Clinical responses to trastuzumab deruxtecan in molecularly defined ependymoma

Area of Science:

• Neuro-oncology
• Molecular Pathology
• Clinical Pharmacology

Background:

• Antibody drug conjugates (ADCs) show activity in brain metastases, but their efficacy in primary central nervous system (CNS) tumors is not well-established.
• Ependymoma, a primary CNS tumor, presents challenges in treatment, especially in recurrent or disseminated forms.

Purpose of the Study:

• To investigate the efficacy of trastuzumab deruxtecan (T-DXd), an ADC, in patients with molecularly defined ependymoma.
• To assess the role of HER2 expression as a predictive biomarker for T-DXd response in ependymoma.

Main Methods:

• Case report of two adult patients with molecularly defined ependymoma (MYCN-amplified and ZFTA-RELA-fused).
• Treatment with trastuzumab deruxtecan (T-DXd).
• Immunohistochemistry and multiplexed imaging to evaluate HER2 expression and tumor microenvironment.

Main Results:

• Both patients demonstrated radiographic response and/or durable clinical and metabolic stability.
• HER2 expression was confirmed in both ependymoma tumors.
• Heterogeneous HER2 expression was observed, with varying associations with EGFR/MAPK pathways and proliferation.

Conclusions:

• These findings provide early clinical evidence supporting HER2-directed ADCs, specifically T-DXd, in the treatment of ependymoma.
• Integrated molecular and spatial profiling is valuable for understanding therapeutic response in rare CNS tumors.