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

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.

• Authors: David Capper, Andreas von Deimling, Alba A Brandes, Antoine F Carpentier, Santosh Kesari, Juan M Sepulveda-Sanchez, Helen R Wheeler, Olivier Chinot, Lawrence Cher, Joachim P Steinbach, Pol Specenier, Jordi Rodon, Ann Cleverly, Claire Smith, Ivelina Gueorguieva, Colin Miles, Susan C Guba, Durisala Desaiah, Shawn T Estrem, Michael M Lahn, Wolfgang Wick
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 18 Issue 5 (May 06 2017) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 28481241 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Biomarkers, Tumor
• Cytokines
• FOXP3 protein, human
• Forkhead Transcription Factors
• Pyrazoles
• Quinolines
• SMAD2 protein, human
• Smad2 Protein
• LY-2157299
• Lomustine
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Adult
• Antineoplastic Combined Chemotherapy Protocols
• Biomarkers, Tumor (blood, metabolism)
• CD4-CD8 Ratio
• Cytokines (blood)
• Female
• Forkhead Transcription Factors (blood, metabolism)
• Glioblastoma (blood, drug therapy, pathology)
• Humans
• Isocitrate Dehydrogenase (metabolism)
• Lomustine (administration & dosage, adverse effects, therapeutic use)
• Male
• Neoplasm Recurrence, Local (blood, drug therapy, pathology)
• Pyrazoles (administration & dosage, adverse effects, therapeutic use)
• Quinolines (administration & dosage, adverse effects, therapeutic use)
• Smad2 Protein (metabolism)
• Survival Analysis