GERSHON

“The needs of patients with neurofibromatosis are large. One of the large unmet needs is an understanding of the neuropsychosocial aspects of neurofibromatosis.”

Timothy R. Gershon, MD, PhD, a professor in the Department of Pediatrics at Emory University School of Medicine, director of the Children's Center for Neurosciences Research, and a member of the Cell and Molecular Biology Research Program at Winship Cancer Institute of Emory University, outlined ongoing research priorities in the management of neurofibromatosis type 1 (NF1)–associated plexiform neurofibromas (PNs).

Treatment options for select patients with NF1-associated PNs grew 

following the February 2025 FDA approval of mirdametinib (Gomekli)

. The agent is indicated for adult and pediatric patients 2 years of age and older with NF1 who have symptomatic PNs not amenable to complete resection.

Although mirdametinib provides a significant therapeutic option for those who cannot have their tumors surgically resected, Gershon emphasized that multiple unmet needs remain, particularly in the neuropsychosocial domain. NF1 is associated with an elevated risk of autism spectrum disorder, learning differences, and other cognitive or psychosocial challenges that may necessitate differentiated educational support. Currently, there is no established method for linking NF1 genotypes to specific neuropsychosocial phenotypes, limiting the ability to identify patients most likely to require targeted interventions. Addressing this knowledge gap could enable earlier, more personalized, supportive care.

In addition to optimizing supportive strategies, Gershon noted that surgery continues to be a key modality for PN management; however, the role of MEK inhibitors, such as mirdametinib, in the perioperative setting remains undefined. He highlighted the need to investigate whether adjuvant mirdametinib administration after surgical resection could reduce recurrence risk—an approach not yet formally evaluated in clinical trials.

Beyond sequencing, research is also needed to enhance the depth and uniformity of tumor shrinkage achieved with MEK inhibition. Although mirdametinib monotherapy has demonstrated clinical benefit, variability in depth of response suggests that combination regimens may further improve outcomes, Gershon said. He underscored the importance of evaluating additional agents with synergistic mechanisms in parallel with MEK inhibitors to achieve greater and more consistent tumor reductions.

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Timothy R. Gershon, MD, PhD, discusses ongoing research priorities neurofibromatosis type 1–associated plexiform neurofibromas

Dr Gershon on Ongoing Research Priorities for NF1-Associated Plexiform Neurofibromas

Dr Gershon on Deep Responses With Mirdametinib in NF1-PN

“We didn’t find that there was a particular patient that we could identify who was more likely to be a strong responder. Male or female, young or old—none of these obvious characteristics helped us define who would be a strong responder. The one trend that we did see least among adults was an association between longer time on therapy and the size of the response.”

Timothy Gershon, MD, PhD, professor, Department of Pediatrics, Emory University School of Medicine; director, the Children's Center for Neurosciences Research; member, the Cell and Molecular Biology Research Program, Winship Cancer Institute, Emory University, discusses results from an exploratory analysis of the phase 2b ReNeu (NCT03962543) evaluating patients with neurofibromatosis type 1–associated symptomatic inoperable plexiform neurofibroma (NF1-PN) who achieved deep responses with mirdametinib.

The current analysis consisted of patients who achieved deep responses, defined as an over 50% best reduction in target PN volume, regardless of objective response status, and was inclusive of those undergoing long-term follow-up. Exploratory assessments also compared baseline characteristics between patients achieving deep response and those with up to 50% volume reduction.

2024 Society for Neuro-Oncology Annual Meeting

 indicated no specific baseline characteristics, including age, sex, or other demographics, were associated with a higher likelihood of achieving a deep response, Gershon reports. This suggests that mirdametinib is effective across a broad spectrum of patient populations, he explains. A trend was observed in which longer treatment duration appeared to correlate with deeper responses, although the causal relationship remains unclear, Gershon notes. It is possible that prolonged therapy contributed to greater tumor shrinkage, or conversely, that patients achieving larger responses remained on therapy longer. These findings highlight the importance of extended treatment in achieving optimal outcomes, he says.

Mirdametinib has previously demonstrated a manageable safety profile, deep responses, and the potential for enhancing health-related quality of life (QOL), according to prior data presented at the 

granted priority review status by the FDA

, with a decision expected by February 28, 2025. These data further support the role of mirdametinib as a valuable therapy for patients with NF1-PN, particularly given its ability to generate meaningful and durable reductions in tumor volume alongside improvements in QOL metrics, Gershon concludes.

Timothy Gershon, MD, PhD, discusses an analysis of patients with NF1-PN who achieved deep responses with mirdametinib in the phase 2b ReNeu study.

Timothy Gershon, MD, PhD

Articles

Dr Gershon on Ongoing Research Priorities for NF1-Associated Plexiform Neurofibromas

Dr Gershon on Deep Responses With Mirdametinib in NF1-PN