Clinical and radiographic responses to trastuzumab deruxtecan in molecularly defined ependymomas.

Abstract

e14097 Background: Ependymomas are rare central nervous system (CNS) tumors lacking approved targeted therapies, and recurrent disease remains difficult to treat. Recent systematic profiling has identified HER2 protein expression in a subset of ependymomas, suggesting a potential role for HER2-directed antibody–drug conjugates (ADCs). Trastuzumab deruxtecan (T-DXd), a next-generation HER2-targeted ADC with documented CNS activity in breast cancer, has not been systematically evaluated in primary CNS tumors. Methods: Two patients with recurrent, molecularly defined ependymoma who had progressed after standard therapies were treated off-label with trastuzumab deruxtecan (T-DXd). The cohort included one patient with MYCN-amplified spinal ependymoma with intracranial dissemination and another with supratentorial ZFTA-RELA–fused ependymoma. Clinical, radiographic, and metabolic responses were assessed using serial MRI and 18 F-FDOPA PET imaging. In the MYCN-amplified case, high-dimensional spatial profiling with multiplexed immunofluorescence (CyCIF) was performed to characterize tumor-cell intrinsic programs related to lineage state, proliferation, and signaling. Results: Both tumors demonstrated membranous HER2 expression by immunohistochemistry (estimated 2+–3+). In the MYCN-amplified case, HER2 expression was widespread across tumor compartments, while spatial profiling identified EGFR/MAPK-linked proliferative niches enriched for cycling and dedifferentiated tumor cell states. Treatment with T-DXd induced marked radiographic responses, with reductions of 84% and 54% in intracranial measurable lesions. The ZFTA-RELA–fused tumor demonstrated durable clinical stability on T-DXd over ~10 months, with a 27% reduction in enhancing tumor burden and a 46% decrease in metabolic tumor volume on serial 18 F-FDOPA PET imaging, meeting PET-RANO criteria for metabolic partial response. Treatment was generally well tolerated, with expected low-grade adverse effects. Conclusions: This study provides early clinical evidence that HER2-directed ADC therapy may benefit select patients with ependymoma across distinct molecular subtypes. Integration of molecular pathology with spatial tumor profiling revealed features that may inform patient selection and rational combination strategies. Together, these results support further prospective evaluation of HER2-targeted ADCs in molecularly selected ependymoma cohorts and highlight the value of protein-level and spatial profiling in identifying actionable vulnerabilities in rare CNS tumors.