RAS/MAPK inhibition in pediatric gliomas

Unresectable pediatric low-grade glioma is a chronic disease that can cause significant morbidity in young patients. Historically, treatment has mainly involved chemotherapy, with many patients needing multiple lines of treatment for a recurring/relapsing disease. Orally administered inhibitors targeting the rat sarcoma virus (RAS)/mitogen-activated protein kinase (MAPK) pathway, which is the most frequently altered pathway in this disease, have resulted in a new era in the management and care for these patients. Some drugs have been already approved for specific indications, based on improved response rates in comparison to chemotherapy regimens. In this manuscript, we review the current landscape of RAS/MAPK-inhibitor use in sporadic, pediatric low-grade, and select subsets of high-grade gliomas. We summarize the recently completed trials that led to the approvals, as well as ongoing and upcoming trials investigating upfront use, combinatorial approaches, and newer agents. We highlight some of the unique challenges the neuro-oncology community is facing in this new age of targeted therapies, including a distinct set of toxicities, current unknowns, including the optimal duration of treatment, durability of response, mechanisms of tumor rebound and resistance, and the long-term impact of therapy. We conclude by focusing on some of the needed areas for research and clinical applications relevant to this patient population in the coming decade.