P2.04-019 A Peripheral Immune Signature Associated with Clinical Activity of Sunitinib in Thymic Carcinoma: Topic: Thymic Malignancies Clinical and Translational

Abstract

We have previously reported an objective response rate of 26% and disease stabilization in 65% of patients with advanced thymic carcinoma (TC) treated with the multi kinase inhibitor sunitinib after failure of platinum-based chemotherapy. The current study investigates the impact of sunitinib on systemic immunity in patients with thymic epithelial tumors with an aim to discover blood-based, predictive immune biomarkers. Patients with thymoma and TC received sunitinib at a dose of 50 mg once daily in 6-week cycles consisting of 4 weeks of treatment followed by 2 weeks without treatment. Results from 15 patients with TC are reported here. Blood samples were collected before initiation of sunitinib therapy (Cycle 1 day 1; C1D1), and prior to treatment on day 1 of cycles 2 and 3 (C2D1; C3D1). Multiparameter flow cytometry was used to study T-cell subsets with immune checkpoint expression, four phenotypes of myeloid-derived suppressor cells (MDSCs) with CD40, and CD14+ monocytes with HLA-DR expression. Expression of 730 immune-related genes in peripheral blood was analyzed by NanoString technology. Differences in paired markers or changes in markers between two time points was evaluated by the Wilcoxon signed rank test. The Kaplan-Meier method was used to obtain estimates of progression-free survival (PFS) and overall survival (OS). Immunosuppressive Tim-3-positive Tregs declined after 2 cycles of sunitinib (p=0.024). A decrease in granulocytic MDSCs (p=0.012), lineage negative (CD3-CD19-CD56-) MDSCs (p=0.013), and immature MDSCs (p=0.01) but not monocytic MDSCs was observed after 1 cycle of sunitinib. TC patients with no objective response to sunitinib had a higher baseline immature MDSC level than responders (p=0.0044). Greater than median declines in granulocytic MDSC CD40 (C2D1 p=0.027, C3D1 p=0.0046) and lineage-MDSC CD40 (C3D1, p=0.0046) after sunitinib therapy was associated with improved PFS. Similarly, a greater than median decline in CD14+HLA-DRlo/neg monocyte levels on C2D1 was associated with longer PFS (p=0.020). Among the immune genes examined, higher baseline FEZ1 expression was associated with improved PFS and OS. Our findings suggest significant interplay between sunitinib and systemic immunity impacts therapeutic outcome in TC. Monitoring CD40 expression on specific MDSC phenotypes and FEZ1 gene expression may predict a survival benefit after treatment with sunitinib. These results, if validated in larger studies, can serve as potential blood-based predictive biomarkers in TC patients treated with sunitinib.