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