Elsevier

The Lancet Oncology

Volume 10, Issue 1, January 2009, Pages 25-34
The Lancet Oncology

Fast track — Articles
Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S1470-2045(08)70285-7Get rights and content

Summary

Background

Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma.

Methods

Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752.

Findings

271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6·5 months (95% CI 5·56–7·56) in patients treated with sorafenib, compared with 4·2 months (3·75–5·46) in those who received placebo (hazard ratio [HR] 0·68 [95% CI 0·50–0·93]; p=0·014). Median TTP was 2·8 months (2·63–3·58) in the sorafenib group compared with 1·4 months (1·35–1·55) in the placebo group (HR 0·57 [0·42–0·79]; p=0·0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10·7%]), diarrhoea (nine patients [6·0%]), and fatigue (five patients [3·4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11·4%]) and diarrhoea (11 patients [7·4%]); these adverse events rarely led to discontinuation.

Interpretation

Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.

Funding

Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc.

Introduction

Hepatocellular carcinoma is the third most common cause of cancer mortality worldwide.1, 2 More than 75% of cases occur in the Asia-Pacific region, largely in association with chronic hepatitis B virus (HBV) infection.3, 4 More than 50% of cases of hepatocellular carcinoma occur in China alone, and an estimated 360 000 patients residing in east Asian countries, including China, Japan, Korea, and Taiwan, die from this disease each year.1, 2 Therefore, it is especially important to assess the efficacy and safety of new agents for hepatocellular carcinoma in these high-risk populations.

Surgical resection leads to a 60–70% 5-year survival for patients with hepatocellular carcinoma who present with solitary tumours and have excellent liver function. However, because most patients present with intermediate or advanced disease, surgical resection is only an option for less than 20% of patients.5 The findings of a meta-analysis6 of treatments used in randomised, controlled clinical trials, done before the availability of sorafenib, showed that a systemic therapy to improve survival is still needed. In fact, no systemic therapies in the meta-analysis were shown to confer a survival advantage over best supportive care.6 Unfortunately, few patients from the Asia-Pacific region present with early-stage disease.7

The aetiological factors of hepatocellular carcinoma vary by geographical region.8 Hepatitis virus infection is a significant risk factor in the Asia-Pacific region, with about 70% of patients with hepatocellular carcinoma presenting with chronic HBV infection and 20% presenting with chronic hepatitis C virus (HCV) infection. These rates are roughly reversed for European, North American, and Japanese patients;8 although Japan is geographically part of the Asia-Pacific region, HCV-related hepatocellular carcinoma represents about 75% of all cases of hepatocellular carcinoma.9 Because of the high prevalence of hepatocellular carcinoma in Asia, there is an urgent need for a systemic treatment that can extend survival. Currently, treatment options for patients in the Asia-Pacific region are limited, with practice guidelines recommending resection, ablation, chemoembolisation, radiotherapy, or chemotherapy, depending on liver function and tumour burden.10, 11 The prognosis of patients from the Asia-Pacific region is frequently worse than for those from other parts of the world, such as North America or Europe.12, 13, 14

Sorafenib is an oral multikinase inhibitor with antiproliferative and antiangiogenic effects. It has been shown to inhibit the activity of the serine/threonine kinases c-Raf (Raf-1) and B-Raf; the mitogen-activated protein kinases MEK and ERK; vascular endothelial growth factor receptors (VEGFR)-1, 2, and 3; platelet-derived growth factor receptors (PDGFR)-α and β; the cytokine receptor c-KIT; the receptor tyrosine kinases Flt-3 and RET; and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway.15, 16, 17, 18, 19 The intracellular signalling pathway Raf/MEK/ERK20, 21 and the extracellular receptors VEGFR and PDGFR22, 23, 24 have been implicated in the pathogenesis of hepatocellular carcinoma.

