Surgery is a treatment option for neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN), but complete resection is often not feasible. Real-world studies are warranted to understand disease burden, progression, and need for medical treatment in patients with inoperable PN. CASSIOPEA was a retrospective study of French pediatric patients (aged ≥3 to <18 years) presenting at a national multidisciplinary team (MDT) review with NF1 and ≥1 symptomatic, inoperable PN. Medical records were reviewed from the time of MDT review and over a follow-up period of up to 2 years. Primary objectives were to describe patient characteristics and target PN-associated therapy patterns. A secondary objective was evolution of target PN-related morbidities. Patients with prior, ongoing, or MDT recommendation of mitogen-activated protein kinase kinase (MEK) inhibitor treatment were excluded. Overall, 78 target PN were identified in 76 patients. At MDT review, median age was 8.4 years, with approximately 30% of patients aged 3-6 years. Target PN were primarily internal (77.3%), and 43.2% were progressive. Target PN location was evenly distributed. 34 target PN had documented MDT recommendations; of these, a majority (76.5%) were for non-medication management, including surveillance. At least one follow-up visit was recorded for 74 target PN. Despite initially being considered inoperable, 12.3% of patients underwent surgery for target PN. At MDT review, most (98.7%) target PN were associated with ≥1 morbidity, primarily pain (61.5%) and deformity (24.4%); severe morbidities were identified in 10.3%. Of 74 target PN with follow-up data, 89.2% were associated with ≥1 morbidity, primarily pain (60.8%) and deformity (25.7%). Of 45 target PN associated with pain, pain improved in 26.7%, was stable in 44.4%, and deteriorated in 28.9%. Deformity improved in 15.8% and remained stable in 84.2% of 19 target PN associated with deformity. None deteriorated. In this real-world study in France, NF1-PN disease burden was considerable, and a considerable proportion of patients were very young. Most patients received only supportive care without medication for target PN management. Target PN-related morbidities were frequent, heterogeneous, and generally did not improve during follow-up. These data highlight the importance of effective treatments that target PN progression and improve disease burden., Competing Interests: Declaration of competing interest PW received consultancy fees from AstraZeneca during the conduct of the study. YC's institution received fees from AstraZeneca during the conduct of the study. MAA has received grants or contracts from Bristol Myers Squibb and Pierre Fabre, payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Pierre Fabre, and Sun Pharma, support for attending meetings and/or travel from Bristol Myers Squibb and Pierre Fabre, and has participated on a Data Safety Monitoring Board or Advisory Board for Sun Pharma. SB has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AstraZeneca, Almirall, Sanofi-Genzyme, AbbVie, Novartis, Janssen, LEO Pharma, Pfizer, Eli Lilly, UCB Pharma, and Chiesi and has also received support for attending meetings and travel from Almirall, Sanofi-Genzyme, AbbVie, and Eli Lilly. CB and TR both report employment at AstraZeneca. AM reports employment at AstraZeneca during the conduct of the study. NEW reports no conflicts of interest. IA has received consulting fees from AstraZeneca and has participated on a Data Safety Monitoring Board or Advisory Board for AstraZeneca. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Emily Clark, of OPEN Health Communications, London, UK and was funded by Alexion, AstraZeneca Rare Disease and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc., Rahway, NJ, USA, in accordance with Good Publications Practice (GPP 2022) guidelines., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)