Mirdametinib Deepens Responses in NF1-Associated Plexiform Neurofibroma

Longer treatment with mirdametinib (Gomekli) was associated with more confirmed and deep responses and a decline in treatment-related adverse effects over time in adults and children with symptomatic neurofibromatosis type 1–associated plexiform neurofibroma, according to a long-term analysis of the phase 2b ReNeu trial (NCT03962543) presented at the 2026 Society for Neuro-Oncology Annual Meeting.¹

After a median duration of exposure of 21.8 months (range, 0.4-67.0) in adult patients (N = 58) and 25.4 months (range, 1.6-61.1) in pediatric patients (N = 56), the confirmed objective response rates were 46.6% in adults and 55.4% in children. Among confirmed responders, 70.4% of adults and 64.5% of children achieved a deep response, defined as a best target plexiform neurofibroma (PN) volume reduction of more than 50% from baseline.

The median time to onset of response was 11.27 months (range, 4.0-29.0) in adults and 7.89 months (range, 4.1-29.0) in children, and the median duration of response was not reached in either cohort. At data cutoff, 96.3% of adult responders (n = 27) and 90.3% of pediatric responders (n = 31) had durable responses.

“The longer patients [received mirdametinib], the more objective responses we saw,” said Angela Hirbe, MD, PhD, in an interview with OncLive^®. “[Among] those patients who did have responses already, there were more who ended up having these deeper responses, [defined as a] greater than 50% reduction in tumor volume.”

Hirbe is an associate professor and director of the sarcoma program and the adult neurofibromatosis clinical program at Washington University School of Medicine in St Louis, Missouri.

How was the phase 2b ReNeu trial of mirdametinib in NF1-associated PN designed?

ReNeu enrolled patients with neurofibromatosis type 1 (NF1)–associated PNs that were inoperable and caused substantial morbidity. The updated analysis used a data cutoff of July 1, 2025, which added approximately 2 years of follow-up to the September 20, 2023, data cutoff used in the earlier report. Patients were required to be 2 years or older and were analyzed in an adult cohort (18 years or older) and a pediatric cohort (2-17 years).

Mirdametinib was given as a capsule or dispersible tablet at 2 mg/m² twice daily (maximum, 4 mg twice daily) in 28-day cycles for 3 weeks on and 1 week off, with no fasting requirement. Patients received up to 24 cycles in the treatment phase, followed by 30 days of safety follow-up. Those who entered the optional long-term follow-up phase could continue to receive mirdametinib at their last assigned dose, which 84% of eligible adults (n = 31) and 86% of eligible children (n = 37) elected to do.

The median age was 34 years (range, 18-69) among adults and 10 years (range, 2-17) among children. Female patients made up 64% of adults and 54% of children, and the median target PN volume was 196 mL (range, 1-3457) in adults and 99 mL (range, 5-3630) in children. The target PN was progressing at study entry in 53% of adults and 62% of children.

A confirmed objective response rate (ORR) required a reduction in target PN volume of at least 20% on 2 consecutive MRI scans obtained 2 to 6 months apart at any point before data cutoff, as assessed by blinded independent central review using Response Evaluation in Neurofibromatosis and Schwannomatosis criteria. Change in target PN volume, safety, and tolerability were additional end points. Confirmed ORR and change in target PN volume were cumulative from baseline across years 1 through 4, whereas treatment-related adverse effect (TRAE) rates were reported for each year individually.

What earlier ReNeu results supported the approval of mirdametinib in NF1-associated PN?

The earlier pivotal ReNeu analysis met its primary end point of confirmed ORR in both cohorts and showed deep responses along with clinically meaningful gains in pain and health-related quality of life.² Confirmed responses occurred in 41% (95% CI, 29%-55%) of adults and 52% (95% CI, 38%-65%) of children during the 24-cycle treatment phase.

Based on these data, the FDA approved mirdametinib on February 11, 2025, for the treatment of adults and children 2 years and older with NF1 and symptomatic PNs that cannot be completely resected.³

The updated analysis assessed mirdametinib at yearly intervals for up to 4 years.¹

How did responses, tumor volume, and safety change over time with mirdametinib in the updated ReNeu analysis?

The cumulative confirmed ORR in adults rose from 29.3% by year 1 to 41.4% by year 2, reaching the final rate by year 3. Deep responses among all adults increased from 12.1% at year 1 to 20.7% at year 2, 31.0% at year 3, and 32.8% at year 4, while stable disease as the best response declined from 56.9% to 39.7%. In children, the cumulative confirmed ORR rose from 42.9% at year 1 to 51.8% at year 2, reaching the final rate by year 3. Deep responses among all children increased from 12.5% to 23.2%, 33.9%, and 35.7% across years 1 through 4, respectively, and stable disease rates declined from 48.2% to 35.7%.

The median best percentage change in target PN volume from baseline deepened with longer treatment among patients with available assessments. In adults, it was −23.88% (range, –73.3% to 12.8%) at year 1 (n = 50), −45.20% (range, –78.9% to –7.0%) at year 2 (n = 26), −52.61% (range, –85.7% to –27.3%) at year 3 (n = 23), and −59.91% (range, –86.4% to –41.1%) at year 4 (n = 11). In children, these change rates were −29.61% (range, –78.6% to 47.6%) at year 1 (n = 54), −45.06% (range, –83.2% to 8.1%) at year 2 (n = 30), −59.14% (range, –91.0% to –22.2%) at year 3 (n = 24), and −61.25% (range, –96.4% to –30.0%) at year 4 (n = 9).

Most TRAEs were grade 1 or 2, and new-onset TRAEs were most frequent in year 1 and became less common with longer treatment. Among adult patients, TRAEs led to dose interruptions in 7% during year 1, 0% in year 2 (n = 35), 0% in year 3 (n = 26), and 13% in year 4 (n = 23). Dose reductions due to TRAEs occurred in 14%, 6%, 0%, and 0% of adults at these respective time points, and discontinuations due to TRAEs occurred in 21%, 3%, 0%, and 4% of adults across years 1 through 4, respectively. Among pediatric patients, dose interruptions occurred in 9% during year 1, 8% in year 2 (n = 40), 3% in year 3 (n = 30), and 0% in year 4 (n = 24); dose reductions due to TRAEs occurred in 12%, 3%, 3%, and 4% of patients, respectively, and discontinuations due to TRAEs occurred in 7%, 3%, 0%, and 4% across years 1 through 4, respectively.

“Importantly, there were no new safety signals that were seen,” Hirbe said. “If we are able to keep patients on medication for a longer period, then we have a better chance of seeing tumor responses. It’s important to know that [it] seems to be safe to receive these medications for long periods.”

What are the next steps for investigating mirdametinib in NF1-associated PN?

Hirbe concluded that the optimal duration of mirdametinib treatment remains unknown.

“We’re doing this longer-term follow-up, but 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,” she explained. She also noted open questions about mirdametinib use before resection or debulking and in the adjuvant setting.

Follow-up of the ReNeu trial will continue to assess whether more responses occur and whether long-term AEs emerge.

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

References

1. 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. Paper presented at: 2026 Society for Neuro-Oncology Annual Meeting; November 12-15, 2026; Philadelphia, PA. Abstract CTNI-06.
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. FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection. FDA. February 11, 2025. Accessed November 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirdametinib-adult-and-pediatric-patients-neurofibromatosis-type-1-who-have-symptomatic