ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma
Christopher L. Moertel, Angela C. Hirbe, Hans Shuhaiber, Kevin Bielamowicz, Alpa Sidhu, David Viskochil, Michael Weber, Armend Lokku, L. Mary Smith, Nicholas K. Foreman, Fouad Hajjar, Rene McNall‐Knapp, Lauren Weintraub, Reuben Antony, Andrea Franson, Julia Meade, David Schiff, Tobias Walbert, Prakash Ambady, Daniela A. Bota, Cynthia Campen, Gurcharanjeet Kaur, Laura J. Klesse, Stefania Maraka, Paul L. Moots, Kathryn Nevel, Miriam Bornhorst, Ana Aguilar-Bonilla, Sarah Chagnon, Nagma Dalvi, Punita Gupta, Ziad Khatib, Laura K. Metrock, Phioanh L. Nghiemphu, Ryan D. Roberts, Nathan Robison, Zsila Sadighi, Stacie Stapleton, Dusica Babovic‐Vuksanovic, Timothy R. Gershon, for the ReNeu Trial Investigators, Ahmed M. Raslan, Alpa Sidhu, Ana Aguilar-Bonilla, Andrea T. Franson, Andrew Walter, Angela C. Hirbe, Brian A. Van Tine, Carl Koschmann, Christopher L. Moertel, Cynthia Campen, Daniela A. Bota, David Schiff, David Viskochil, Dusica Babovic‐Vuksanovic, Fouad M. Hajjar, Gurcharanjeet Kaur, Hans Shuhaiber, Jamie K. Capal, John M. Slopis, Jonathan Gill, Julia Meade, Kathryn Nevel, Laura K. Metrock, Kevin Bielamowicz, Laura J. Klesse, Lauren Weintraub, Leia Nghiemphu, Lindsay Kilburn, Maciej M. Mrugała, Mary Lou Schmidt, Miriam Bornhorst, Nagma Dalvi, Nathan Robison, Nick K. Foreman, Paul L. Moots, Prakash Ambady, Punita Gupta, Radhika Dhamija, Rene McNall‐Knapp, Rueben Antony, Ryan D. Roberts, Ryan Merrell, Sarah Chagnon, Stacie Stapleton, Stefania Maraka, Timothy R. Gershon, Tobias Walbert, Ziad Khatib, Zsila Sadighi
Abstract
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: 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.