Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: Subset analyses of the phase III Sorafenib Asia–Pacific trial

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Abstract

Background

The phase III Sorafenib Asia–Pacific (AP) trial—conducted in China, Taiwan and South Korea – confirmed that sorafenib improves overall survival (OS) and is safe for patients with advanced hepatocellular carcinoma (HCC). We performed a series of exploratory subset analyses to determine whether baseline status affected response to sorafenib.

Methods

In the Sorafenib AP trial, 226 patients with well-preserved liver function (>95% Child-Pugh A) were randomised 2:1 to sorafenib 400 mg bid or matching placebo. Subanalyses were based on aetiology (hepatitis B virus present/absent); tumour burden (macroscopic vascular invasion and/or extrahepatic spread present/absent); presence or absence of either lung or lymph node metastasis at baseline, Eastern Cooperative Oncology Group performance status (0, 1–2); serum concentrations of alanine aminotransferase/aspartate aminotransferase (normal, mildly elevated, moderately elevated), alpha-fetoprotein (normal/elevated) and total bilirubin (normal/elevated); and whether or not there was a history of hepatectomy or transarterial chemoembolisation/embolisation. Subgroup assessments included OS, time to progression (TTP), disease control rate and safety.

Findings

Sorafenib consistently improved both median OS and median TTP, compared with placebo (range of hazard ratios (HR), 0.32–0.87 and 0.31–0.75, respectively). The most common grade 3/4 adverse events were hand-foot skin reaction, diarrhoea and fatigue, the incidence of which was similar between subgroups.

Interpretation

The efficacy and safety profiles of sorafenib in the subpopulations described were comparable with those in the overall study population. These exploratory analyses suggest that sorafenib is effective for patients from the AP region with advanced HCC, irrespective of baseline status.

Introduction

Globally, hepatocellular carcinoma (HCC) is the sixth most common cancer, with over 700,000 newly diagnosed patients per year,1 at least three-quarters of whom are from the Asia–Pacific (AP) region.2 In geographic areas in which hepatitis B virus (HBV) is endemic or hyperendemic, such as the AP region, HBV infection and resultant liver cirrhosis are responsible for up to 90% of HCC cases.3 Despite advances in medical and surgical oncology and transplantation medicine, most patients who present with advanced HCC do not live beyond 12 months.1 Hence, there is a need for systemic therapies that improve survival rates.

Sorafenib is an oral inhibitor of multiple protein kinases, including c-Raf, B-Raf, mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase (ERK) and vascular endothelial growth factor (VEGF), as well as platelet-derived growth factor (PDGF) receptors, c-kit and effectors in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway; it therefore exerts antiproliferative, antiapoptotic and antiangiogenic effects.4, 5 Sorafenib targets the key signalling cascades involved in hepatocarcinogenesis, including those mediated by Raf/MEK/ERK, VEGF receptors and PDGF receptors.6, 7, 8, 9, 10, 11 The phase III, randomised, double-blind, placebo-controlled Sorafenib HCC Assessment Randomised Protocol (SHARP) trial evaluated the efficacy and safety of sorafenib 400 mg twice daily in patients with advanced HCC, most of whom were from North America and Europe, had a Child-Pugh designation of class A and had not received previous systemic therapy.12 Sorafenib significantly enhanced median overall survival (OS; 10.7 versus 7.9 months; P < 0.001) and median time to progression (TTP; 5.5 versus 2.8 months; P < 0.001), compared with placebo. Subgroup analyses of the SHARP trial demonstrated the activity of sorafenib in patients with hepatitis C virus (HCV)-related HCC; patients with HCC who failed prior curative treatment (resection, local ablation, percutaneous ethanol injection and radiofrequency ablation); those treated previously with transarterial chemoembolisation/embolisation (TACE/TAE); those with and without macrovascular invasion (MVI) and/or extrahepatic spread (EHS); those with or without lung or lymph node metastasis at baseline; patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1–2; patients with normal, mildly elevated and moderately elevated serum concentrations of alanine aminotransferase (ALT)/aspartate aminotransferase (AST); and patients with normal and elevated serum alpha-fetoprotein (AFP) and total bilirubin concentrations.12, 13, 14, 15, 16, 17, 18

We conducted a second multinational, randomised controlled, phase III trial – the Sorafenib AP trial – which evaluated the efficacy and safety of sorafenib in patients with advanced HCC from the AP region.19 Sorafenib therapy enhanced median OS (6.5 versus 4.2 months; P = 0.014) and TTP (2.8 months versus 1.4; P = 0.0005), compared with placebo. Patient demographic and clinical characteristics at baseline can affect responses to therapy. We therefore performed a series of exploratory subgroup analyses of data from the Sorafenib AP trial to determine whether baseline patient and tumour characteristics affected the efficacy and safety of sorafenib. Because the study was not powered for this analysis of subgroups, full statistical testing was not performed and hazard ratios and 95% confidence intervals (CI) were reported only.

