SAN FRANCISCO—LY2157299 monohydrate, a novel transforming growth factor-beta 1 (TGF-β1) receptor kinase inhibitor, showed promising efficacy results in patients with advanced hepatocellular carcinoma (HCC) with tumors that overexpress alpha-fetoprotein (AFP), according to results of a phase 2 study presented at the 2014 Gastrointestinal Cancers Symposium.

In moderate to poorly differentiated tumors that overexpress AFP, TGF-β signaling is associated with HCC progression, noted Sandrine J. Faivre, MD, PhD, of Beaujon University Hospital in Clichy, France, and colleagues.

The study enrolled 109 patients with advanced HCC who had progressed on or were ineligible to receive sorafenib, had received no more than one prior systemic regimen, and had AFP levels ≥ 1.5 x ULN. Patients were randomly assigned to receive LY2157299 monohydrate, administered 14 days on/off (28 days = one cycle) in doses of either 160 mg/day (Arm A; n=37) or 300 mg/day (Arm B; n=72).

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In Arm A, median age was 61 years; 97% had Child-Pugh A etiology; 30% hepatitis C, 27% hepatitis B, and 24% alcohol etiology; 78% had received prior sorafenib; and 57% had AFP levels greater than 400 ng/mL. In Arm B, median age was 63 years; 88% had Child-Pugh A etiology; 38% hepatitis C, 24% hepatitis B, and 25% alcohol etiology; 83% had received prior sorafenib; and 53% had AFP levels greater than 400 ng/mL.

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Median time to progression, one of two co-primary endpoints, was 12 weeks (90% CI: 6.6-12.6 weeks) in the overall population, 12.1 weeks in Arm A, and 10.0 weeks in Arm B. In patients who were sorafenib-naïve, time to progression was 18.3 weeks (90% CI: 6.6-42.4 weeks); time to progression was also higher in the non-alcohol compared with alcohol-only etiology group (median, 12.1 vs. 6.1 weeks).

The other co-primary endpoint was biomarker changes (eg, serum AFP, TGF-β, and E-cadherin) for each dose, with AFP responders defined as a greater than 20% decline from baseline. The study found an AFP decline of greater than 20% in 24% of patients.

Based on the latest interim data, median overall survival (OS) was 36 weeks. When examined by AFP response, median OS was 93.1 weeks in responders versus 29.6 weeks in nonresponders (log rank P = 0.0006.

The most common grade 3/4 adverse events (AEs) were neutropenia (three patients), fatigue (two patients), and anemia (three patients); four patients discontinued treatment due to AEs. Preliminary pharmacokinetic (PK) analysis demonstrated moderate inter-patient exposure variability (42%).

Based on the manageable toxicity profile, evidence for biomarker responses, and analysis of aggregate PK/pharmacodynamic, the 300 mg/day dose was selected for future studies in HCC, Dr. Faivre concluded.

The 2014 Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association (AGA) Institute, the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Surgical Oncology (SSO).


  1. Faivre SJ, Santoro A, Kelley RK, et al. Abstract LBA173. Presented at: 2014 Gastrointestinal Cancers Symposium. Jan. 16-18, 2014; San Francisco.