A Pilot Study of Galunisertib Plus Stereotactic Body Radiotherapy in Patients with Advanced Hepatocellular Carcinoma.

TGF-β is a pleiotropic cytokine with immunosuppressive activity. In pre-clinical models blockade of TGF-β enhances the activity of radiation and invokes T cell anti-tumor immunity. Here, we combined galunisertib, an oral TGF-β inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy and immunological correlatives. Patients (n=15) with advanced HCC who progressed on, were intolerant of, or refused sorafenib were treated with galunisertib (150mg PO BID) on days 1-14 of each 28-day cycle. A single dose of SBRT (18-Gy) was delivered between days 15-28 of Cycle 1. Site of index lesions treated with SBRT included liver (9), lymph node (4) and lung (2). Blood for high-dimensional single cell profiling was collected. The most common treatment-related adverse events (AEs) were fatigue (53%), abdominal pain (46.6%), nausea (40%) and increased alkaline phosphatase (40%). There were two instances of grade 2 alkaline phosphatase increase and two instances of grade 2 bilirubin increase. One patient developed grade 3 achalasia possibly-related to treatment. Two patients achieved a partial response. Treatment with galunisertib was associated with a decrease in the frequency of activated T regulatory cells in the blood. Distinct peripheral blood leukocyte populations detected at baseline distinguished progressors from non-progressors. Non-progressors also had increased CD8+PD-1+TIGIT+ T cells in the blood after treatment. We found galunisertib combined with SBRT to be well-tolerated and associated with anti-tumor activity in patients with HCC. Pre- and post-treatment immune profiling of the blood was able to distinguish patients with progression versus non-progression.