Background:
We evaluated long-term mirdametinib treatment from ReNeu (NCT03962543). Mirdametinib is the first FDA- and EC-approved MEK1/2 inhibitor in both adults and children (≥2y) with NF1 for the treatment of symptomatic PN not amenable to complete resection (FDA) or symptomatic, inoperable PN (EC).

Methods:
Year (Y) 1 through Y4 results were evaluated (data cutoff 1-July-2025). Confirmed objective response rates (ORRs) and confirmed responders with deep responses (best target PN volume reduction from baseline of >50%) were summarized cumulatively (Y1-Y4). Treatment-related adverse event (TRAE) rates in Y1 and Y4 were reported.

Results:
Median (range) mirdametinib exposure: 21.8mo (0.4-67.0) in adults; 25.4mo (1.6-61.1) in children. Confirmed ORR by Y1 and Y4, respectively: 29.3% (17/58) and 46.6% (27/58) in adults; 42.9% (24/56) and 55.4% (31/56) in children. Percentages of confirmed responders with deep responses by Y1 and Y4, respectively: 41.2% (7/17) and 70.4% (19/27) in adults; 29.2% (7/24) and 64.5% (20/31) in children. Disease progression: 10.3% (6/58) of adults; 23.2% (13/56) of children. All-grade TRAE rates during Y1 and Y4, respectively: 98.3% (57/58) and 43.5% (10/23) in adults; 92.9% (52/56) and 45.8% (11/24) in children. TRAEs leading to dose reductions during Y1 and Y4, respectively: 13.8% (8/58) and 0% (0/23) in adults; 12.5% (7/56) and 4.2% (1/24) in children. TRAEs leading to discontinuations during Y1 and Y4, respectively: 20.7% (12/58) and 4.3% (1/23) in adults; 7.1% (4/56) and 4.2% (1/24) in children.

Conclusions:
Long-term mirdametinib treatment in ReNeu demonstrated increased confirmed ORRs, additional deep responses, and decreased TRAE rates over time in adults and children with NF1-PN.

Background: In NF1, the head and neck regions (HNR) are frequently severely affected by plexiform neurofibroma (PNF). This study analyzes the distribution pattern of facial PNF (FPNF) and HNR-PNF.
Methods: The localization and treatment data of NF1 patients were analyzed (FPNF:179, HNR-PNF: 69). Photographically documented tumors were manually transferred to a topographic scheme and digitized (extension and entity further determined by MRI and histology). The digitized registrations of the facial extensions of the tumors of each patient were overlaid in a single image (Photoshop™). A file of the facial scheme contained the sum of the tumor localization. Frequency of tumor localization was indicated with a color code (heat map).
Results: The predominant treatment need of patients with orbital/periorbital manifestations (FPNF group) and the sternocleidomastoid region (HNR group) became evident in the graphic representations (no side preference of lesions). Tumors do not respect anatomical units. The mean number of surgical measures per patient was 2.21 (median: 1) in FPNF, and 1.33 in HNR patients. Extensive swelling, hematoma, and delayed wound healing were all common postoperative findings. The removal or debulking of large tumors in these regions clarified the biology of the tumors and improved the patients' function and appearance.
Conclusion: An analysis of patients who underwent surgery for PNF reveals characteristic clusters of affected anatomical structures. The data provides insights into the care needs of patients affected by these lesions.

Background: Mirdametinib is the first Food and Drug Administration- and European Commission-approved MEK1/2 inhibitor (MEKi) in both adults and children (≥2 y) with NF1 for the treatment of symptomatic PN not amenable to complete resection or symptomatic, inoperable PN, respectively. Data are limited on patient experiences with different MEKis after previous MEKi failure for lack of efficacy or tolerability. This analysis from ReNeu assessed efficacy/safety of mirdametinib in adults and children with NF1-PN and prior MEKi exposure.
Methods: Patients with NF1-PN and prior MEKi exposure in ReNeu (n=4 adults, 19–43 y; n=6 children, 7–13 y) were evaluated post hoc for clinical outcomes, including volumetric tumour response and treatment-related adverse events (TRAEs). Additionally, patient cases from SpringWorks Early Access Program were described.
Results: Four patients had baseline progressive disease (PD). Mirdametinib treatment duration ranged 8–40 months. All mirdametinib-treated patients had a best overall confirmed response of partial response or stable disease. Most patients (80%; 8/10) had target PN volume reduction. Best percentage target PN volume change from baseline ranged from −66.8% to 5.8%, within 4.0–32.7 months. Common TRAEs included dermatitis acneiform (n=2/4 adults; n=3/6 children) and diarrhoea (n=2/4 adults; n=2/6 children). Of 5 patients who discontinued prior MEKi for PD or pain, 1 discontinued mirdametinib for PD. Of 3 patients who discontinued prior MEKi for toxicity, 2 discontinued mirdametinib for TRAEs.
Conclusion: In MEKi-exposed patients with NF1-PN, including those who discontinued prior MEKi due to toxicity or PD, data suggest that some of these patients can benefit from mirdametinib treatment.

