ID #394 Superior tumor control using weaning MEK inhibitors for RAS/MAPK altered pediatric low-grade glioma (pLGG)
Duhita Sengupta, Amit Ringel, Anthony Pak, Yin Liu, Julie Bennett, Anirban Das, Annie Huang, Vijay Ramaswamy, Ute Bartels, Tara Mckeown, George Ibrahim, Peter Dirks, James Rutka, Abhaya Kulkarni, Adrian Levine, Eric Bouffet, Cynthia Hawkins, Uri TaboriAbstract
Introduction
Targeted therapy is emerging as frontline care for pLGG, yet optimal dose and duration remain unclear. Long-term use risks chronic toxicity, while abrupt cessation can trigger rebound growth, and retreatment response is less favorable. A structured weaning strategy may preserve tumor control while reducing toxicity and financial burden.
Methods
We analyzed children with pLGG treated with trametinib at our institution to evaluate (1) the minimum dose required for tumor stability, (2) proportion of regrowth after treatment cessation, and (3) differences in durability of tumor control between the weaning and retreatment cohorts.
Results
Fifty-five patients met inclusion criteria (non-BRAF V600E altered pLGG treated with trametinib). Most pLGG were BRAF fused (69%), followed by NF1-associated (20%). Eight patients (14%) progressed on trametinib, predominantly those with disseminated pLGG, and were excluded from further analysis.When examining the dose of trametinib which enabled stable tumor response, 70% of patients (33/47) maintained stable response at a median of 67% of weight-based dose (range: 26-96%). Of patients who stopped therapy after tumor response/stabilization, 64% (25/39) experienced regrowth at a median 0.63 year (range: 0.3-4 years); of those, 92% (23/25) required further systemic treatment. We therefore initiated a weaning protocol for patients after >1.5 years of stability and compared durability of control against patients who stopped therapy with subsequent retreatment. The tumor size of patients who stopped treatment was on average 48% larger at the end of the second trametinib treatment compared to the best response during first treatment. In contrast, the tumor size of patients who weaned treatment differed only by 4% between best response and the current size during weaning (p = 0.03).
Conclusion
This study provides evidence for safety and efficacy of weaning rather than abrupt stopping of therapy. These findings guide future strategies which may reduce treatment costs and side effects while ensuring tumor control in this chronic disease.