ID #972 Response to combined MEK and mTOR inhibition in refractory pediatric low-grade gliomas: a limited case series
Andrew Cluster, Ashley Meyer, Michele McHugh, Mary Schriewer, Andrea Ogle, Mohamed AbdelbakiAbstract
Background
Pediatric low-grade gliomas (LGGs) often harbor alterations in the MAP kinase pathway. Targeted therapy, including MEK inhibitors, have been increasingly used for patients with incompletely resected and relapsed LGGs. Nevertheless, patients still need several lines of therapy for refractory and progressive tumors. Preclinical studies have suggested combination MEK and mTOR pathway inhibition may be synergistic, however, adult clinical trials have raised concerns over the associated toxicity.
Case presentation
Patient 1 was a 24-year-old male with suprasellar KIAA1549-BRAF fused pilocytic astrocytoma previously treated with single agent carboplatin, trametinib, a failed re-trial of trametinib, and substantial progression through tovorafenib. After further progression, he started trametinib (0.025 mg/kg/day) and everolimus (2 mg/m2/day). Within 10 months, the tumor has remained stable by RAPNO LGG criteria but showed substantial reduction in extensive surrounding T2/FLAIR signal. Dose reductions were necessary due to symptomatic peripheral edema and mucositis. Patient 2 was a 7-year-old girl with an NF-1 associated optic pathway glioma (with FGFR1 mutation) who has been on therapy since age 1. Interventions included vinblastine, carboplatin/vincristine, MEK inhibitor, mTOR inhibitor, retrial of MEK inhibitor, Avastin, and clinical trial with poly-ICLC. She started trametinib (0.025 mg/kg/day) and everolimus 2 mg/m2/day 5 days on, 2 off). Over 13 months, she had stable disease (minimally decreased in size). Fifty percent dose reduction of trametinib was required due to surgical site wound infection.
Conclusion
Combination therapy with trametinib and everolimus has stabilized two refractory LGGs who were previously treated with MEKi therapy and failed to respond to retreatment. Treatment has been well tolerated after initial dose reductions.