Mirdametinib Shows Benefit in MEK Inhibitor–Pretreated NF1-Associated Plexiform Neurofibroma

Mirdametinib (Gomekli) provided benefit to adults and children with neurofibromatosis type 1–associated plexiform neurofibroma who had previously received another MEK inhibitor, according to findings from a post hoc analysis of the phase 2b ReNeu trial (NCT03962543) presented in a poster session at the 2026 SNO Annual Meeting (SNO 2026).¹

As of the September 20, 2023, data cutoff, 10 patients with neurofibromatosis type 1–associated plexiform neurofibroma (NF1-PN) enrolled in ReNeu (adult cohort, n = 4; pediatric cohort, n = 6) had a history of MEK inhibitor treatment, including selumetinib (Koselugo; n = 6), trametinib (Mekinist; n = 3), cobimetinib (Cotellic; n = 1), and an unknown agent (n = 1); 1 patient had received both trametinib and selumetinib. The best overall confirmed response with mirdametinib among children was partial response in 2 patients and stable disease in 4, and all 4 adults had stable disease (SD). The best change in target NF1-PN volume from baseline on MRI ranged from an increase of 5.8% to a decrease of 56.9% in children and from an increase of 0.9% to a decrease of 66.8% in adults.

The time to best change in target NF1-PN volume ranged from 4.0 months to 32.7 months in children and from 4.0 months to 11.6 months in adults. Among 4 children who stopped receiving a prior MEK inhibitor because of progressive disease or pain, 1 had a deep response, defined as a confirmed partial response with a best reduction of more than 50% in target NF1-PN volume; 1 remained on mirdametinib in long-term follow-up with SD; 1 stopped mirdametinib because of progressive disease; and 1 stopped because of a treatment-related adverse effect (rash).

“It is a small subset of patients, but there were a handful of patients who [had received] other MEK inhibitors before; even in those patients who had been exposed to MEK inhibitors in the past, we saw improvement in pain and some reduction in tumor volume,” Angela C. Hirbe, MD, PhD, an associate professor of medicine in the John T. Milliken Department of Medicine in the Division of Oncology at Washington University School of Medicine in St Louis, Missouri, stated in an interview with OncLive^®.

What was the design of the post hoc analysis of the ReNeu trial of mirdametinib in NF1-PN after prior MEK inhibitor exposure?

ReNeu was a multicenter, open-label, single-arm trial that enrolled adults and children 2 years of age and older with symptomatic, inoperable NF1-PN that was measurable on imaging. In the trial, 114 patients (adult cohort, n = 58; pediatric cohort, n = 56) received mirdametinib at 2 mg/m² (maximum, 4 mg) twice daily for 3 weeks of each 28-day cycle, followed by 1 week off, for up to 24 cycles. The median duration of exposure was 21.8 months (range, 0.4-45.6). After selumetinib gained FDA approval for pediatric patients, the ReNeu trial protocol was changed so that adults and children previously treated with a MEK inhibitor could no longer enroll.

The investigators captured prior MEK inhibitor use at baseline and later reviewed efficacy and treatment-related adverse effects (TRAEs) descriptively in patients with that history, with best confirmed responses determined by blinded independent central review of volumetric MRI. The poster also described 2 patients (1 child and 1 adult) who received mirdametinib through an early access program after stopping treatment with a prior MEK inhibitor because it was ineffective or poorly tolerated. These patients were chosen from 13 early access program (EAP) patients with prior MEK inhibitor exposure because their case data were complete and their treatment was recent or ongoing.

What did earlier ReNeu results show with mirdametinib in NF1-PN?

In the primary ReNeu analysis, published in 2025, the confirmed objective response rate by blinded independent central review was 41% (95% CI, 29%-55%) in adults (n = 58) and 52% (95% CI, 38%-65%) in children (n = 56), and the median best changes in target NF1-PN volume were −41% (range, −90% to 13%) and −42% (range, −91% to 48%), respectively.²

Longer-term data presented at SNO 2026 showed that at a median duration of exposure of 21.8 months (range, 0.4-67.0) in adults (N = 58) and 25.4 months (range, 1.6-61.1) in children (N = 56), the confirmed objective response rates were 46.6% and 55.4%, respectively.³ Additionally, 70.4% of adult patients and 64.5% of pediatric patients with confirmed responses achieved deep responses.

How durable and tolerable was mirdametinib in patients with NF1-PN and prior MEK inhibitor exposure?

