Plexiform neurofibromas in neurofibromatosis type 1: current and emergent therapeutic strategies

INTRODUCTION

Neurofibromatosis type 1 (NF1) is a rare neurogenetic disorder that affects approximately 1 in 2,500 individuals worldwide^[1]. This genetic defect causes a wide range of clinical manifestations, including, but not limited to, nervous system tumors, skeletal manifestations, vasculopathies, seizures, headaches, and learning disabilities. One hallmark manifestation of NF1 is the development of plexiform neurofibromas (PNs), which occurs in 30%-60% of individuals with NF1^[1,2]. Although benign, PNs can cause substantial morbidity due to pain, motor or sensory impairment, disfigurement, and compression of vital anatomical structures including the spinal cord, airway, or major blood vessels. More importantly, 8%-13% of the PNs may transform into malignant peripheral nerve sheath tumors (MPNSTs), a type of aggressive sarcoma associated with high morbidity and mortality rates^[1]. Historically, treatment options have been limited to surgical resection, which carries significant risk in many patients because of the location of the tumors. Recent targeted therapies have introduced a new era of pharmacologic management.

DRUGS THAT WERE PREVIOUSLY TRIALED

Developing effective treatments for NF1-associated PNs has remained an ongoing challenge^[3]. Although several targeted agents showed preclinical or early-phase promise, most failed to demonstrate sufficient efficacy or acceptable safety to support regulatory approval, reflecting the complexity of PN biology and underscoring the limitations inherent to dysregulated Ras signaling^[3].

For example, sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, was evaluated in a Phase II trial for patients with progressive PNs and showed no significant clinical benefit or tumor shrinkage [Table 1]^[4]. Imatinib, a tyrosine kinase inhibitor, showed a partial response in some patients, suggesting some therapeutic potential^[5]. However, the modest and variable responses underscore tumor heterogeneity and limit generalizability, and highlight the need for biomarker-guided, personalized approaches. Pirfenidone, an antifibrotic agent with anti-inflammatory and antioxidant properties, showed no significant reduction in tumor volume or enhanced quality of life compared to placebo^[6].

Other pathway-directed strategies also proved unsuccessful. Tipifarnib, a farnesyltransferase inhibitor, did not significantly prolong time to progression of PNs; however, it was well tolerated and was associated with some improvements in quality of life, suggesting a potential in supportive care^[7]. Sunitinib, a multi-targeted tyrosine kinase inhibitor, was terminated early due to a patient death of uncertain cause with no meaningful response observed^[8]. Given limited efficacy, safety concerns, and non-durable response, earlier agents were not adopted into practice until the recent success of mitogen-activated protein kinase kinase (MEK 1/2) inhibitors.

APPROVED MEK INHIBITORS

The emergence of MEK1/2 inhibitors, selumetinib and mirdametinib, has led to Food and Drug Administration (FDA)-approved therapies for patients with symptomatic, inoperable PNs [Table 1]^[9,10]. MEK inhibitors are allosteric inhibitors of MEK1 and MEK2. MEK1/2 function within the mitogen-activated protein kinase (MAPK) signaling cascade, referred to as the Rat sarcoma (RAS)-rapidly accelerated fibrosarcoma (RAF)-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway, which regulates cellular growth, differentiation, proliferation, and survival [Figure 1]^[9,11]. In NF1, Ras signaling becomes dysregulated due to loss or reduced activity of neurofibromin, leading to prolonged and uncontrolled downstream MAPK activation and growth of peripheral nerve sheath tumors in some individuals. By inhibiting MEK1/2, selumetinib and mirdametinib prevent downstream activation of ERK, thereby suppressing cell proliferation and angiogenesis and producing tumor shrinkage and disease stabilization^[9,11].

Figure 1. Mechanism of MEK inhibition by selumetinib and mirdametinib. Loss of NF1 function leads to overactive Ras signaling, promoting tumor growth. Created in BioRender. Kim, H. (2025) https://BioRender.com/796ondy. NF1: Neurofibromatosis type 1; MEK 1/2: mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase.

Selumetinib (Koselugo), approved on April 10, 2020, was the first FDA-approved therapy for PNs for pediatric patients ≥ 2 years with symptomatic, inoperable PNs [Table 1]^[9]. The approval was based on results from the Phase II SPRINT trial (NCT01362803), in which 70% of the patients achieved partial response, defined as a ≥ 20% reduction in tumor volume on volumetric magnetic resonance imaging (MRI), with the median tumor volume-reduction of 27.9%^[9,12]. Notably, 56% of participants had a durable response lasting ≥ 12 cycles (approximately 1 year)^[12]. Progression-free survival at 3 years was substantially higher in patients taking selumetinib compared with a matched natural-history cohort from the National Cancer Institute (NCI), in which 78% of untreated individuals had ≥ 20% tumor growth with median progression-free survival of 1.3 years^[12]. In addition to tumor shrinkage, there were clinically meaningful improvements in function, pain, and disfigurement in the majority of patients, highlighting the impact beyond tumor shrinkage^[12]. More recently, selumetinib has been approved for adults with PNs in November 2025^[13]. In the randomized KOMET study (NCT04924608), selumetinib achieved objective response rate (ORR) of 20% (95% confidence interval (CI): 11, 31) by end of cycle 16, with 86% of the responders maintaining a durable response of ≥ 6 months^[13,14]. Further, individuals who had chronic pain scores of ≥ 3 reported meaningful reduction in pain^[14].

