Phase II Trial of Bintrafusp Alfa in Subjects with Thymoma and Thymic Carcinoma

Division Of Basic Sciences - Nci

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Abstract

Transforming growth factor b (TGF-b), a tightly regulated cytokine involved in tumor eradication, can paradoxically become a tumor promoter when excessively produced and activated by malignant cells through enhancement of an immunosuppressive tumor microenvironment and immune evasion. Robust TGF-b gene expression signature indicating high TGF-b activity and signaling competency, and increased circulating plasma TGF-b levels are seen in several cancers. In thymic epithelial tumors (TETs), a small, retrospective study found high TGF-b expression in the majority of thymic carcinomas and in a subset of thymomas. High TGF-b expression was associated with worse clinical outcomes (median overall survival 30 months versus 63 months). Bintrafusp alfa is a bifunctional fusion protein that consists of the extracellular domain of the human TGF-b receptor II and an immunoglobulin G1 antibody blocking PD-L1. Preclinically, combination immunotherapy with a TGF-b inhibitor and a PD-L1 antibody has been shown to reduce TGF-b signaling in stromal cells, facilitate T-cell penetration into the tumor, and cause tumor regression. This NIH IRB-approved phase 2, open-label clinical trial (NCT04417660) is evaluating the clinical activity of bintrafusp alfa in patients with relapsed TETs. Participants with unresectable thymoma or thymic carcinoma that has progressed after at least one platinum-containing chemotherapy, with measurable disease and no history of autoimmunity (except well-controlled autoimmune thyroid disease, pure red cell aplasia or vitiligo) are eligible. Response is assessed every six weeks by RECIST v1.1. At 12 months, participants with an ongoing response or stability may discontinue bintrafusp alfa and reinstitute treatment if disease progression is observed. Blood and tumor tissue (optional) are collected to study changes in immune cell subsets, soluble factors and cytokines, and evaluate changes in the tumor immune microenvironment. Enrollment is ongoing.