Nghiemphu, Leia

PURPOSE Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration–approved for adults. METHODS ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m 2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. RESULTS Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was –41% (−90 to 13) in adults and –42% (−91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. CONCLUSION In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

Abstract Neurofibromatosis type 2 (NF2) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. We developed an adaptive platform-basket trial to screen multiple drugs against any type of progressive NF2-related tumor. We report the interim analysis of the first treatment arm with brigatinib, an ALK inhibitor that inhibits multiple tyrosine kinases. We conducted a multicenter, phase II, open-label study for subjects ≥12 years old with NF2 and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma). Up to 5 non-target tumors were followed in each participant. In stage 1, 20 participants (minimum of 2 participants per basket) were treated with brigatinib 180 mg daily. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. Radiographic response (RR) was defined as ≥20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Per protocol, the brigatinib arm would be discontinued if no target tumor achieved a RR at interim analysis. Twenty subjects (median age=25 years, 7 pediatric, 12 females) were treated. Target tumors included 10 VS, 3 NVS, 5 meningiomas, and 2 ependymomas; non-target tumors included 18 VS, 36 NVS, and 14 meningiomas. RR rate for target and non-target tumors was 5% and 22%, respectively. By tumor basket, RR was 28% for meningioma, 26% for non-VS, 4% for VS, and 0% for ependymomas. Annualized tumor growth rates decreased for VS, NVS, and meningioma during treatment. Brigatinib was well tolerated with one dose reduction and one discontinuation due to grade 2 diarrhea. Brigatinib treatment was associated with RR in meningiomas, VS, and NVS. In stage 2, the study will enroll 20 participants in the two most promising baskets (meningioma and NVS). This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.