In the multicentre, double-blind, randomised phase III Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) study,25 sorafenib was shown to be efficacious and well-tolerated in patients with advanced hepatocellular carcinoma. Patients with advanced hepatocellular carcinoma who had not received previous systemic therapy were randomly assigned to placebo (n=303) or sorafenib 400 mg twice a day (n=299). The SHARP study mainly recruited patients from North America and Europe. The primary endpoints of the study were overall survival and time to symptomatic progression (TTSP), with secondary endpoints including time to radiological progression (TTP) and safety. The baseline aetiological factors for hepatocellular carcinoma in the SHARP trial reflected the geographical patient pool, and included HCV (29% vs 27%), alcohol-associated liver disease only (26% vs 26%), and HBV (19% vs 18%) for the sorafenib and placebo groups, respectively. Median overall survival was significantly longer in the sorafenib group (10·7 months [range 9·4–13·3]) than in the placebo group (7·9 months [6·8–9·1]; hazard ratio [HR] 0·69 [95% CI 0·55–0·87]; p<0·001), but median TTSP did not differ significantly between the study groups (4·1 months [3·5–4·8] vs 4·9 months [4·2–6·3]; HR 1·08 [0·88–1·31]; p=0·77). Median TTP was significantly longer in the sorafenib group (5·5 months [4·1–6·9]) than in the placebo group (2·8 months [2·7–3·9]; HR 0·58 [0·45–0·74]; p<0·001). The most common drug-related adverse events for all grades of severity in the sorafenib and placebo groups, respectively, included diarrhoea (39% [116 of 297] vs 11% [34 of 302]), fatigue (22% [64 of 297] vs 16% [47 of 302]), hand–foot skin reaction (HFSR; 21% [63 of 297] vs 3% [8 of 302]), and rash or desquamation (16% [47 of 297] vs 11% [34 of 302]).25

The SHARP study was designed for regulatory approval of sorafenib in the USA, Europe, and other geographical regions; subsequent to this study, sorafenib was approved for the treatment of unresectable hepatocellular carcinoma by the US Food and Drug Administration and for the treatment of hepatocellular carcinoma by the European Medicines Agency. To achieve regulatory approval in China, however, it was necessary to undertake a parallel study of sorafenib in about 200 patients from the Asia-Pacific region, the findings of which are reported here. In designing this study, we chose a 2:1 drug-to-placebo randomisation method to maximise the number of patients exposed to drug, but still providing a placebo comparator to confirm the efficacy of sorafenib in this population. By doing both the Asia-Pacific study and the SHARP study in parallel, a unique opportunity was presented to assess the efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma in different geographical regions and with varying underlying aetiological factors.

Section snippets

Patients

Patients at least 18 years old with advanced (unresectable or metastatic) hepatocellular carcinoma who had not received previous systemic therapy were eligible for this trial. Eligibility criteria also included histologically or cytologically proven hepatocellular carcinoma; Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1, or 2; Child-Pugh liver function class A;26 and a life expectancy of at least 12 weeks. Patients were required to have adequate renal, haematological,

Results

Between Sept 20, 2005, and Jan 31, 2007, 271 patients from China, South Korea, and Taiwan were enrolled and randomised in the study. Of the eligible patients, 226 were randomly assigned to receive either sorafenib (n=150) or placebo (n=76) and were included in the intention-to-treat population (figure 1).

The sorafenib and placebo groups were well balanced with regard to baseline demographic and disease characteristics (table 1). Most patients in both groups had ECOG PS 1 and extrahepatic

Discussion

The objective of this study was to assess the efficacy and safety of sorafenib in Asia-Pacific patients with advanced hepatocellular carcinoma. Although there was no primary endpoint for this trial, patients who were randomised to treatment with sorafenib had significantly longer overall survival than did those who received placebo. Additionally, sorafenib significantly prolonged TTP and improved DCR compared with placebo. No difference in the median TTSP, however, was detected between the

References (40)

  • M Makuuchi et al.

    Clinical practice guidelines for hepatocellular carcinoma: the first evidence based guidelines from Japan

    World J Gastroenterol

    (2006)
  • JW Park

    [Practice guideline for diagnosis and treatment of hepatocellular carcinoma]

    Korean J Hepatol

    (2004)
  • JM Llovet et al.

    Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials

    Hepatology

    (1999)
  • YP Yeung et al.

    Natural history of untreated nonsurgical hepatocellular carcinoma

    Am J Gastroenterol

    (2005)
  • A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators

    Hepatology

    (1998)
  • MA Avila et al.

    New therapies for hepatocellular carcinoma

    Oncogene

    (2006)
  • A de La Coste et al.

    Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas

    Proc Natl Acad Sci USA

    (1998)
  • F Carlomagno et al.

    BAY 43-9006 inhibition of oncogenic RET mutants

    J Natl Cancer Inst

    (2006)
  • S Wilhelm et al.

    Discovery and development of sorafenib: a multikinase inhibitor for treating cancer

    Nat Rev Drug Discov

    (2006)
  • H Huynh et al.

    Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis

    BMC Gastroenterol

    (2003)
  • Cited by (4950)

    • Precision Oncology in Hepatopancreatobiliary Cancer Surgery

      2024, Surgical Oncology Clinics of North America
    View all citing articles on Scopus
    View full text