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

Abstract

Background and Aims: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). Methods: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 150 mg galunisertib BID for 14 days 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).Results: Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (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 (21.5 months vs 6.8 months). 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). Conclusions: 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. Trial Registration Number: NCT01246986 at ClinicalTrials.gov. K E Y W O R D S alpha fetoprotein, galunisertib, hepatocellular carcinoma, liver cancer, TGF-β1, TGF-β1 receptor I inhibitor See Editorial on Page 1391 | 1469 FAIVRE Et Al.

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

“…This was an open-label, multicentre, two-part phase 2 study in patients aged 18 years or older with histological evidence of HCC (not amenable to curative surgery), Child-Pugh Class A or B7, measurable disease (RECIST 1.1), Eastern Cooperative Oncology Group Performance Status �1, and who had received sorafenib and had progressed or were ineligible for sorafenib treatment. Part A included patients with baseline serum AFP�1.5x upper limit of normal (ULN); these patients were randomly assigned to two cohorts based on initial dose of galunisertib (80 or 150 mg BID) [15]. Part B enrolled patients with AFP<1.5x ULN to receive galunisertib at 150 mg BID.…”

Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma

“…In HCC patients with elevated alpha-fetoprotein prior to treatment and who had previously progressed on sorafenib or were considered not eligible to receive sorafenib, galunisertib monotherapy achieved a median OS of 7.3 months (95% CI, 4.9-10.5). OS was longer for those patients who showed reduced alpha-fetoprotein (>20% from baseline) compared to non-responders (21.5 months vs 6.8 months) [33]. While these signals were encouraging, the sponsor discontinued future clinical development for galunisertib in mid-2017 [34].…”

Suppression of TGF-beta activity with remobilization attenuates immobilization-induced joint contracture in rats

“…It has also shown promising results in clinical trials due to its acceptable safety pro le. It produced a prolonged overall survival outcome in phase 1/2 trials for patients with hepatocellular carcinoma, myelodysplastic syndrome, and other neoplastic diseases [38][39][40][41][42].…”