2015 American Society of Clinical Oncology Annual Meeting:

Potential to Improve Overall Survival in Advanced Hepatocellular Carcinoma

Masatoshi Kudo, MD, PhD, Professor and Chairman, Department of Hepatology and Gastroenterology, Kinki University School of Medicine, Osaka, Japan, reported results of a randomized, double-blind, placebo-controlled phase 3 study of S-1 in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE). Dr. Kudo spoke at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, from May 29–June 2.

Sorafenib-Refractory Advanced Hepatocellular Carcinoma Remains a Challenge
An unmet medical need persists for patients with sorafenib-refractory advanced hepatocellular carcinoma.

S-1 Was Evaluated in Patients with Sorafenib-Refractory Advanced Hepatocellular Carcinoma
The efficacy and safety of S-1 were evaluated in patients with sorafenib-refractory advanced hepatocellular carcinoma.

  • Japanese men and women (age ≥20 years) with Child-Pugh A or B liver function and hepatocellular carcinoma progression with or intolerance to sorafenib were randomized to S-1 or placebo in a 2:1 ratio.
  • S-1 (80, 100, or 120 mg daily) or placebo was administered orally, according to body surface area on days 1–28 of a 42-day cycle until disease progression or unacceptable toxicities occurred.

A total of 334 patients were enrolled (S-1, 223; placebo, 111). Patient characteristics were well-balanced:

  • Median age: 70.0 years
  • Child-Pugh A liver function: 81.0%
  • Vascular invasion: 17.7%
  • Extra hepatic metastasis: 53.8%.

The primary endpoint measured was overall survival. Secondary endpoints included progression-free survival, overall response rate, and safety.

Primary Endpoint of Overall Survival Was Not Met
Median overall survival was 337.5 days with S-1 and 340.0 days with placebo (hazard ratio, 0.86; 0.67 - 1.10; not significant).

Median progression-free survivals were 80 and 42 days, respectively (hazard ratio, 0.60; 0.46 - 0.77; P < .001). Overall response rates were 5.4% and 0.9%, respectively (P = .068).

Subgroup Results Depended on Patient Characteristics
Subgroup analysis of the heterogeneous population with advanced hepatocellular carcinoma showed the efficacy of S-1 for overall survival was different depending on patient characteristics: Child-Pugh liver function, hazard ratio was 0.79 (Child-Pugh A) and 1.19 (Child-Pugh B). Tumor stage hazard ratios were 2.08 (stage 1/2) and 0.79 (stage 3/4).

Adverse Events Were Mild to Moderate
The main adverse events with S-1 were anorexia, fatigue, elevated total bilirubin, and diarrhea. Most adverse events were mild to moderate, and the discontinuation rate due to adverse events was 19.2% with S-1.

Though S-1 did not extend overall survival statistically significantly compared to placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma, the subgroup analysis demonstrated the potential of S-1 to improve overall survival in the clinically important population.

The observed benefit in the terms of progression-free survival and subgroup analysis warrants further investigation.

June 30, 2015

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