TY - JOUR
T1 - Selumetinib in children with inoperable plexiform neurofibromas
AU - Gross, Andrea M.
AU - Wolters, Pamela L.
AU - Dombi, Eva
AU - Baldwin, Andrea
AU - Whitcomb, Patricia
AU - Fisher, Michael J.
AU - Weiss, Brian
AU - Kim, Ae Rang
AU - Bornhorst, Miriam
AU - Shah, Amish C.
AU - Martin, Staci
AU - Roderick, Marie C.
AU - Pichard, Dominique C.
AU - Carbonell, Amanda
AU - Paul, Scott M.
AU - Therrien, Janet
AU - Kapustina, Oxana
AU - Heisey, Kara
AU - Wade Clapp, D.
AU - Zhang, Chi
AU - Peer, Cody J.
AU - Figg, William D.
AU - Smith, Malcolm
AU - Glod, John
AU - Blakeley, Jaishri O.
AU - Steinberg, Seth M.
AU - Venzon, David J.
AU - Austin Doyle, L.
AU - Widemann, Brigitte C.
N1 - Publisher Copyright:
© 2020 Massachusetts Medical Society.
PY - 2020/4/9
Y1 - 2020/4/9
N2 - BACKGROUND No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS We 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). RESULTS A 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. CONCLUSIONS In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib.
AB - BACKGROUND No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS We 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). RESULTS A 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. CONCLUSIONS In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib.
UR - https://www.scopus.com/pages/publications/85082768289
U2 - 10.1056/NEJMoa1912735
DO - 10.1056/NEJMoa1912735
M3 - Article
C2 - 32187457
AN - SCOPUS:85082768289
SN - 0028-4793
VL - 382
SP - 1430
EP - 1442
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 15
ER -