SAFETY AND EFFICACY OF TRAMETINIB IN THE MANAGEMENT OF CHILDREN WITH RASOPATHIES

There is emerging evidence regarding the efficacy of agents targeting the MAPK pathway in children with RASopathies. We report our experience with the use of trametinib, a MEK inhibitor, in this population. Three patients with neurofibromatosis type 1 (NF-1) and plexiform neurofibromas refractory to imatinib, and 4 patients with low grade gliomas (LGGs) (3 NF-1; 1 encephalocraniocutaneous lipomatosis), with progression on multiple chemotherapy regimens (carboplatin/vincristine; vinblastine; bevacizumab/irinotecan) were treated with trametinib (median dose 1 mg/m2/day; 0.7 - 1.5 mg/m2/day) Tumor response was evaluated by MRI using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. All patients with plexiform neurofibromas had stable disease (median follow-up 8 months), but reported improvement of vision, cosmesis and snoring respectively. Of 3 patients with optic pathway glioma, one had partial response, two had stable disease, and 1 of these patients had complete response of a cerebellar LGG (median follow-up 8 months). Two patients were taken off-therapy due to grade III adverse events, with bleeding scalp excoriations within 2 weeks, and pyogenic granulomas of multiple fingers and toes 5 months after treatment initiation, respectively. One patient needed 25% dose-reduction for grade II mouth sores. Six patients developed grade 1-2 maculopapular rash on the face, trunk or arms, with improvement using steroid and emollient ointments. MEK inhibitors can be effective in the treatment of multiply-progressive cranial and peripheral nerve tumors, in patients with RASopathies. Long-term follow-up in a larger study population is needed to determine the efficacy and adverse effects of these agents.