학술논문
Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine.
Document Type
Article
Author
Capper, David; von Deimling, Andreas; Brandes, Alba A.; Carpentier, Antoine F.; Kesari, Santosh; Sepulveda-Sanchez, Juan M.; Wheeler, Helen R.; Chinot, Olivier; Cher, Lawrence; Steinbach, Joachim P.; Specenier, Pol; Rodon, Jordi; Cleverly, Ann; Smith, Claire; Gueorguieva, Ivelina; Miles, Colin; Guba, Susan C.; Desaiah, Durisala; Estrem, Shawn T.; Lahn, Michael M.
Source
Subject
*TRANSFORMING growth factors
*GLIOBLASTOMA multiforme
*MACROPHAGES
*CHEMOKINES
*ISOCITRATE dehydrogenase
*
*
*
*
Language
ISSN
1661-6596
Abstract
Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor, blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was evaluated to identify markers associated with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein) and TGF-β-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments included chemokine, cytokine, and T cell subsets alterations. 158 patients were randomized to galunisertib plus lomustine (n = 79), galunisertib (n = 39) and placebo+lomustine (n = 40). In 127 of these patients, tissue was adequate for central pathology review and biomarker work. Isocitrate dehydrogenase (IDH1) negative glioblastoma patients with baseline pSMAD2+ in cytoplasm had median overall survival (OS) 9.5 months vs. 6.9 months for patients with no tumor pSMAD2 expression (p = 0.4574). Eight patients were IDH1 R132H+ and had a median OS of 10.4 months compared to 6.9 months for patients with negative IDH1 R132H (p = 0.5452). IDH1 status was associated with numerically higher plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and reduced tumor CD3+ T cell counts. Compared to the baseline, treatment with galunisertib monotherapy preserved CD4+ T cell counts, eosinophils, lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was associated with better OS with MDC/CCL22 as a prominent prognostic marker. [ABSTRACT FROM AUTHOR]