Plasma ISG15 as predictor of outcome from antiangiogenic therapy in solitary fibrous tumor: Analysis from the GEIS-69 trial.

Abstract

e23520 Background: Solitary fibrous tumor (SFT) is a rare sarcoma subtype characterized by limited therapeutic options in advanced disease. Tyrosine kinase inhibitors (TKIs) with antiangiogenic properties show clinical activity, but predictive biomarkers of response are lacking. ISG15, an interferon-stimulated gene involved in immune and stress responses, has been implicated in resistance mechanisms to antiangiogenic TKIs, including pazopanib, in previous studies. Methods: Plasma ISG15 levels were quantified by ELISA in paired blood samples from 13 SFT patients within GEIS-69, treated with sunitinib followed by combination with nivolumab. Samples were collected at baseline and after 3 weeks of sunitinib monotherapy. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan–Meier methodology. Survival differences were assessed using the log-rank test and univariate Cox proportional hazards regression. Optimal cut-offs for baseline ISG15 were defined using maxstat. Results: Baseline plasma ISG15 levels ranged from 162 to 3358 pg/mL (median 731 pg/mL). Patients with high baseline ISG15 levels showed significantly shorter PFS compared with those with low levels (median 2.8 vs 5.1 months; p = 0.049), while no statistically significant differences in OS were observed. In univariate Cox regression analysis, high baseline plasma ISG15 levels were associated with an increased risk of progression (HR 3.52, 95% CI 0.93–13.32; p = 0.064). Following sunitinib treatment, ISG15 levels increased in most patients (10/12 evaluable cases), with dynamic changes ranging up to 19.2-fold. However, neither OS nor PFS differed significantly according to the magnitude of ISG15 induction during treatment. Conclusions: High baseline plasma ISG15 levels are associated with shorter PFS in SFT patients treated with sunitinib, supporting its potential role as a predictive biomarker in the antiangiogenic setting. Antiangiogenic therapy represents the current standard first-line treatment for unresectable or advanced disease. In contrast, treatment-induced ISG15 upregulation does not appear to correlate with clinical outcome. These findings warrant validation in larger cohorts.