Durable treatment response to Trastuzumab deruxtecan in two patients with recurrent grade III anaplastic ependymoma

Abstract Background Anaplastic ependymoma is a rare and aggressive central nervous system malignancy for which effective systemic treatment options are limited. Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate targeting human epidermal growth factor receptor 2 (HER2), has demonstrated intracranial activity in patients with HER2-positive solid tumors. We report two patients with recurrent, heavily pretreated anaplastic ependymoma and molecular evidence of HER2 activation who received T-DXd as off-label therapy. Methods Both patients underwent comprehensive molecular profiling, including whole-genome and transcriptome sequencing and proteomic analyses. HER2 expression was subsequently assessed by immunohistochemistry. Treatment response was evaluated by serial magnetic resonance imaging (MRI), while clinical benefit and treatment-related toxicities were documented longitudinally. Results Both patients had multiply recurrent anaplastic ependymoma and had exhausted conventional local and systemic treatment options. Molecular profiling identified elevated ERBB2 expression at the transcriptomic and/or proteomic level, with HER2 immunohistochemical positivity in approximately 80% and 15% of tumor cells, respectively. The first patient received T-DXd and achieved sustained disease stabilization after an initial mixed radiographic response, with ongoing disease control for 26 months. The second patient initially received temozolomide plus lapatinib but experienced progressive disease. Following treatment with T-DXd disease stabilization was achieved and maintained for 14 months at the most recent follow-up. Treatment-related hematologic and hepatic toxicities were manageable with supportive measures, dose modification, and temporary treatment interruption. Conclusions These two cases demonstrate durable disease stabilization with T-DXd in heavily pretreated patients with recurrent anaplastic ependymoma and molecular evidence of HER2 activation. The clinical benefit observed, including after failure of lapatinib-based HER2-targeted therapy, supports further investigation of T-DXd in molecularly selected patients with recurrent ependymoma. Comprehensive molecular profiling may help identify patients who could benefit from HER2-directed treatment in this rare and therapeutically challenging disease.