Mirdametinib Responses Deepen Through Year 4 in ReNeu Long-Term Data

Confirmed objective response rates reached 46.6% in adults and 55.4% in children with NF1-associated plexiform neurofibroma after prolonged mirdametinib (Gomekli) treatment — and deep responses, meaning tumor volume shrinkage beyond 50%, kept accruing through year 4. That is the headline from a long-term analysis of the phase 2b ReNeu trial (NCT03962543) presented at the 2026 Society for Neuro-Oncology Annual Meeting in Philadelphia, with a data cutoff of July 1, 2025.

Median exposure ran 21.8 months in adults (range, 0.4–67.0; N = 58) and 25.4 months in children (range, 1.6–61.1; N = 56). Among confirmed responders, 70.4% of adults and 64.5% of children achieved a deep response. Responses held: median duration of response was not reached in either cohort, and at cutoff 96.3% of adult responders (n = 27) and 90.3% of pediatric responders (n = 31) still had durable responses.

"The longer patients [received mirdametinib], the more objective responses we saw," said Angela Hirbe, MD, PhD, associate professor and director of the sarcoma program and the adult neurofibromatosis clinical program at Washington University School of Medicine in St Louis. "[Among] those patients who did have responses already, there were more who ended up having these deeper responses."

How was ReNeu designed?

ReNeu enrolled patients aged 2 and older with inoperable NF1-associated PNs causing substantial morbidity. Adults (median age, 34; range, 18–69) and children (median age, 10; range, 2–17) were analyzed separately. Median target PN volume was 196 mL in adults and 99 mL in children, and the target PN was progressing at entry in 53% of adults and 62% of children.

Dosing: 2 mg/m² twice daily (max, 4 mg twice daily) as a capsule or dispersible tablet, 3 weeks on and 1 week off in 28-day cycles, no fasting required. Patients could receive up to 24 cycles plus 30 days of safety follow-up; 84% of eligible adults (n = 31) and 86% of eligible children (n = 37) opted into long-term follow-up at their last assigned dose.

A confirmed ORR required at least a 20% target PN volume reduction on 2 consecutive MRIs 2 to 6 months apart, per blinded independent central review using Response Evaluation in Neurofibromatosis and Schwannomatosis criteria.

The earlier pivotal analysis — confirmed ORR of 41% (95% CI, 29%–55%) in adults and 52% (95% CI, 38%–65%) in children, plus gains in pain and quality of life — underpinned the FDA approval on February 11, 2025, for patients 2 years and older with symptomatic PNs not amenable to complete resection.

What did longer treatment change?

The trajectory matters as much as the endpoints.

• Adults: cumulative confirmed ORR climbed from 29.3% at year 1 to 41.4% at year 2, plateauing by year 3. Deep responses among all adults grew from 12.1% to 20.7%, 31.0%, and 32.8% across years 1–4. Stable disease as best response fell from 56.9% to 39.7%.
• Children: cumulative confirmed ORR rose from 42.9% to 51.8% by year 2, final by year 3. Deep responses grew from 12.5% to 23.2%, 33.9%, and 35.7%; stable disease dropped from 48.2% to 35.7%.

Median best percentage change in target PN volume deepened steadily. In adults: −23.88% at year 1 (n = 50), −45.20% at year 2 (n = 26), −52.61% at year 3 (n = 23), −59.91% at year 4 (n = 11). In children: −29.61%, −45.06%, −59.14%, and −61.25% (n = 54, 30, 24, 9). Median time to response onset was 11.27 months in adults and 7.89 months in children.

Safety moved the right direction. Most TRAEs were grade 1 or 2, and new-onset events clustered in year 1. Discontinuations due to TRAEs fell from 21% to 3%, 0%, and 4% in adults across years 1–4, and from 7% to 3%, 0%, and 4% in children. Adult dose reductions dropped from 14% to 0% by year 3; pediatric interruptions fell from 9% to 0%.

"Importantly, there were no new safety signals that were seen," Hirbe said. "It seems to be safe to receive these medications for long periods."

What's next?

The optimal treatment duration remains unknown. "It's going to be important in both the pediatric and adult populations to better define how long a patient needs to be receiving the medication over time," Hirbe said. Open questions also include mirdametinib before resection or debulking and in the adjuvant setting. ReNeu follow-up continues to track whether additional responses emerge and whether long-term adverse events surface.

Hirbe disclosed consulting or advisory roles with Alexion Pharmaceuticals, AstraZeneca, Intellisphere, and SpringWorks Therapeutics; intellectual property with Boehringer Ingelheim RCV; and travel support from Alexion and SpringWorks.