2015 American Society of Clinical Oncology Annual Meeting:

Phase 3 Study, S-1 Demonstrates Potential to Improve Overall Survival in Sorafenib-Refractory 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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