(P 38) VALIDATION OF THE SIGNIOS SEVEN-GENE SIGNATURE FOR PREDICTING ANTI-PD-1 INHIBITOR EFFICACY IN SARCOMA

Objective: Immune checkpoint inhibitors (ICIs) show limited efficacy in sarcomas, primarily attributed to an immunologically "cold" tumor microenvironment. A previously identified 7-gene signature (CD86, CHI3L1, CXCL10, CXCL9, LAG3, NR4A1, VCAM1; designated SIGNIOS - SIGNature for Immuno-Oncology anti-PD-1 inhibitors in Sarcoma) predicted response to combined antiangiogenic/PD-1 inhibitor therapy in soft-tissue sarcoma (STS). This study aimed to externally validate SIGNIOS’ predictive value for efficacy to ICI in an independent cohort of patients (pts) with advanced sarcomas.

Methods: Using transcriptomic data (RNA-Seq) from pre-treatment tumor samples from the SARC028 phase 2 trial (pembrolizumab for advanced sarcomas), we calculated the SIGNIOS score. Patients were stratified into low (score 0-4) and high (score 5-7) risk groups. Progression-free survival (PFS) and clinical benefit (complete response, partial response, or stable disease vs. progression of disease [PD]) were compared between groups.

Results: The validation cohort included 31 patients (median age: 33 years; 45.2% female). Key histologic subtypes included osteosarcoma (25.8%), Ewing sarcoma (19.4%), leiomyosarcoma (12.9%), synovial sarcoma (12.9%), and undifferentiated pleomorphic sarcoma (12.9%). The SIGNIOS score was significantly associated with PFS (median PFS of low-score vs high-score groups: 49 vs 170 days, Hazard Ratio = 0.71; p=0.007). The 7-gene-based signature was unable to distinguish between patients who experienced clinical benefit from pembrolizumab and patients with PD (p=0.15).

Conclusion: This external validation in a pembrolizumab-treated cohort confirms the SIGNIOS 7-gene signature as a robust biomarker for predicting ICI efficacy in patients with advanced sarcomas. Prospective studies are warranted to refine its clinical utility across diverse sarcoma subtypes and explore applicability in other tumor types.