Treatment patterns and outcomes in advanced clear cell sarcoma and gastrointestinal neuroectodermal tumors.

BACKGROUND: Clear cell sarcoma (CCS) and gastrointestinal neuroectodermal tumor (GNET) are ultra-rare soft tissue sarcomas with no established standard of care for advanced disease. Data evaluating outcomes of systemic therapy remain limited. We aimed to evaluate systemic therapy in patients with metastatic CCS/GNET treated at a tertiary referral institution. METHODS: This is a retrospective, single-institution study of patients with metastatic CCS/GNET diagnosed between January 2000 and May 2025. The primary objective was to describe patterns of systemic therapy use and secondary endpoints included overall survival (OS) and real-world progression free survival (rwPFS). Survival outcomes were estimated using the Kaplan-Meier method. Hazard ratios were estimated using Cox proportional hazards models. Exploratory analyses evaluated outcomes by treatment class. RESULTS: Sixty-six patients were included; 55 received systemic therapy. Median follow-up was 192 months, and patients received a median of two treatment lines with heterogeneous sequencing. Median OS was 18 months (95%CI 13.6-28.0). In first-line analyses, tyrosine kinase inhibitors (TKI) based therapy and immune-checkpoint inhibitors (ICI) was associated with improved OS compared with doxorubicin-based chemotherapy (TKI: HR 0.33, 95% CI 0.14-0.79; p = 0.01, ICI: HR 0.39, 95% CI 0.10-0.94; p = 0.04). Median first-line rwPFS was 3.8 months (95% CI, 2.9-6.3), with no significant differences between treatment classes. Non-doxorubicin-based chemotherapy was associated with shorter rwPFS compared with doxorubicin regimens (HR 4.1, 95% CI, 1.71-9.83; p < 0.001). CONCLUSIONS: Metastatic CCS/GNET is highly aggressive with limited effective systemic options. Outcomes remain poor, highlighting the need for novel therapies and collaborative studies.