Lessons from Exceptional Responders with High-Grade Brain Tumors Treated with Precision Targeted Therapies

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ABSTRACT Background High-grade gliomas are associated with dismal outcomes and have devastating neurologic sequelae. Standard-of-care surgery, radiation, and temozolomide yield a median survival of 14–16 months in patients with glioblastoma (GBM). Methods We report four patients with high-grade glioma (two with GBM; one initially diagnosed with GBM, now classified as World Health Organization grade 4 IDH1- mutant astrocytoma; and one with oligosarcoma [grade 4]). Tumor next-generation sequencing (NGS) was performed for all four patients, and they were treated based on their biomarkers. Results NGS yielded actionable alterations targeted after conventional surgery/chemoradiation therapy: imatinib (for KIT and PDGRA amplification) and bevacizumab (for KDR [ VEGFR2 ] amplification); everolimus (mTOR inhibitor for TSC2 and PTEN loss-of-function alterations); and ivosidenib (IDH1 inhibitor for IDH1 mutations in two cases, including the oligosarcoma). Three patients remain in radiographic and clinical remission at 39+, 48, and 52+ months; the patient with oligosarcoma showed clinical and imaging response lasting 8 months. Conclusions Our exceptional responders with high-grade gliomas suggest that biomarker-matched targeted therapy can benefit select patients with high-grade glioma and warrants prospective clinical trials.

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