Traditional drug development in humans follows a sequential path from phase 1 trials (dose finding studies with focus on toxicity at escalating dose levels) to phase 2 trials (efficacy studies with focus on clinical benefit and safety at recommended dose) to phase 3 trials (effectiveness studies in larger number of patients with comparison to standard of care). More recently, novel clinical designs have been used to accelerate drug approvals, to increase efficiency, to treat patients most likely to respond, and to increase patient satisfaction. Neurofibromatosis 1 (NF1) and NF2-related schwannomatosis (NF2-SWN) are rare neurogenetic conditions with diverse disease manifestations that share a common molecular cause (NF1 gene loss for NF1 and NF2 gene loss for NF2-SWN). Ideally, clinical trial design for these conditions should be disease-specific, phenotype-driven, and patient-centric. In this talk, we will review examples of clinical trials that have addressed specific challenges for trials in NF1 and NF2-SWN.

NF2-related schwannomatosis (NF2-SWN) is a tumor predisposition syndrome caused by loss-of-function variants in the NF2 gene. Affected individuals develop multiple benign tumors, involving the central and peripheral nervous systems, as well as cutaneous and ocular manifestations. Despite significant clinical morbidity, effective targeted therapies remain unavailable, in part due to the lack of robust human cellular models that faithfully recapitulate NF2-SWN cell tumorigenesis.

Progress in understanding NF2 pathogenesis and therapy development has been limited by the absence of human non-perishable Schwann cell–based models harboring pathogenic NF2 variants and reflecting the biallelic inactivation that drives schwannoma formation. To address this gap, we generated and characterized isogenic paired induced pluripotent stem cell (iPSC) lines with mono-allelic or bi-allelic NF2 disruption by combining direct reprogramming of vestibular schwannoma cells with CRISPR/Cas9 genome editing.

Using 3D differentiation protocols, we successfully directed iPSCs toward the neural crest–Schwann cell lineage. The resulting Schwann cell–like spheroids showed homogeneous expression of canonical lineage markers. Importantly, NF2(–/–) spheroids exhibited dysregulation of key signaling pathways previously implicated in merlin-deficient Schwann cells and human schwannomas, supporting the biological relevance of the model.

Finally, we evaluated the therapeutic potential of an exon-11–skipped NF2 isoform (merlin_e-11), induced using antisense oligomers, to address truncating variants located in exon 11. Treatment successfully induced merlin_e-11 expression and normalized major NF2-associated signaling abnormalities without detectable toxicity.

These findings support exon-skipping–based strategies as a promising personalized therapeutic approach for NF2-SWN patients harboring truncating mutations in exon 11 and establish this iPSC-derived system as a powerful platform for disease modeling and preclinical drug evaluation.

:Background: The INTUITT-NF2 adaptive platform study with basket design was published in 2024, suggesting a radiographic response in 10% of target tumours. Response rates were higher in Meningiomas. The Highly Specialised NF2 and Schwannomatosis service based in Manchester UK has accessed Brigatinib on compassionate grounds via a Extended Access Programme with the Pharmaceutical Industry. We will present real world clinical outcomes for patients treated with Brigatinib for NF2 meningiomas

Methods: Of the 532 patients under the Manchester Service, 5 patients have received treatment with Brigatinib due to progressive and inoperable meningiomas. Basic Demographics, genetic variant data, side effects, drug attrition and radiographic response were collected and will be presented

Results: Median age 40yr (range 37-42). Target lesions in 4/5 were inoperable CNS meningiomas and in the final case it was given for multiple NF2 mutated lung meningiomas. CNS Meningiomas progressed after initial stability in 2/5. One patient stopped due to side effects( pneumonitis) after 3 months. Ongoing clinical stability has been seen in 2/5.

Conclusion: Brigatinib may be a option for Meningiomas in NF2-SWN but further extended real world data is required.

Background: Selumetinib is approved for the treatment of NF1-related plexiform neurofibromas (PN). Treatment interruptions can cause PN regrowth. Data on re-response after reinstating selumetinib are limited.

Methods: Participants enrolled on NCI clinical trials of selumetinib for NF1-PN (NCT01362803; NCT02407405). Volumetric MRI was used to measure PN size. In participants with prolonged selumetinib interruption (≥90-days) and PN volumes available within 60-days of restarting selumetinib we compared the best response before treatment interruption (period-1) and after restarting treatment (period-2).

Results: Among 132 participants, 15 met criteria for inclusion in this analysis. Median duration of observation from first to final evaluation was 2954 days (range 1755, 4445). Median treatment duration prior to interruption was 849 days (140, 2983). Median baseline volume for period-1 was 492mL (42, 7480); for period-2 549mL (32.3, 7904). Nine participants had larger PN volume at start of period-2 than period-1. Median time to best response in period-1 was 336 days (103, 2128); in period-2 342 days (68, 2949). Median volume change from period baseline to best response in period-1 was -26.5% (-46.6, -15.0); in period-2 -8.5% (-39.4, 6.0). For 11 participants, PN volume at best response in period-2 stayed above the best response of period-1.

Conclusions: PN regrowth occurred in some participants with prolonged selumetinib interruption, followed by PN volume reduction after resuming treatment. However, in most participants, volume reduction did not reach the level of best response before treatment interruption. We are currently analyzing impact of clinical variables including age and selumetinib dose reductions on re-response.

Background: We previously published preliminary outcomes of patients with NF2-related schwannomatosis treated with brigatinib, an oral ALK/FAK inhibitor. We now report final results for these participants.

Methods: This multicenter, phase II, open-label study included participants ≥12 years with NF2-SWN and progressive target tumors (baskets: VS, non-VS, meningioma, or ependymoma). Patients were treated with brigatinib 180 mg daily until progression of target tumors or study discontinuation. One target and up to 5 non-target tumors were monitored in each participant. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter with radiographic response (RR) defined as ≥20% decrease in volume compared to baseline.

Results: Forty participants (28 adults, 12 pediatrics) were treated for a median of 47 months. Final imaging data is available on 164 tumors (46 VS, 58 non-VS, 55 meningiomas, and 5 ependymomas). RR rate for all tumors was 29% including 22% for VS, 31% for non-VS, 31% for meningioma, and 60% for ependymomas. RR for all tumors was 35% in adult patients and 14% in pediatric patients. Annualized tumor growth rate for all tumors was 62.6% prior to treatment (70% in adults, 45% in pediatric) and 5.2% during treatment (1% in adult, 15% in pediatrics). The 24-month freedom from tumor progression was 63% for all tumors, 43% for VS, 76% for non-VS, 65% for meningioma, and 100% for ependymoma.

Conclusion: Brigatinib treatment was associated with clinically significant antitumor activity across multiple tumor types in patients with NF2-related schwannomatosis.