• Andrea M Gross, Pamela L Wolters, Eva Dombi, Andrea Baldwin, Patricia Whitcomb, Michael J Fisher, Brian Weiss, AeRang Kim, Miriam Bornhorst, Amish C Shah, Staci Martin, Marie C Roderick, Dominique C Pichard, Amanda Carbonell, Scott M Paul, Janet Therrien, Oxana Kapustina, Kara Heisey, D Wade Clapp, Chi Zhang, Cody J Peer, William D Figg, Malcolm Smith, John Glod, Jaishri O Blakeley, Seth M Steinberg, David J Venzon, L Austin Doyle, and Brigitte C Widemann.
• From the Pediatric Oncology Branch (A.M.G., P.L.W., E.D., P.W., S.M., M.C.R., D.C.P., A.C., J.T., O.K., J.G., B.C.W.) and the Clinical Pharmacology Program (C.J.P., W.D.F.), Center for Cancer Research, National Cancer Institute, and the Rehabilitation Medicine Department, Clinical Center (S.M.P), National Institutes of Health, Bethesda, the Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick (A.B., K.H.), the Cancer Therapy Evaluation Program (M.S., L.A.D.) and the Biostatistics and Data Management Section, Center for Cancer Research (S.M.S., D.J.V.), National Cancer Institute, National Institutes of Health, Shady Grove, and Johns Hopkins University School of Medicine, Baltimore (J.O.B.) - all in Maryland; Children's Hospital of Philadelphia, Philadelphia (M.J.F., A.C.S.); Cincinnati Children's Hospital, Cincinnati (B.W.); Children's National Hospital, Washington, DC (A.K., M.B.); and Indiana University School of Medicine, Indianapolis (D.W.C., C.Z.).
• N. Engl. J. Med. 2020 Apr 9; 382 (15): 143014421430-1442.

BackgroundNo approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1.MethodsWe conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable).ResultsA total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia.ConclusionsIn this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).Copyright © 2020 Massachusetts Medical Society.

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