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Page 4 of 8 Kim et al. Rare Dis Orphan Drugs J. 2026;5:6

Table 2. Most common side effects of mirdametinib and selumetinib [26]
Side effect Selumetinib Mirdametinib

Cardiac 38% (Grade 1-2); 2% (Grade 3) Not reported to date
(decreased ejection fraction/shortening fraction)
Diarrhea 54% (Grade 1-2); 4% (Grade 3) Not reported to date
Fatigue 56% (Grade 1-2) 26% (Grade ≥ 2)
Nausea/vomiting 44% (Grade 1-2) 21% (Grade ≥ 2)
Ophthalmologic No dose limiting toxicity No dose limiting toxicity
Paronychia 38% (Grade 1-2); 6% (Grade 3) Not reported to date
Rash/skin toxicity 52%-58% (Grade 1-2); 4%-10% (Grade 3) 53% (Grade ≥ 2)
mTOR: Mechanistic target of rapamycin; MEK 1/2: mitogen-activated protein kinase kinase; FDA: food and drug administration.

function, pain, and disfigurement in the majority of patients, highlighting the impact beyond tumor
shrinkage . More recently, selumetinib has been approved for adults with PNs in November 2025 . In the
[13]
[12]
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 . In the ReNeu clinical trial (NCT03962543), the confirmed
[10]
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) . Patient-reported outcomes showed clinically meaningful improvements in pain severity,
[15]
interference, and health-related quality of life, similar to the pediatric findings with selumetinib .
[15]

Tolerability and safety considerations
Both drugs were generally well tolerated, but adverse events (AEs) are common [9,12,15,16] . Common AEs include
gastrointestinal upset, xerosis, fatigue, muscle pain, acne, stomatitis, paronychia, and headache. Most were
Grade 1-2 with the use of NCI common terminology criteria for adverse events (CTCAE) v 4/5 [Table 2] [12,15] .
However, about 10% of patients taking selumetinib and 9% of adults and 14% of children taking
mirdametinib discontinued treatment because of toxicity [12,15] , underscoring the need for proactive AE
prevention and dose modification.

Comparative effectiveness and implications
In an indirect treatment comparison, using matching-adjusted indirect comparison (MAIC) and simulated
treatment comparison (STC), mirdametinib demonstrated a significantly greater mean best reduction in
tumor volume compared to selumetinib (MAIC: -36.0% vs. -22.8%; STC: -36.2% vs. -22.8%) .
[17]
Dose reductions due to treatment-related adverse events (TRAEs) were significantly lower in mirdametinib
(MAIC: 12% vs. 28%, odds ratio [OR] = 0.355, P = 0.048; STC: 11% vs. 28%, OR = 0.309, P = 0.028). Several
common TRAEs, including acneiform rash, diarrhea, nausea, vomiting, fatigue, stomatitis, and elevated
creatine phosphokinase, occurred less frequently. No significant differences in ORR or selected safety
outcomes (paronychia, alopecia, neutropenia, asymptomatic left ventricular ejection fraction (LVEF)
decline) were observed . Since the drugs were not tested in the same study and patient differences may bias
[17]
results, the findings should be validated in head-to-head trials and could be strengthened through
biomarker-informed studies.