ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma
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 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.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (56)
Michael D. Weber
SpringWorks Therapeutics, Inc, Stamford, CT
Armend Lokku
SpringWorks Therapeutics, Inc, Stamford, CT
L. Mary Smith
SpringWorks Therapeutics, Inc, Stamford, CT
Nicholas K. Foreman
Reuben Antony
University of California Davis, Sacramento, CA
Cynthia J. Campen
Stanford/Lucile Packard Children's Hospital and Stanford Children's Health, Palo Alto, CA
P. Leia Nghiemphu
Christopher L. Moertel, MD, Department of Pediatrics, University of Minnesota, Minneapolis, MN; Angela C. Hirbe, MD, PhD, Washington University School of Medicine in St Louis, St Louis, MO; Laura J. Klesse, MD, PhD, University of Texas Southwestern/Children's Health, Dallas, TX; P. Leia Nghiemphu, MD, University of California Los Angeles (UCLA), Los Angeles, CA; Dusica Babovic-Vuksanovic, MD, Mayo Clinic, Rochester, MN; and Timothy R. Gershon, MD, PhD, Department of Pediatrics, Emory University, Atlanta, GA
Ahmed Raslan
Alpa Sidhu
University of Iowa Hospitals and Clinics, Iowa City, IA
Ana Aguilar-Bonilla
Orlando Health, Inc, Orlando, FL
Andrea T. Franson
C. S. Mott Children's Hospital, Ann Arbor, MI
Andrew Walter
Angela C. Hirbe
Christopher L. Moertel, MD, Department of Pediatrics, University of Minnesota, Minneapolis, MN; Angela C. Hirbe, MD, PhD, Washington University School of Medicine in St Louis, St Louis, MO; Laura J. Klesse, MD, PhD, University of Texas Southwestern/Children's Health, Dallas, TX; P. Leia Nghiemphu, MD, University of California Los Angeles (UCLA), Los Angeles, CA; Dusica Babovic-Vuksanovic, MD, Mayo Clinic, Rochester, MN; and Timothy R. Gershon, MD, PhD, Department of Pediatrics, Emory University, Atlanta, GA
Brian Van Tine
Carl Koschmann
Christopher L. Moertel
Christopher L. Moertel, MD, Department of Pediatrics, University of Minnesota, Minneapolis, MN; Angela C. Hirbe, MD, PhD, Washington University School of Medicine in St Louis, St Louis, MO; Laura J. Klesse, MD, PhD, University of Texas Southwestern/Children's Health, Dallas, TX; P. Leia Nghiemphu, MD, University of California Los Angeles (UCLA), Los Angeles, CA; Dusica Babovic-Vuksanovic, MD, Mayo Clinic, Rochester, MN; and Timothy R. Gershon, MD, PhD, Department of Pediatrics, Emory University, Atlanta, GA
Cynthia Campen
Daniela A. Bota
University of California, Irvine, CA
David Schiff
31Department of Neurology, Division of Neuro-Oncology, University of Virginia, Charlottesville, VA
David Viskochil
University of Utah, Salt Lake City, UT
Dusica Babovic-Vuksanovic
Christopher L. Moertel, MD, Department of Pediatrics, University of Minnesota, Minneapolis, MN; Angela C. Hirbe, MD, PhD, Washington University School of Medicine in St Louis, St Louis, MO; Laura J. Klesse, MD, PhD, University of Texas Southwestern/Children's Health, Dallas, TX; P. Leia Nghiemphu, MD, University of California Los Angeles (UCLA), Los Angeles, CA; Dusica Babovic-Vuksanovic, MD, Mayo Clinic, Rochester, MN; and Timothy R. Gershon, MD, PhD, Department of Pediatrics, Emory University, Atlanta, GA
Fouad M. Hajjar
AdventHealth for Children, Orlando, FL
Gurcharanjeet Kaur
New York Presbyterian Morgan Stanley Children's Hospital, Columbia University Medical Center, New York, NY
Hans H. Shuhaiber
University of Florida Clinical Research Center, Gainesville, FL
Jamie K. Capal
John Slopis
Jonathan Gill
Julia Meade
University of Pittsburgh School of Medicine, Pittsburgh, PA
Kathryn Nevel
Indiana University Health/Indiana University School of Medicine, Indianapolis, IL
Laura K. Metrock
University of Alabama at Birmingham, Birmingham, AL
Kevin Bielamowicz
The University of Arkansas for Medical Sciences/Arkansas Children's Hospital, Little Rock, AR
Laura J. Klesse
Lauren Weintraub
Albany Medical Center, Albany, NY
Leia Nghiemphu
Lindsay Kilburn
Maciej M. Mrugala
Mary Lou Schmidt
University of Illinois at Chicago, Chicago, IL
Miriam Bornhorst
Nagma Dalvi
Montefiore Medical Center/Children's Hospital at Montefiore, New York City, NY
Nathan J. Robison
Children's Hospital Los Angeles, Los Angeles, CA
Nick K. Foreman
Paul L. Moots
Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, TN
Prakash Ambady
Providence Health and Services, Portland, OR
Punita Gupta
St Joseph's Regional Medical Center, Paterson, NJ
Radhika Dhamija
Rene Y. McNall-Knapp
University of Oklahoma Health Sciences Center, Oklahoma City, OK
Rueben Antony
Ryan D. Roberts
Nationwide Children's Hospital, Columbus, OH
Ryan Merrell
Sarah Chagnon
Children's Hospital of the Kings Daughters, Norfolk, VA
Stacie Stapleton
Johns Hopkins All Children's Hospital, St Petersburg, FL
Stefania Maraka
University of Illinois at Chicago, Chicago, IL
Timothy R. Gershon
Tobias Walbert
Henry Ford Health, Michigan State and Wayne State University, Detroit, MI
Ziad Khatib
Nicklaus Children's Hospital, Miami, FL
Zsila Sadighi
University of Texas MD Anderson Cancer Center, Houston, TX