Abstract
270 Background: TGF-β, the strongest known immunosuppressive cytokine, modulates the hepatic immune response to various antigens and to ionizing radiation. When activated, TGF-β blocks the effector T-cell response to cellular destruction and the release of tumor-specific antigens. Preclinical data demonstrate that neutralizing TGF-β during radiation effectively generates a CD8+ T-cell response to multiple endogenous tumor antigens, thereby generating an in-situ vaccine against a tumor. We hypothesized that the combination of TGF-β receptor inhibition plus SBRT would produce a potent and clinically effective antitumor immune response against HCC. Methods: Patients received galunisertib (LY2157299 monohydrate) on days 1-14 of each 28 day cycle. SBRT was delivered in a single fraction of 18 Gy between days 15-28 of C1. Pre-treatment and on-treatment biopsies were obtained, as well as serial blood collections for CTCs, ctDNA and PBMCs. Results: 15 patients with advanced HCC and Child’s Pugh A cirrhosis were treated. 9/15 (60%) had a prior history of infectious hepatitis, three of whom had active viremia at time of enrollment. 6/15 (40%) had received prior systemic therapy for HCC and 12/15 (80%) had received prior liver directed therapy. The most common treatment-related toxicities were: fatigue (53%), nausea (47%), increased alkaline phosphatase (33%), abdominal pain (33%), vomiting (20%), decreased white blood cell count (20%). All drug-related toxicities were grade 1 or 2, with the exception of one patient who had grade 3 achalasia, thought possibly to be related to study drug. Median PFS was 3.68mo. There were two confirmed partial responses (PRs) and six additional patients had stable disease (SD) for at least four months, resulting in a disease control rate (DCR) of 53%. Both PRs included shrinkage of lesions that had not been radiated. Translational studies are currently underway. Conclusions: The combination of galunisertib with SBRT in patients with advanced HCC is a well-tolerated regimen. In this small pilot study, we observe a DCR of 53% including two PRs. These results warrant further study of this therapeutic combination in advanced HCC. Clinical trial information: NCT02906397.
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