Validation of a Seven-Gene Predictive SIGNature for the Efficacy of Immuno-Oncology PD-1 Inhibitors in Patients with Sarcoma

PURPOSE: Immune checkpoint inhibitors (ICI) have transformed cancer therapy, but their efficacy in sarcomas remains limited. A seven-gene predictive signature (CD86, CHI3L1, CXCL10, CXCL9, LAG3, NR4A1, and VCAM1) was previously identified as a biomarker for response to combined antiangiogenic and PD-1 inhibitor therapy in soft-tissue sarcomas. This study aimed to externally validate the predictive utility of this signature [SIGNature for immuno-oncology PD-1 inhibitors in sarcoma (SIGNIOS)] in an independent cohort of patients with sarcoma treated with ICIs. EXPERIMENTAL DESIGN: Using RNA sequencing data from pretreatment tumor samples from the SARC028 phase II trial (pembrolizumab for advanced sarcomas) and the GEIS-32 phase II trial (pazopanib in advanced solitary fibrous tumor), we calculated the SIGNIOS score. Patients were stratified into low (score 0-4) and high (score 5-7) risk groups. RESULTS: The SARC028 validation cohort comprised 31 patients, with a median age of 33 years, and 45.2% were female. The most common histologic subtypes included osteosarcoma (25.8%) and Ewing sarcoma (19.4%). The seven-gene signature significantly stratified patients into groups with significantly different progression-free survival (PFS): Those with scores of 0 to 4 had a median PFS of 49 days, whereas those with scores of 5 to 7 had a median PFS of 170 days [HR = 0.71 (95% confidence interval, 0.55-0.91), P = 0.007]. CONCLUSIONS: This external validation confirms the seven-gene signature as a potential biomarker for predicting ICI efficacy in advanced sarcomas. Prospective studies are needed to determine the prognostic versus predictive value of SIGNIOS, refine its use across sarcoma subtypes, and explore its applicability in other tumor types.