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Page 2 of 8 Kim et al. Rare Dis Orphan Drugs J. 2026;5:6

Table 1. Summary of drugs previously trialed, FDA-approved, and currently in the pipeline. Partial response for all trials was defined as
≥ 20% reduction

Drug name Mechanism of action Trial phase Outcome Refs.
Phase II,
Sirolimus mTOR inhibitor No significant tumor shrinkage or clinical benefit [4]
completed
Partial response (PR) in 17% of intent-to-treat,
and 26% in patients treated for ≥ 6 months; 30%
Imatinib Tyrosine kinase inhibitor Phase II, completed [5]
subjective improvement in symptoms and
function
Antifibrotic, anti-inflammatory, No objective responses (no tumor volume
Pirfenidone Phase II, completed [6]
antioxidant reduction or improvement in QoL)
Improvement in QoL but no significant change in
Tipifarnib Farnesyltransferase inhibitor Phase II, completed [7]
time to progression of tumor volume
Multi-targeted tyrosine kinase Trial terminated because of death of uncertain
Sunitinib Phase II, terminated [8]
inhibitor cause but possibly related to drug
70% of the patients achieved PR; 48%
FDA approved
Selumetinib MEK 1/2 inhibitor (pediatrics and improvement in child-reported health-related QoL [9,12-14]
adults) 20% objective response rate; meaningful pain
intensity reduction
FDA approved 52% PR in pediatrics, 41% PR in adults, defined as
Mirdametinib MEK 1/2 inhibitor (pediatrics and ≥ 20% reduction in tumor volume [10,15]
adults)
Binimetinib MEK 1/2 inhibitor Phase II, completed 74% of the patients achieved PR [19,25]
42% (8/19) in adolescents and adults; No
Receptor tyrosine kinase inhibitor
Cabozantinib Phase II, completed significant change in global QoL scores; 3-point [21]
(VEGF, MET, TAM, RET)
decrease in worst tumor-pain in the PR group
Combination therapy with receptor
Cabozantinib + Phase I, Ib, 2; No data yet but assessing the synergistic effects
Selumetinib tyrosine kinase inhibitor and MEK Not yet recruiting of cabozantinib with selumetinib [22]
1/2 inhibitor
Mitochondrial modulation,
Healx Phase 2, recruiting No data yet [20]
multi-pathway
mTOR: Mechanistic target of rapamycin; MEK 1/2: mitogen-activated protein kinase kinase; FDA: food and drug administration; QoL: qualitiy of life.

DRUGS THAT WERE PREVIOUSLY TRIALED
Developing effective treatments for NF1-associated PNs has remained an ongoing challenge . Although
[3]
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] . Imatinib, a tyrosine kinase inhibitor, showed a partial response in some patients, suggesting some
[4]
therapeutic potential . However, the modest and variable responses underscore tumor heterogeneity and
[5]
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 . Sunitinib, a multi-targeted
[7]
tyrosine kinase inhibitor, was terminated early due to a patient death of uncertain cause with no meaningful
response observed . Given limited efficacy, safety concerns, and non-durable response, earlier agents were
[8]
not adopted into practice until the recent success of mitogen-activated protein kinase kinase (MEK 1/2)

inhibitors.