Long-term data revealed improved confirmed objective response rates (ORRs) by blinded independent central review (BICR) with additional time on mirdametinib (Gomekli) in adults and children with neurofibromatosis type 1 (NF1)–associated symptomatic plexiform neurofibroma (PN) enrolled in the phase 2b ReNeu trial (NCT03962543).1 Notably, most responses proved to be deep and durable.
The findings, which were originally presented at the Children’s Tumor Foundation NF Conference, showed that in adult patients (n = 58), the confirmed ORR for the treatment phase plus long-term follow-up (LTFU) as of September 20, 2023, was 45%; as of June 12, 2024, this rate was 47%, signifying a difference of +1. At the respective time points, 58% (n = 15/26) and 67% (n = 18/27) of responders achieved a deep response (difference, +3). There was no difference in median best change in target PN volume from baseline.
Mirdametinib continued to show durable target PN volume reductions. The median duration of therapy was 21.8 months for both the September (range, 0.4-45.6) and June (range, 0.4-54.4) cutoffs. The median time to onset of response at the respective time points were 9.6 months (range, 4.0-29.0) and 11.3 months (range, 4.0-29.0; difference, +1.7), and the median time to best percentage change increased from 15.2 months (range, 4.0-40.0) to 17.5 months (range, 4.0-47.3), signifying a difference of +2.3. There was no difference in median DOR from September to June; 96% of patients at both time points had durable responses at data cutoff (difference, +1). The percentage of patients who had a DOR of at least 12 months increased from 69% at the September cutoff to 85% at the June cutoff (difference, +16%).
In children (n = 56), the confirmed ORR as of the September cutoff was 54% vs 55% at the June cutoff, translating to a difference of +1. The percentage of responders who achieved a deep response increased from 50% (n = 15/30) in September to 61% (n = 19/31) in June (difference, +4). In this population, a 1% greater median reduction in target PN volume from baseline was observed from September (–42; range, –91 to 48) to June (–43; range, –98 to 48).
Durable target PN volume reductions were also observed in the pediatric population. The median duration of treatment was 22.0 months (range, 1.6-40.0) at the September cutoff vs 25.4 months (range, 1.6-48.5) at the June cutoff (difference, +3.4). There was no difference in median time to onset of response between the time points (7.9 months at both cutoffs), although the median time to best percentage change increased from 13.5 months (range, 4.0-32.7) at the September cutoff to 15.2 months (range, 4.0-40.5) at the June cutoff (difference, +1.7). Again, there was no difference in median DOR; all patients had durable responses at the time of both data cutoffs (difference, +1). Notably, the percentage of patients who had a DOR spanning at least 12 months increased from September to June cutoffs, rising from 73% to 84% (difference, +11%).
“The key take-home [message] from the LTFU phase is that if patients are on [mirdametinib] 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,” Angela C. Hirbe, MD, PhD, associate professor of medicine in the John T. Milliken Department of Medicine of the Division of Oncology at WashU Medicine in St. Louis, Missouri, and presenting author of the data, said in an exclusive interview with OncLive®.2
What was the design of the ReNeu trial examining mirdametinib in NF1-PN?
The multicenter, single-arm ReNeu study enrolled patients at least 2 years of age with symptomatic, inoperable NF1-associated PN causing significant morbidity; of the 114 patients enrolled, 56 were children ranging from 2 years of age to 17 years of age, and 58 were adults who were 18 years of age or older.1,3
For the treatment phase, patients were administered mirdametinib as a capsule or dispersible tablet at a twice-daily dose of 2 mg/m2 as part of a 3-weeks-on/1-week-off schedule. Treatment continued until progressive disease or intolerable toxicity.3
After the treatment phase, patients entered a 30-day safety follow-up period, and they were assessed for eligibility for optional LTFU.1 Specifically, 84% of adults (n = 26/31) and 86% of children (n = 32/37) elected to continue mirdametinib in the LTFU period. This was followed by another 30-day safety follow-up period.
