ID #58 A NATIONWIDE EVALUATION OF MAPK INHIBITORS FOR PAEDIATRIC LOW-GRADE GLIOMA IN THE UNITED KINGDOM: SAFETY, EFFICACY, VISUAL MORBIDITY, AND OUTCOMES.
Katie Green, Ashley Vardon, Jai Sidpra, Kshitij Mankad, Simon Bailey, Timothy Ritzmann, Stefanie Thust, Shaun Wilson, Vasiliki Ganosi, Richard Gagen, Laura Ramm, Lena Uzunova, Susan Picton, Kevin Badloo, Patricia O’Hare, Darren HargraveAbstract
Background
MAPK inhibitors (MAPKi) targeting MEK and BRAF are increasingly used inPaediatric Low-Grade Glioma(PLGG) outside clinical trials without standardised guidelines regarding indication, treatment line, or supportive care. We report national real-world efficacy and toxicity data from a large PLGG cohort receiving MAPKi outside clinical trials.
Methods
Children <18yrs receiving compassionate BRAF/MEK inhibitors for PLGG 2016-2024 from 7 UK centres were retrospectively evaluated for standardised neuro-radiological (RANO-LGG) response, visual acuity (logMAR) and overall/progression-free (OS/PFS) survival. We calculated MAPKi:prior chemotherapy PFS ratios as a recognised measure of MAPKi treatment benefit. MAPKi toxicities, dose reduction/cessation and treatment duration informed tolerability analysis. Logistic regression analysis of patient, tumour and treatment factors associated with PFS was performed.
Results
50 children diagnosed with PLGG at median 3.25yrs received MAPKi at median 4.5yrs from diagnosis, mostly asfourth-line therapy. Many had adverse prognostic factors for PFS: 88% non-NF1,74% hypothalamic/chiasmatic,54% unresectable,24%BRAFV600E-mutant. Toxicity was generally minimal, dermatological, and manageable with supportive care. OS was 96% at median 3.5yrs from MAPKi start. Overall radiological control occurred in 74% (CR 2%, PR 18%, SD 54%). Overall ‘per patient’ visual control rate was 72% in 35 OPGs (63% stable, 9% improved). Median time to best response was 3 months for both visual and radiological responses. 77% hadsignificantly prolonged MAPKi:prior chemotherapy PFS ratio, without significant prognostic associations between prolonged ratio and patient age, prior chemotherapy regimen, tumour location, MAPKi type or therapy line.77% had prolonged MAPKi:prior chemotherapy PFS ratio (>1.3:1.0) without significant prognostic associations between prolonged ratio and prior chemotherapy regimen, MAPKi type or therapy line. Eight of 23 (35%) patients off MAPKi at analysis progressed at median 6 months from MAPKi cessation.Two deaths (both from sepsis) occurred on MAPKi therapy in children with central lines.
Conclusions
MAPKi provide safe and effective treatment for PLGG, including in high-risk patients with multiply progressed disease, and resulted in significantly prolonged PFS compared to prior chemotherapy.