Mirdametinib (Gomekli) was recently approved on February 11, 2025, for adults and pediatric patients ≥ 2 years with symptomatic, non-resectable PNs^[10]. In the ReNeu clinical trial (NCT03962543), the confirmed partial response rate was 52% (29/56) in pediatrics and 41% (24/58) in adults, with 75% of individuals maintaining durable response for ≥ 12 months^[10,15]. The median reduction in tumor volume was 41% (range, -90 to 13)^[15]. Patient-reported outcomes showed clinically meaningful improvements in pain severity, interference, and health-related quality of life, similar to the pediatric findings with selumetinib^[15].

DRUGS IN THE PIPELINE

Several therapies are currently in clinical trials for NF1-associated PNs with efforts focused both on expanding the utility of MEK inhibitors and exploring alternative therapeutic targets. Within MEK inhibitors, binimetinib (MEK162) has shown partial responses (≥ 20% volumetric reduction) in Phase II cohorts [Table 1]^[20]. Healx Limited is investing in artificial intelligence (AI)-driven drug discovery approaches that target mitochondrial dysregulation to inhibit the growth of NF1 cells by modulating various pathways involved in tumor development^[19]. Beyond MEK inhibition, cabozantinib, a multi-kinase inhibitor, has shown tumor-volume reduction, improved quality of life, and minimal adverse effects^[21]. The results suggested that cabozantinib has clinical activity in reducing tumor burden and alleviating pain in NF1-associated PNs, particularly in adolescents and adults. Along with monotherapies, combination strategies are underway; cabozantinib in combination with selumetinib will assess the tolerability, synergy, and efficacy as a dual therapy^[22].

CONCLUSIONS AND FUTURE DIRECTIONS

The therapeutic landscape for PNs has rapidly evolved since 2020, largely driven by the success of MEK1/2 inhibitors such as selumetinib and mirdametinib. These agents have redefined the standard of care for NF1-associated inoperable PNs by demonstrating clinically meaningful tumor shrinkage, disease stabilization, and improved quality of life. However, no studies to date evaluate whether MEK inhibition can prevent or delay malignant transformation.

MPNSTs are aggressive sarcomas with high morbidity and mortality, which arise from pre-existing PNs^[1,2]. Although all individuals with NF1 carry a lifetime risk of approximately 8%-13%, patients with internal PNs have a 20-fold greater risk of transformation compared with other patients without internal PNs and compared to the general public without NF1^[1,2]. Complete surgical resection remains the only potentially curative option, yet 5-year overall survival remains poor even after excision, and no FDA-approved systemic therapies are available for MPNSTs^[1,2]. Further research is needed to understand the mechanisms driving resistance to MEK inhibitors and biomarkers that can inform individualized strategies. Emerging liquid-biopsy approaches using cell-free DNA (cfDNA) suggest that copy-number alteration-based assays can only identify MPNST, whereas fragmentomic signatures may distinguish premalignant stages from benign PNs (e.g., atypical neurofibroma) noninvasively, enabling early intervention^[23]. Prospective, multicenter validation is needed to establish cfDNA as a routine surveillance tool and enable risk-adapted management of PNs.

As the pipeline for novel and targeted therapies continues to grow, development should not only be evaluated for volumetric response and symptomatic improvement, but also for the reduction in malignant transformation risk and early detection of resistance using biomarkers, such as cfDNA or fragmentomic signatures. Finally, there is a critical need to develop therapeutic strategies beyond pharmaceutical interventions including early pain interventions, physical and occupational rehabilitation, psychosocial support groups, and integrative care models to fully address the needs of individuals with NF1-associated PNs across their life span.

Preclinical work suggests that restoring the missing neurofibromin gene could reduce PN burden and alleviate symptoms^[24]. In an NF1 xenograft model, an engineered adeno-associated virus for NF (AAV-NF) (K55) vector showed reduced hepatic uptake and enhanced tumor targeting, improving intratumoral delivery bringing gene therapy a step closer to first-in-human clinical trials^[24]. Sustained collaboration among patients, researchers, and philanthropic partners, such as the Children’s Tumor Foundation and the Gilbert Family Foundation, will accelerate the development of these promising treatment strategies and may ultimately lead to a cure for NF1.