Long-Term Mirdametinib Data Shows Improved Response Rates and Deeper Tumor Shrinkage in NF1-Associated Plexiform Neurofibromas
核心洞察
Extended treatment with mirdametinib led to improved confirmed overall response rates in both adult (47%) and pediatric (55%) patients with NF1-associated symptomatic plexiform neurofibromas.
Deep responses, defined as greater than 50% tumor volume reduction, increased significantly with longer treatment duration, reaching 67% of adult responders and 61% of pediatric responders.
The MEK1/2 (搜索) inhibitor demonstrated durable responses with 85% of adult patients and 84% of pediatric patients maintaining responses for at least 12 months.
Extended treatment with mirdametinib (Gomekli) demonstrated improved response rates and deeper tumor shrinkage in patients with neurofibromatosis type 1 (搜索) (NF1)-associated symptomatic plexiform neurofibroma (搜索) (PN), according to long-term follow-up data from the phase 2b ReNeu trial presented at the 2025 SNO Annual Meeting.
The updated analysis, conducted approximately 9 months after the prior data cutoff, showed that confirmed overall response rates (ORRs) by blinded independent central review improved with additional time on therapy. In adult patients (n = 58), the confirmed ORR increased from 45% as of September 20, 2023, to 47% as of June 12, 2024. In the pediatric population (n = 56), response rates rose from 54% to 55% over the same period.
Enhanced Depth and Durability of Responses
The most striking finding was the significant increase in deep responses, defined as greater than 50% reduction in target PN volume. Among adult responders, the percentage achieving deep responses increased from 58% (15/26 patients) in September to 67% (18/27 patients) in June. In pediatric patients, deep response rates rose from 50% (15/30 patients) to 61% (19/31 patients).
"The key take-home message from the long-term follow up phase is that patients are on this medication longer, then we end up seeing both more patients who actually respond and have at least a 20% shrinkage in their tumor, as well as a significantly increased number of patients with deep responses," said Angela C. Hirbe, MD, PhD, associate professor of medicine in the Division of Oncology at Washington University School of Medicine.
Duration of response data further supported the durability of treatment benefits. In adults, the percentage of patients with responses lasting at least 12 months increased from 69% at the September cutoff to 85% at the June cutoff. Similarly, in pediatric patients, this percentage rose from 73% to 84%.
Treatment Characteristics and Patient Population
The ReNeu trial enrolled 114 patients with symptomatic, inoperable NF1-associated PN causing significant morbidity. Patients received mirdametinib at 2 mg/m² twice daily on a 3-weeks-on/1-week-off schedule until progressive disease or intolerable toxicity.
In the adult population, the median age was 34 years, 64% were female, and the median target PN volume was 196 mL. The most common location of target PN was head and neck (48%), and pain was the predominant type of PN-related morbidity (90%).
The pediatric cohort had a median age of 10 years, 54% were female, and a median target PN volume of 99 mL. Similar to adults, head and neck was the most common tumor location (50%), with pain being the primary morbidity (70%).
Sustained Safety Profile
Long-term follow-up revealed no additional safety signals with extended mirdametinib treatment. In adults, any-grade treatment-related adverse effects (TRAEs) occurred in 98% of patients, with 17% experiencing grade 3 or higher events. The most common TRAEs were dermatitis acneiform (78%), diarrhea (48%), and nausea (36%).
In pediatric patients, 95% experienced any-grade TRAEs, with 25% being grade 3 or higher. The safety profile mirrored that of adults, with dermatitis acneiform (43%), diarrhea (38%), and nausea (21%) being most frequent.
"No additional serious TRAEs and no additional dose interruptions were observed; there was 1 additional dose reduction and 1 additional discontinuation due to TRAEs compared to the prior data cutoff," Hirbe noted.
Regulatory Impact and Clinical Significance
These long-term data support the February 2025 FDA approval of mirdametinib as the first MEK1/2 (搜索) inhibitor for both adults and children 2 years of age or older with NF1 who have symptomatic PN not amenable to complete resection. The European Commission also granted conditional marketing authorization for mirdametinib (Ezmekly) in July 2025.
The median duration of therapy reached 21.8 months in adults and 25.4 months in pediatric patients by the June 2024 cutoff, with median time to best percentage change extending to 17.5 months and 15.2 months, respectively. These findings indicate that patients who continue treatment for longer periods are more likely to experience tumor regression and improvements in pain and quality of life.