This is an adaptive platform-basket trial that aims to evaluate the safety and efficacy of multiple novel agents and combination therapies in patients with NF2-related schwannomatosis (NF2-SWN). The study employs a basket design to assess treatment responses across four tumor types commonly associated with NF2-SWN: vestibular schwannomas, non-vestibular schwannomas, meningiomas, and ependymomas.
A shared natural history observational cohort, receiving routine clinical follow-up without investigational treatment, serves as a common control for all substudies. The adaptive platform enables the dynamic addition or closure of substudies based on interim analyses, thereby optimizing trial efficiency.
Eligible patients who meet the master protocol criteria and satisfy substudy-specific safety requirements will be assigned to receive the corresponding intervention. Currently open substudies include:
* Substudy A: Selumetinib * Substudy B: Luvometinib plus Serplulimab
Bilateral vestibular schwannomas (VS)
An identical NF2 pathogenic variant in at least 2 anatomically distinct NF2-related tumors (schwannoma, meningioma, and/or ependymoma). (Note: if the variant allele fraction (VAF) in unaffected tissues such as blood is clearly <50%, the diagnosis is mosaic NF2-related schwannomatosis)
Unilateral VS
First-degree relative other than sibling with NF2-related schwannomatosis
Coexisting other genetic syndromes that may cause multiple intracranial tumors (e.g., SMARCB1/LZTR1-related schwannomatosis, Cowden syndrome);
Expected survival <12 months;
Presence of severe psychiatric disorders or cognitive impairment that precludes cooperation with imaging or hearing assessments;
Extreme social or geographic factors that, in the investigator's judgment, may impede follow-up for more than 12 months;