Journal Article

Biomarkers and overall survival in patients with advanced hepatocellular carcinoma treated with TGF-βRI inhibitor galunisertib

Wang, Shuaicheng, Raymond, Eric, Man, Michael, Benhadji, Karim A., Lahn, Michael M., Santoro, Armando, Gane, Ed, Faivre, Sandrine, Paradis, Valerie, Kelley, Robin K., Estrem, Shawn T., Giannelli, Gianluigi, Cleverly, Ann, Smith, Claire

2020

Overview

Transforming growth factor beta (TGF-β) signalling is involved in the development of hepatocellular carcinoma (HCC). We followed changes in biomarkers during treatment of patients with HCC with the TGF-βRI/ALK5 inhibitor galunisertib. This phase 2 study (NCT01246986) enrolled second-line patients with advanced HCC into one of two cohorts of baseline serum alpha-fetoprotein (AFP): Part A (AFP ≥1.5x ULN) or Part B (AFP <1.5x ULN). Baseline and postbaseline levels of AFP, TGF-β1, E-cadherin, selected miRNAs, and other plasma proteins were monitored. The study enrolled 149 patients (Part A, 109; Part B, 40). Median OS was 7.3 months in Part A and 16.8 months in Part B. Baseline AFP, TGF-β1, E-cadherin, and an additional 16 plasma proteins (such as M-CSF, IL-6, ErbB3, ANG-2, neuropilin-1, MIP-3 alpha, KIM-1, uPA, IL-8, TIMP-1, ICAM-1, Apo A-1, CA-125, osteopontin, tetranectin, and IGFBP-1) were found to correlate with OS. In addition, a range of miRs were found to be associated with OS. In AFP responders (21% of patients in Part A with decrease of >20% from baseline) versus non-responders, median OS was 21.5 months versus 6.8 months (p = 0.0015). In TGF-β1 responders (51% of all patients) versus non-responders, median OS was 11.2 months versus 5.3 months (p = 0.0036). Consistent with previous findings, both baseline levels and changes from baseline of circulating AFP and TGF-β1 function as prognostic indicators of survival. Future trials are needed to confirm and extend these results.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Aged / Aged, 80 and over / alpha-Fetoproteins - analysis / Antigens, CD - blood / Biology and Life Sciences / Biomarkers / Biomarkers, Tumor - blood / Biomedical materials / Cadherins - blood / Carcinoma, Hepatocellular - blood / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - mortality / Cerebrospinal fluid / Clinical trials / Cohort Studies / E-cadherin / ErbB-3 protein / Female / Growth factors / Hepatocellular carcinoma / Humans / Inhibitors / Insulin-like growth factor-binding protein 1 / Intercellular adhesion molecule 1 / Interleukin 6 / Interleukin 8 / Laboratories / Liver cancer / Liver Neoplasms - blood / Liver Neoplasms - drug therapy / Liver Neoplasms - mortality / Macrophage colony-stimulating factor / Male / Medicine and Health Sciences / MicroRNAs / MicroRNAs - blood / Middle Aged / Neuropilin / Neutrophils / Osteopontin / Plasma proteins / Prognosis / Proteins / Pyrazoles - pharmacology / Pyrazoles - therapeutic use / Quinolines - pharmacology / Quinolines - therapeutic use / Receptor, Transforming Growth Factor-beta Type I - antagonists & inhibitors / Survival / Survival Rate / Tissue inhibitor of metalloproteinase 1 / Transforming Growth Factor beta1 - analysis / Transforming growth factor-b / Transforming growth factor-b1 / Treatment Outcome / α-Fetoprotein