ID #856 Serial ROS1 Inhibition Achieves Long-Term Disease Control in a H3K27M-Mutant Glioma: A Case Report
Margit Mikkelsen, Nicole Ramirez, Sandeep Dhanda, Giles RobinsonAbstract
Background
H3K27M-mutant gliomas are associated with an abysmal prognosis in children. However, increasing molecular characterization has revealed rare but potentially significant biological heterogeneity within these tumors that may alter clinical behavior and therapeutic responsiveness.
Case Description
A 4-year-old female presented with new-onset seizures. Neuroimaging revealed multiple (n = 5) left frontal lobe lesions, both enhancing and non-enhancing. Biopsy demonstrated histopathologic features consistent with anaplastic astrocytoma with a H3K27M mutation. Despite the off-midline location, a diagnosis of diffuse midline glioma, H3K27M-mutant, WHO grade IV, was given, and large-field radiation therapy was considered. However, additional molecular testing revealed a GOPC–ROS1 fusion and a methylation profile that aligned with infant hemispheric glioma. Given the patient’s age and the unusual presentation of off-midline multifocal disease, with an actionable alteration, alternative therapy to radiation was explored.She enrolled on the STARTRK trial (NCT02650401) and was treated with entrectinib for 2 years, achieving a partial response with complete resolution of several lesions.Her course on therapy was complicated by significant adverse effects, including fractures and weight gain that eventually led to treatment discontinuation. Twelve months later, her disease progressed with the appearance of new enhancing lesions and she was started on lorlatinib, a selective ALK/ROS1 inhibitor. Radiographic response was again achieved, but weight gain and severe mood disturbances forced discontinuation of therapy after 1 year.Surprisingly, a period of prolonged disease stability followed, lasting three years before her disease returned. She was then started on taletrectinib, a highly selective ROS1 tyrosine kinase inhibitor, which she is tolerating without treatment-limiting toxicity and with good radiographic response. She is now eight years from diagnosis with ongoing clinical benefit from ROS-1 inhibition.
Conclusion
This report highlights the biological heterogeneity of H3K27M-mutant gliomas and supports a paradigm in which integrated molecular characterization can identify subsets of patients who may benefit from targeted therapies, even within tumor types traditionally considered universally lethal.