reported pain interference (P = .03), and parent-reported HRQOL (P = .005). Overall, 79% of pediatric patients reported an improvement in their status.
Tolerability and Adverse Events
Common treatment-related adverse events (TRAEs) in adults included dermatitis acneiform (78%), diarrhea (48%), and nausea (36%). In pediatric patients, common TRAEs included dermatitis acneiform (43%), diarrhea (38%), and paronychia (30%). Dose interruptions, reductions, and terminations due to AEs were reported, but no symptomatic ejection fraction decreases, retinal vein occlusion, or serious TRAEs occurred in the pediatric cohort.
Clinical Implications
"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, MD, medical director of Pediatric Neuro-Oncology and Neurofibromatosis Programs at the University of Minnesota. He added that the study results, along with the availability of a formulation suitable for young children, highlight the potential of mirdametinib as a valuable new treatment option.
Regulatory Status
The FDA granted priority review to mirdametinib for adult and pediatric NF1-PN in August 2024, with a Prescription Drug User Fee Act (PDUFA) date of February 28, 2025.
