ReNeu: A Pivotal Phase 2b Trial of Mirdametinib in Children and Adults With Neurofibromatosis Type 1 (NF1)-Associated Symptomatic Plexiform Neurofibroma (PN)
Hans Shuhaiber1, Christopher Moertel2, Angela Hirbe3, David Viskochil4, Alpa Sidhu5, Kevin Bielamowicz6, Michael Weber7, Armend Lokku7, L. Mary Smith8, Lauren Weintraub9, Rene McNall-Knapp10, Fouad Hajjar11, Nicholas Foreman12, Timothy Gershon13, Dusica Babovic-Vuksanovic14
1University of Florida Clinical Research Center, 2University of Minnesota, 3Washington University School of Medicine, 4University of Utah, 5University of Iowa Hospitals and Clinics, 6The University of Arkansas for Medical Sciences/Arkansas Children's Hospital, 7SpringWorks Therapeutics, Inc, 8Formerly SpringWorks Therapeutics, Inc, 9Albany Medical Center, 10University of Oklahoma Health Sciences Center, 11AdventHealth for Children, 12Children’s Hospital Colorado, 13Emory University School of Medicine, 14Mayo Clinic
Objective:
ReNeu (NCT03962543) is a pivotal, phase 2b trial evaluating efficacy and safety of mirdametinib (investigational MEK1/2 inhibitor) in adults and children (≥2y) with symptomatic inoperable NF1-PN.
Background:
Pharmacologic therapies for NF1-PN are limited.
Design/Methods:
Patients received mirdametinib capsule or dispersible tablet (2mg/m2 BID, max 4mg BID, 3-weeks-on/1-week-off 28-d cycles). Primary endpoint was confirmed objective response rate (ORR; proportion of patients with ≥20% reduction of target PN volume by MRI on consecutive scans within 2-6mo during 24-cycle treatment phase assessed by blinded independent central review [BICR]); minimum clinically relevant ORR (null) defined as 23% (adults), 20% (children). Patients could continue treatment in a long-term follow-up (LTFU) phase.
Results:
Fifty-eight adults and 56 children received mirdametinib. As of data cutoff (20-Sept-2023), BICR-confirmed ORR (95%CI) was 41% (29%, 55%; P<.001) in adults and 52% (38%, 65%; P<.001) in children. Two adults and 1 child also had confirmed response in the LTFU. Median (range) target PN volumetric best response from baseline was -41% (-90%, 13%) in adults, -42% (-91%, 48%) in children. Median treatment duration was 22mo for both cohorts; median duration of response was not reached. Median (range) time to response was 7.8mo (4-19mo) in adults, 7.9mo (4-19mo) in children. Patients or parents reported significant improvements from baseline to Cycle 13 in worst tumor pain severity, pain interference, and health-related quality-of-life measures. Most frequent (≥25% patients) treatment-related adverse events (TRAEs) were dermatitis acneiform, diarrhea, nausea, and vomiting in adults; and dermatitis acneiform, diarrhea, and paronychia in children. Grade ≥3 TRAEs were reported by 16% and 25% of adults and children, respectively; 21% and 9% of adults and children, respectively, discontinued due to TRAEs.
Conclusions:
Mirdametinib demonstrated deep and durable tumor responses, significant improvement in pain and HRQoL, and manageable safety in adults and children, underscoring mirdametinib’s potential to become an important new NF1-PN treatment option.
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