Neurofibromatosis type 1 (NF1) is a genetic disorder affecting approximately 1 in 3,000 individuals, characterized by the development of benign tumors, including plexiform neurofibromas (PN)—complex, infiltrative growths that often cause significant morbidity such as pain, disfigurement, functional impairment, and reduced quality of life. In adults, symptomatic, inoperable PN represents a particularly challenging subset, as surgical resection is frequently infeasible due to tumor encasement of vital structures, invasiveness, or vascularity, leaving limited therapeutic options.
On November 19, 2025, the U.S. Food and Drug Administration (FDA) approved selumetinib (KOSELUGO, AstraZeneca Pharmaceuticals LP), a selective MEK1/2 inhibitor, for the treatment of adults with NF1-associated symptomatic, inoperable PN. This approval builds on the drug’s 2020 authorization for pediatric patients aged 2 years and older requiring systemic therapy, marking a significant expansion to address adult disease progression and unmet needs in this population.
The approval stems from the KOMET trial (NCT04924608), a pivotal, international, multicenter, double-blind, placebo-controlled phase 3 study enrolling 145 adults (aged ≥18 years) with NF1 and target PN ≥3 cm in longest diameter. Participants were randomized 1:1 to receive oral selumetinib (25 mg/m² twice daily, adjusted for body surface area) or matching placebo for up to 16 cycles (28 days each). The primary endpoint was confirmed objective response rate (ORR) by Cycle 16, assessed via independent central review using Response Evaluation in Neurofibromatosis: Functional Outcomes and Response Evaluation in Neurofibromatosis and Schwannomatosis (RENFORMS) criteria, defined as ≥20% reduction in target PN volume.
Selumetinib achieved a robust ORR of 20% (95% CI: 11-31%; 14/70 patients) compared to 5% (95% CI: 2-13%; 4/75 patients) in the placebo arm (p=0.011), with responses characterized by tumor shrinkage and symptom palliation. Exploratory analyses revealed that 86% of responders maintained duration of response (DOR) for at least 6 months, underscoring clinical durability. Common adverse events mirrored the pediatric profile, including rash (77%), diarrhea (57%), nausea (51%), and vomiting (43%), alongside class-specific risks such as left ventricular dysfunction (up to 9%), ocular toxicity (e.g., retinopathy in 4%), and gastrointestinal perforation (rare but serious). Dose modifications or interruptions occurred in 62% of patients, with discontinuations due to toxicity in 13%.
Administered continuously until progression or unacceptable toxicity, selumetinib’s orphan drug designation highlights its role in this rare disease (prevalence <200,000 U.S. cases). The FDA’s expedited review leveraged the Assessment Aid program for efficiency. Healthcare providers should monitor echocardiograms, ophthalmologic exams, and serum creatine phosphokinase levels per prescribing guidelines. This approval heralds a new era in NF1 management, potentially improving long-term outcomes for adults burdened by progressive PN, though ongoing surveillance for embryo-fetal toxicity warrants contraception counseling. Future studies may explore combination regimens or biomarkers to enhance efficacy.
