A phase 2 study of a novel transforming growth factor-beta (TGF-β1) receptor I kinase inhibitor, LY2157299 monohydrate (LY), in patients with advanced hepatocellular carcinoma (HCC).

Abstract

LBA173 Background: TGF-β signaling is associated with HCC progression in moderate to poorly differentiated tumors overexpressing alpha-fetoprotein (AFP) levels. We report here the safety, antitumor activity, and overall survival (OS) in HCC patients with elevated AFP treated with LY. Methods: Patients with advanced HCC who progressed on sorafenib (SF) or are ineligible to receive SF, advanced Child-Pugh A/B7 HCC, AFP ≥1.5x ULN, ECOG PS ≤1, measurable disease (RECIST 1.1), and ≤1 prior systemic regimen were eligible. LY was administered as intermittent dosing of 14 days on/off (28 days=1 cycle). Patients were randomized to either 160 mg/day (Arm A) or 300 mg/day (Arm B) LY. Primary endpoints were time-to-progression (TTP) and biomarker changes (serum AFP, TGF-β and E-cadherin) for each dose. AFP responders were defined as >20% decline from baseline. Secondary endpoints included toxicity (CTCAE, V 4.0) and pharmacokinetics (PK). Available data from interims are presented. Results: 109 patients were enrolled (Arm A=37; B=72). Baseline characteristics were (Arm A/B): median age 61/63 years; PS=0, 60%/53%; Child-Pugh A 97%/88%; etiology: hepatitis C 30%/38%, hepatitis B 27%/24%, alcohol 24%/25%. Overall, 78%/83% of patients had received prior SF; 57%/53% had AFP >400 ng/mL. Median TTP was 12.0 weeks (90% CI: 6.6, 12.6) in the overall population (Arm A/B, 12.1/10.0 weeks). In SF-naive patients, TTP was 18.3 weeks (90% CI: 6.6-42.4). TTP was higher in the non-alcohol compared to alcohol-only etiology group (median 12.1 vs. 6.1 weeks). Median baseline serum TGF-β1 was 3.4 ng/mL (range: 1.4-3.7) and E-cadherin was 6.1 mg/mL (range: 1.9-17.3). AFP decline of >20% occurred in 24% of patients. Based on the latest interim, median OS was 36 weeks. In AFP responders, median OS was 93.1 weeks vs 29.6 weeks in non AFP responders (Log Rank p=0.0006). Four patients discontinued treatment due to AEs. Most common grade 3/4 related AEs were: neutropenia (n=3), fatigue (n=2), and anemia (n=3). Preliminary PK analysis (n=51) demonstrated moderate interpatient exposure variability (42%). Conclusions: Based on the manageable toxicity profile, the evidence for biomarker responses, analysis of the aggregate PK/PD data, the 300 mg/day dose was chosen for future studies in HCC. Both TTP and overall survival in AFP responding patients is promising.