Randomized phase III trial of sorafenib versus placebo in patients with advanced hepatocellular carcinoma (HCC)

Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 4, 2007

Presenter: Llovet, J.
Presenter's Affiliation: Mount Sinai School of Medicine, New York, NY
Type of Session: Plenary


  • Hepatocellular carcinoma (HCC) represents the 5th most common cancer across the globe.
  • Over 600,000 new cases are diagnosed each year, 370,000 of which occur in East Asia, 32,000 in Europe, and 19,000 in the United States.
  • No survival advantage has previously been demonstrated with systemic therapy for any disease stage. Patients with early-stage disease may be offered surgical or other localized treatment; however, few treatment options exist for those with advanced-stage disease.
  • HCC tumor progression is felt to be related to reduced cellular apoptosis, vascular endothelial growth factor (VEGF) over-expression, Raf kinase overexpression, and imbalance in MAP kinase signaling.
  • Sorafenib inhibits the VEGF receptor, platelet-derived growth factor (PDGF) receptor, and Raf/MEK/ERK. Through its multi-kinase inhibitor activity, it decreases tumor cell proliferation and angiogenesis.
  • Sorafenib has been shown previously to have anti-tumor activity in HCC in both animal models, and in a phase II clinical trial which demonstrated mean overall survival of 7 months, and mean time to progression of 4.2 months with use of sorafenib.
  • This phase III clinical trial was carried out by the SHARP Investigators Study Group to assess the role of sorafenib in treatment of advanced-stage HCC.

Materials and Methods

  • The trial was designed as a phase III, randomized, placebo-controlled trial, which accrued patients internationally and from multiple centers.
  • Eligible patients had advanced HCC (and were not eligible for localized treatments), had no prior treatment, ECOG performance status of 0-2, Child-Pugh status A, and life expectancy > 12 weeks.
  • Overall survival (OS) and time to symptom progression (TTSP) were co-primary endpoints of the study. Symptom progression was defined as the first symptomatic progression event after randomization, defined as one of the following: Deterioration to ECOG performance status 4, a 4-point decline from baseline in response to the Functional Assessment of Cancer Treatment Hepatobiliary Index (FACT-FHSI-8), or death.
  • The study was designed to randomize 560 patients in order to have 90% power to detect a 40% improvement in OS.
  • Patients were randomized to either sorafenib 400 mg twice daily or placebo.
  • Sorafenib treatment was discontinued in the setting of both radiologic and clinical progression, or in the setting of an adverse event felt to be drug-related.


  • 902 patients were evaluated as study participants, and 602 were deemed eligible for enrollment between March, 2005 and April, 2006. After randomization, 299 patients were randomized to sorafenib, and 308 to placebo. No statistically significant demographic differences were observed between the two groups.
  • Overall survival in the sorafenib group was 46 weeks versus 34 weeks in the placebo group (hazard ratio [HR] 0.69, p = 0.0058), representing a 44% increase in OS with sorafenib when compared with placebo.
  • Time to symptom progression was 24 weeks in the sorafenib group versus 12 weeks in the placebo group (HR 0.58, p < 0.0007), representing a 73% increase in TTSP with sorafenib as compared to placebo.
  • In comparison of the sorafenib group to the placebo group, stabilization of disease (SD) was observed in 71% (211) of patients in the sorafenib group and 68% (204) patients in the placebo group. Partial disease response (PR), defined as at least 50% reduction in tumor burden, was observed in 2.3% (7) of patients in the sorafenib group, and 0.7% (2) patients in the placebo group. Complete response (CR) was not observed in any patient within either treatment group.
  • No statistically significant difference in toxicity (nausea, vomiting, diarrhea, neutropenia) was observed between the two groups.

Author's Conclusions

  • Sorafenib, a multi-kinase inhibitor, prolonged both OS and TTSP in this population of patients with advanced-stage HCC. Both of these findings were highly statistically significant.
  • Sorafenib is well-tolerated, with minimal side-effects beyond placebo.
  • Based on these data, sorafenib represents the first known effective systemic therapy for HCC.

Clinical/Scientific Implications

  • The risk of development of HCC is closely related to incidence of hepatitis B and/ or C, as well as chronic liver disease. In developed countries, many cases of HCC are preventable with hepatitis B vaccination at birth and population-based risk education; still, HCC remains a major global health issue.
  • The course of HCC is generally aggressive, and, thus far, no effective therapy has been identified for patients with advanced-stage disease. Patients with early-stage disease may be offered loco-regional treatments such as surgical resection followed by liver transplantation, radioablation treatment, proton therapy, or trans-arterial chemoembolization (TACE). Even when loco-regional treatments are available, however, they come with significant toxicity and risk, and are many times not effective. To this end, identification of effective systemic agents for this disease may benefit all HCC patients.
  • This trial shows a clear benefit on sorafenib for patients with advanced-stage HCC. From this data, the drug appears effective and well-tolerated, supporting its use in the clinical setting. Further trials investigating the efficacy of sorafenib for patients with early-stage disease may be warranted.