Key trial end points comprised BICR-assessed confirmed ORR, which was defined as the percentage of patients who experienced a reduction in target PN volume of at least 20% by MRI on consecutive scans at any time before data cutoff; change in target PN volume from baseline; DOR; and safety and tolerability.
In the adult population, the median age was 34 years (range, 18-69), 64% were female, the median volume of target PN was 196 mL (range, 1-3457), and 53% had target PN progressing at the time of trial entry. The most common location of target PN was head and neck (48%), followed by lower/upper extremities (29%), paraspinal (9%), torso (9%), and other (5%). The most common type of PN-related morbidity was pain (90%), followed by disfigurement or major deformity (52%), motor dysfunction or weakness (40%), other (17%), or airway dysfunction (5%).
In the pediatric population, the median age was 10 years (range, 2-17), 54% were female, the median volume of target PN was 99 mL (range, 5-3630), and 62% of patients had target PN progressing at the time of entering the trial. Again, the most common location of target PN was head and neck (50%), followed by lower/upper extremities (14%), torso (14%), other (14%), and paraspinal (7%). The most common type of PN-related morbidity in this population was again pain (70%), followed by disfigurement or major deformity (50%), motor dysfunction or weakness (27%), other (21%), and airway dysfunction (12%).
What was learned about the long-term safety profile of mirdametinib in NF1-associated PN?
No new drug-related safety signals emerged with LTFU.
In the adult population, any-grade treatment-related adverse effects (TRAEs) occurred in 98% of patients, 17% of which were grade 3 or higher. The most common TRAEs experienced by at least 20% of patients included dermatitis acneiform (any grade, 78%; grade ≥3, 9%), diarrhea (48%; 0%), and nausea (36%; 0%). Serious TRAEs were experienced by 2% of patients. Additionally, TRAEs led to dose reductions, interruptions, or discontinuations for 17%, 9%, and 22% of patients, respectively.
In the pediatric population, any-grade TRAEs occurred in 95% of patients; 25% of cases were grade 3 or higher in severity. The most common TRAEs in this population were, again, dermatitis acneiform (any grade, 43%; grade ≥3, 2%), diarrhea (38%; 2%), and nausea (21%; 0%). TRAEs led to dose reductions, interruptions, or discontinuations for 14%, 14%, and 9% of patients, respectively.
“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 in the presentation.
What prior data have been reported from ReNeu?
Previous data showed that in adult patients (n = 58), the confirmed ORR was 41% (95% CI, 29%-55%) with 88% of patients experiencing a DOR of at least 12 months and 50% experiencing a DOR of at least 24 months.3 In pediatric patients, the confirmed ORR with mirdametinib was 52% (95% CI, 38%-65%), with 90% and 48% of patients experiencing a DOR lasting for at least 12 or 24 months, respectively. Early, sustained, and clinically meaningful improvements in pain and health-related quality of life (QOL) were also reported.4
The prior data supported the February 2025 FDA approval of mirdametinib for adult and pediatric patients aged 2 years and older with NF1 who have symptomatic PN not amenable to complete resection.5 At the time of the decision, Christopher L. Moertel, MD, told OncLive in an exclusive interview:6,7 “The approval of mirdametinib is significant because this a highly selective MEK inhibitor that will provide benefit to both adults and children with neurofibromatosis type 1 who have plexiform neurofibromas that are not amenable to surgery and are causing significant QOL or pain issues.”