Among the 10 patients included in the current post hoc analysis, the approximate duration of mirdametinib exposure ranged from 7.8 months to 39.8 months.¹ Responses lasted for 10 months in 1 child and 18 months in another, and no progression events occurred in those 2 patients. Dermatitis acneiform was the most commonly listed TRAE, occurring in 5 patients. Two patients discontinued mirdametinib because of TRAEs (rash in 1 child and diarrhea in 1 adult), 1 child discontinued mirdametinib because of radiographic progressive disease, 2 patients (1 adult and 1 child) discontinued mirdametinib by their own decision, and 1 adult could not undergo MRI because of rod placements in the back. Three patients (2 children and 1 adult) completed the 24-cycle treatment phase, and 1 child remained in long-term follow-up.

What did EAP cases show with mirdametinib after selumetinib or trametinib in NF1-PN?

One child with a progressive periorbital mass had stopped receiving selumetinib because poor tolerability led to noncompliance and because the drug was not effective; he switched to mirdametinib at 4 mg daily at 15 years of age. After approximately 2 years of treatment, which was ongoing as of March 2026, his tumor was flatter and softer, and he reported better vision and fewer headaches. A pruritic rash was managed with moisturizers, and intermittent acne was managed with a topical medication.

One adult patient with NF1-PN in the lower extremities, pelvis, and abdomen had stopped trametinib treatment twice, first after 1 year because of cutaneous intolerability, including pyoderma gangrenosum, and again after 2.5 years because of increasing tumor size and symptoms. He switched to receive mirdametinib at 3 mg twice daily at 24 years of age, with the same 3-weeks-on, 1-week-off schedule, and had received it for approximately 4 years as of September 2026 without dose modifications. His pyoderma gangrenosum resolved, the rate of tumor progression slowed, his pain medication use stabilized after earlier escalation, and PET and MRI showed no malignant transformation. He had a minor acneiform rash that was managed with topical treatment.

What are the next steps for evaluating mirdametinib in NF1-PN after prior MEK inhibitor exposure?

According to the authors, mirdametinib can help adults and children with NF1-PN who previously received a MEK inhibitor, including those who stopped receiving their prior MEK inhibitor because of AEs or progressive disease. Additionally, the 2 EAP patients benefited after switching to mirdametinib from agents that had not served them well.

Hirbe emphasized these practical clinical implications, saying, “If [a patient does not have favorable outcomes with] one MEK inhibitor, it’s reasonable to try a different MEK inhibitor, knowing that the patient may still have benefit. It’s something that should be looked at in a larger prospective cohort. It would be helpful for us to study the benefits of patients switching from one MEK inhibitor to another when the prior MEK inhibitor stops working.”

Disclosures: Hirbe reported consulting or advisory roles with Alexion Pharmaceuticals, AstraZeneca, Intellisphere, LLC, and SpringWorks Therapeutics, a healthcare company of Merck KGaA, Darmstadt, Germany; having patents, royalties, or other intellectual property with Boehringer Ingelheim RCV GmbH & Co KG; and receiving travel expenses from Alexion Pharmaceuticals and SpringWorks Therapeutics, a healthcare company of Merck KGaA, Darmstadt, Germany.

References

1. Bielamowicz K, McNall-Knapp RY, Foreman NK, et al. Use of mirdametinib for the treatment of neurofibromatosis type 1–associated plexiform neurofibromas (NF1-PN) in patients with prior mitogen-activated protein kinase (MAPK) kinase inhibitor (MEKi) exposure. Paper presented at: 2026 Society for Neuro-Oncology Annual Meeting; November 12-15, 2026; Philadelphia, PA. Poster CTNI-17.
2. Moertel CL, Hirbe AC, Shuhaiber HH, et al. ReNeu: a pivotal, phase IIb trial of mirdametinib in adults and children with symptomatic neurofibromatosis type 1-associated plexiform neurofibroma. J Clin Oncol. 2025;43(6):716-729. doi:10.1200/JCO.24.01034
3. Hirbe AC, Creed E, Hoerig C, et al. Long-term analysis of mirdametinib treatment in adults and children with symptomatic neurofibromatosis type 1-associated plexiform neurofibroma (NF1-PN): updated phase 2b ReNeu trial findings. Presented at: 2026 SNO Annual Meeting; November 12-15, 2026; Philadelphia, PA. Abstract CTNI-06.