INNV-15. First report of a clinical and radiologic response to vorasidenib in IDH-mutant brainstem astrocytoma

Abstract The discovery of isocitrate dehydrogenase (IDH) mutations marked a significant advancement in glioma biology, enhancing our understanding of tumorigenesis in lower-grade gliomas and leading to the development of small-molecule IDH inhibitors as a novel targeted therapy. IDH-mutant gliomas of the brainstem are exceedingly rare. In the INDIGO trial, patients with brainstem gliomas were excluded, thus, no data exists on the use of vorasidenib in brainstem gliomas, highlighting the need for further research in this population. Here, we describe the case of a 20-year-old female with no significant medical history who developed progressive left facial myokymia and horizontal diplopia on leftward gaze over two years. Brain MRI revealed a non-enhancing expansile T2/FLAIR hyperintense lesion in the left greater than right brainstem extending from the dorsal pons into the cervicomedullary junction. The slowly progressive nature of her symptoms and radiologic appearance were most suggestive of a lower-grade, infiltrative neoplasm. Inflammatory and infectious etiologies were ruled out by CSF analysis. CSF NGS was negative for tumor cfDNA. She underwent a left suboccipital burr hole for stereotactic biopsy of the left middle cerebellar peduncle, which confirmed an IDH R132C-mutant astrocytoma, WHO grade 2. With shared decision making, the patient elected to initiate therapy with vorasidenib 40 mg once daily. After six months of treatment, her diplopia and facial myokymia have nearly resolved. Brain MRI also shows a reduction in the size of the T2/FLAIR hyperintense lesion with decreased mass effect. She has not experienced treatment emergent toxicities. This case is the first to report a favorable clinical and radiographic response to vorasidenib in a patient with an IDH-mutant brainstem astrocytoma, a population excluded from original trials. This suggests the potential use of IDH inhibitors such as vorasidenib in this group and underscores need for further research.