Moertel serves as a pediatric neuro-oncologist and professor at the University of Minnesota School of Medicine in Minneapolis, where he directs the Pediatric Neuro-Oncology Fellowship Program and co-leads the Pediatric Neuro-Oncology and Neurofibromatosis Programs. Listen to the interview via OncLive On Air.8
Moreover, in July 2025, the European Commission granted conditional marketing authorization for mirdametinib (Ezmekly) for the same indication based on ReNeu data.9 In another exclusive interview with OncLive,10Ignacio Blanco, MD, PhD, director of the Catalan Reference Center for Neurofibromatosis in Barcelona, Spain, discussed the significance of this decision: “For Europeans, this is a great achievement because…we had no treatment for adult patients with NF1‑associated PNs. In the context of NF1, there are a lot of adult patients with symptomatic PNs where [there was] no possibility to offer anything.” Listen to the full OncLive On Air podcast episode.11
References
- Hirbe AC, Moertel CL, Shuhaiber HH, et al. Update from the long-term follow-up (LTFU) phase of ReNeu: A pivotal phase 2b trial of mirdametinib in adults and children with neurofibromatosis type 1 (NF1)-associated symptomatic plexiform neurofibroma (PN). Presented at: 2025 SNO Annual Meeting; November 19-23, 2025; Honolulu, Hawaii. Abstract CTNI-06.
- Hirbe AC. Dr Hirbe on long-term efficacy and safety outcomes with mirdametinib in symptomatic NF1-PN. OncLive.com. November 22, 2025. Accessed November 22, 2025. https://www.onclive.com/view/dr-hirbe-on-long-term-efficacy-and-safety-outcomes-with-mirdametinib-in-symptomatic-nf1-pn
- Gomekli. Prescribing information; SpringWorks Therapeutics; 2025. https://springworkstx.com/wp-content/uploads/2025/02/GOMEKLI-USPI-Final-Feb-11-2025_.pdf
- Moertel CL, Hirbe AC, Shuhaiber HH, et al. ReNeu: a pivotal phase 2b trial of mirdametinib in adults and children with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN). J Clin Oncol. 2024;42(suppl 16):3016. doi:10.1200/JCO.2024.42.16_suppl.3016
- FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection. FDA. Feburary 11, 2025. Accessed November 22, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirdametinib-adult-and-pediatric-patients-neurofibromatosis-type-1-who-have-symptomatic
- Moertel CL. Dr Moertel on the FDA approval of mirdametinib for NF1-associated plexiform neurofibromas. OncLive.com. February 11, 2025. Accessed November 22, 2025. https://www.onclive.com/view/dr-moertel-on-the-fda-approval-of-mirdametinib-for-nf1-associated-plexiform-neurofibromas
- DiEugenio J. Mirdametinib provides long-awaited treatment option in NF1-associated PN: Q&A with Christopher L. Moertel, MD. OncLive.com. February 18, 2025. Accessed November 22, 2025. https://www.onclive.com/view/mirdametinib-provides-long-awaited-treatment-option-in-nf1-associated-pn
- Moertel CL. FDA Approval Insights: Mirdametinib for NF1-associated plexiform neurofibromas: with Christopher L. Moertel, MD. OncLive.com. February 20, 2025. Accessed November 22, 2025. https://www.onclive.com/view/da-approval-insights-mirdametinib-for-nf1-associated-plexiform-neurofibromas-with-christopher-l-moertel-md
- The European Commission has granted conditional approval of Ezmekly (mirdametinib) for the treatment of adult and pediatric patients with neurofibromatosis type 1–associated plexiform neurofibromas (NF1-PN). News release. SpringWorks Therapeutics. July 18, 2025. Accessed November 22, 2025. https://springworkstx.gcs-web.com/news-releases/news-release-details/european-commission-grants-conditional-approval-ezmeklyr
- Blanco I. Dr Blanco on the conditional EU approval of mirdametinib for NF1-associated PNs. OncLive.com. July 31, 2025. Accessed November 22, 2025. https://www.onclive.com/view/dr-blanco-on-the-conditional-eu-approval-of-mirdametinib-for-nf1-associated-pns
- Blanco I. The European approval of mirdametinib expands the treatment paradigm for NF1-associated plexiform neurofibromas: with Ignacio Blanco, MD, PhD. OncLive.com. August 7, 2025. Accessed November 22, 2025. https://www.onclive.com/view/the-european-approval-of-mirdametinib-expands-the-treatment-paradigm-for-nf1-associated-plexiform-neurofibromas-with-ignacio-blanco-md-phd
