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Kim et al. Rare Dis Orphan Drugs J. 2026;5:6 Page 5 of 8

Long-term considerations
Longer-term tolerability, resistance, and toxicity of MEK inhibitors have not been well studied. Emerging
follow-up data on selumetinib demonstrate that only four participants (5.4%) experienced > 20% of tumor
growth over seven years, with sustained improvements in PN-related pain intensity and reduced pain
interference . No new safety signals were identified during long-term follow-up; however, some known
[18]
toxicities of selumetinib were observed for the first time after years of therapy, reinforcing the need for
continued surveillance [9,19] . Further, little is known about tumor regrowth after treatment discontinuation and
the mechanisms of primary or acquired MEK inhibitor resistance. While MEK1/2 inhibitors have marked
significant advances in treatment of PNs, non-responders underscore the need for alternate RAS-pathway
agents and other novel mechanisms, which are currently under investigation in clinical trials.

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] . Healx Limited is investing in artificial intelligence (AI)-driven drug discovery
[20]
approaches that target mitochondrial dysregulation to inhibit the growth of NF1 cells by modulating various
pathways involved in tumor development . Beyond MEK inhibition, cabozantinib, a multi-kinase inhibitor,
[19]
has shown tumor-volume reduction, improved quality of life, and minimal adverse effects . The results
[21]
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 . Complete surgical resection remains the only potentially
[1,2]
curative option, yet 5-year overall survival remains poor even after excision, and no FDA-approved systemic
therapies are available for MPNSTs . Further research is needed to understand the mechanisms driving
[1,2]
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 . Prospective,
[23]
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