Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma.

Abstract

We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-β1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP). Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS≤1 were enrolled into Part A (AFP≥1.5× ULN) or Part B (AFP<1.5× ULN). Patients were treated with 80 or 150mg galunisertib BID for 14days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-β1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS). Patients (n=149) were enrolled with median age 65years. Median TTP was 2.7months (95% CI: 1.5-2.9) in Part A (n=109) and 4.2months (95% CI: 1.7-5.5) in Part B (n=40). Median OS was 7.3months (95% CI: 4.9-10.5) in Part A and 16.8months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (>20% decrease from baseline, Part A) compared to non-responders (21.5months vs 6.8months). OS was longer in TGF-β1 responders (>20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n=4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n=2). Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-β1 levels (vs no response) correlated with longer survival. NCT01246986 at ClinicalTrials.gov.