Mucin 16-Directed Therapy in Pediatric Sarcomas: Case Evidence of Ubamatamab Efficacy in Epithelioid Sarcoma and Its Implications for Other Sarcoma Subtypes.
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PURPOSE: Epithelioid sarcoma (ES) and malignant rhabdoid tumor (MRT) are rare soft tissue sarcomas with poor prognoses. Although mucin 16 (MUC16) and its soluble form, cancer antigen 125 (CA125), are established as biomarkers and therapeutic targets in ovarian cancer, emerging data suggest MUC16 may also be expressed in ES and MRT. In this study, we present a patient with ES, who demonstrated a response to ubamatamab, a novel bispecific T-cell engager (MUC16xCD3), and analyze treatment resistance after disease progression. Additionally, we examine MUC16 expression across pediatric and adolescent and young adult (AYA) sarcomas, to evaluate the frequency of this target and explore the broader application of ubamatamab in this population. MATERIALS AND METHODS: We performed a retrospective clinical case review and immunohistochemical analysis of pediatric and AYA (0-25 years) sarcoma samples from 2015 to 2021, evaluating MUC16 expression using anti-CA125 immunohistochemistry (IHC) on the DAKO Omnis platform. RESULTS: A 23-year-old female patient with multiply relapsed metastatic ES, harboring MUC16 expression by IHC and elevated serum CA125, received intravenous ubamatamab (250 mg) once per week as part of a single patient study. After 11 weeks of ubamatamab, a RECIST v1.1 partial response was demonstrated, along with serum CA125 normalization, lasting 43 weeks. During the initial step-up dosing, the patient experienced grade 2 cytokine release syndrome. Treatment-emergent adverse events included grade 2 pleural effusion, pericardial effusion, and palmar-plantar erythrodysesthesia, all resolving without intervention. IHC analysis of retrospective samples showed positive MUC16 staining in six of eight (75%) ES and two of four (50%) MRT samples, with no immunoreactivity observed in other pediatric/AYA sarcoma subtypes. CONCLUSION: MUC16 is frequently detected in ES and MRTs. Ubamatamab is an encouraging anti-MUC16 therapy, demonstrating clinical efficacy. Ongoing trials (ClinicalTrials.gov identifier: NCT06444880) are evaluating ubamatamab in other rare MUC16-positive tumors.