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Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma
Author(s) -
Faivre Sandrine,
Santoro Armando,
Kelley Robin K.,
Gane Ed,
Costentin Charlotte E.,
Gueorguieva Ivelina,
Smith Claire,
Cleverly Ann,
Lahn Michael M.,
Raymond Eric,
Benhadji Karim A.,
Giannelli Gianluigi
Publication year - 2019
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.14113
Subject(s) - medicine , hepatocellular carcinoma , gastroenterology , sorafenib , neutropenia , adverse effect , bilirubin , toxicity
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.