Biomarker and Histopathology Evaluation of Patients with Recurrent
Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of
Galunisertib and Lomustine
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.
View Full-Tex