Background: Mirdametinib and selumetinib, which are FDA-approved MEK inhibitors for both adults and children with NF1-PN, have distinct drug-drug interaction (DDI) profiles. Selumetinib, primarily metabolized by CYP3A4, requires dose modifications when used concomitantly with CYP3A4 inhibitors/inducers. Mirdametinib, primarily metabolized by glucuronidation and oxidation via UGT and CES enzymes, does not require dose modifications when used concomitantly with CYP3A4 inhibitors/inducers. Selumetinib, containing vitamin E, may increase bleeding risk when combined with vitamin K antagonists and antiplatelet agents.

Methods: Use of systemic moderate-to-strong CYP3A4 inhibitors/inducers, vitamin K antagonists, and antiplatelet agents in patients with NF1-PN was quantified from a US claims database (01OCT2015-30SEP2024). First PN diagnosis was identified as index, with a 1-year post-index (follow-up) continuous enrollment period to assess medication use.

Results: A total of 1241 children and 3650 adults with NF1-PN were eligible (median age at index [interquartile range]: children, 11 [6, 14] years; adults, 44 [31, 56] years). During follow-up, 6.9% (86/1241) of children and 16.7% (611/3650) of adults filled ≥1 prescription(s) for a moderate-to-strong CYP3A4 inducer/inhibitor. Additionally, 0.6% (8/1241) of children and 4.8% (175/3650) of adults filled ≥1 prescription(s) for vitamin K antagonists or antiplatelet agents.

Conclusion: The use of moderate-to-strong CYP3A4 inhibitors/inducers in patients with NF1-PN in the US highlights the importance of thorough concomitant drug assessment prior to starting MEK inhibitor treatment. For NF1-PN treatment, mirdametinib and selumetinib have differentiated drug metabolism profiles that should be carefully considered.

Background: Plexiform neurofibromas (PNs) occur in 30-50% of individuals with Neurofibromatosis type 1 (NF1) and represent a significant cause of morbidity. Selumetinib was approved by EMA in September 2025 for adults with inoperable and symptomatic NF1-PNs. Real-world evidence is essential to optimize patient management.
Methods: Italian retrospective, multicenter, observational study in adults with NF1 and symptomatic, inoperable PNs treated with selumetinib through the Nominal Compassionate Use program (NCU) in 7 centers. Responses were assessed via chart abstraction from medical records. Outcomes included Best Overall Response (BOR) assessed using REiNS criteria with 1 or 2 MRI(s). Demographic/clinical characteristics of patients and selumetinib treatment duration were described. Follow-up after NCU start (2017) lasted up to 9 years (2026).
Results: Twenty-eight (28) patients were enrolled; the full analysis set (FAS) included 23 patients (5 lacked pre- and post-baseline MRI; median age: 27 years). Nine cases (39.13%) had one or more prior PN-removal surgery, 6 (26.09%) prior non-MEK-inhibitor treatments. PNs were mostly located in back (6, 26.1%), spine (6, 26.1%) and head/neck (4, 17.4%). Most frequent baseline morbidities were pain (20, 86.96%), motor dysfunction/weakness (16, 69.57%) and disfigurement/major deformity (12, 52.17%). BOR was confirmed Partial Response (cPR) in 10/22 evaluable patients (45.45%), stable disease (SD) in 9/22 (40.91%) and unconfirmed PR (uPR) in 3/22 (13.64%). 59% of participants experienced a PN volume reduction of at least 20% versus baseline at last assessment. Median treatment duration was 41.3 months (range: 5-88 months).
Conclusion: This study shows real-world effectiveness of selumetinib in adults with NF1-PNs, aligning with clinical trials outcomes.