Section snippets

Study design

The design of the Sorafenib AP trial has been reported.19 Briefly, patients ⩾18 years of age with advanced (unresectable or metastatic) HCC, well-preserved liver function (>95% Child-Pugh class A), ECOG PS of 0–2, no history of systemic therapy and life expectancy ⩾12 weeks were randomised 2:1 to sorafenib 400 mg or matching placebo twice daily and treated in 6-week cycles.

For subset analyses of baseline characteristics, the 226 patients in the AP trial (sorafenib 150, placebo 76) were categorised

Demographics

A total of 226 patients from China (n = 152), Taiwan (n = 43) and South Korea (n = 31) were randomised in the Sorafenib AP trial and were included in the subanalyses. Baseline demographic and clinical characteristics of patient subsets are shown in Table 2, Table 3. The treatment groups were generally well balanced for demographic and baseline characteristics.

Subanalysis by aetiology

Two subsets were included in the analysis of aetiology (Fig. 1): patients positive for anti-HBV antibody or HBV surface antigen (n = 165) and

Discussion

We have assessed the effects of baseline patient characteristics on the outcome of sorafenib treatment in patients with advanced HCC from the AP region. Overall, patients in the AP trial had more advanced disease and a higher prevalence of chronic HBV infection than patients in the SHARP trial; patient outcomes, however, were similar, in that median OS and TTP were significantly longer with sorafenib than with placebo in the overall AP cohort. Our subgroup analyses indicate that the

Conclusion

Sorafenib is effective for the treatment of advanced HCC in patients from the AP region, irrespective of baseline ECOG PS, MVI/EHS, HBV status, ALT/AST/AFP/bilirubin concentrations, or previous therapy. The efficacy and safety profiles of sorafenib in the subpopulations described were comparable to those in the overall study population. The results of the subset analyses of the AP trial support the broad utility of sorafenib across a variety of prognostic classes in patients with advanced HCC.

Author contributions

Dr. Ann-Lii Cheng was the Principal Investigator of the AP study and was involved with the study concept and design; acquisition of data; analysis and interpretation of primary and subset data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis and study supervision.

Drs. Zhongzhen Guan, Zhendong Chen, Chao-Jung Tsao, Shukui Qin, Jun Suk Kim, Tsai-Sheng Yang, Won Young Tak, Hongming Pan, Shiying Yu, Jianming Xu and Yoon-Koo

Clinical trial

ClinicalTrials.gov Identifier NCT00492752.

Conflict of interest statement

Ann-Lii Cheng has had a consultant/advisory role, has received honoraria and has participated in advisory boards for Bayer Schering Pharma, Pfizer and Merck Serono. Zhongzhen Guan has received honoraria from Bayer HealthCare Pharmaceuticals. Fang Fang, Jessie Zou and Dimitris Voliotis are employed by Bayer HealthCare Pharmaceuticals. Giuseppe Lentini is employed by Bayer Schering Pharma. Yoon-Koo Kang has had a consultant/advisory role, received honoraria, participated in an advisory board and

Acknowledgments

This study was supported by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. Editorial support was provided by John D. Zoidis, MD, Bayer HealthCare Pharmaceuticals, Montville, New Jersey, United States of America (USA), and John A. Ibelli, CMPP, BelMed Professional Resources, New Rochelle, New York, USA.

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    Presented in part in abstract form at: (1) 33rd Congress of the European Society for Medical Oncology (ESMO), Stockholm, Sweden, 12–16th September 2008; (2) American Association for the Study of Liver Diseases (AASLD) 59th Annual Meeting; San Francisco, California, USA, 31st October–4th November 2008; (3) American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, 15–17th January 2009, San Francisco, California, USA; (4) 19th Conference of the Asian Pacific Association for the Study of the Liver (APASL); Hong Kong, China, 13–16th February 2009; (5) European Association for the Study of the Liver (EASL) 44th Annual Conference; Copenhagen, Denmark, 22–26th April 2009; (6) 45th ASCO Annual Meeting; Orlando, Florida, USA, 29th May–2nd June 2009; (7) 5th World Conference on Interventional Oncology (WCIO), Beijing, China, 25–28th June 2009; (8) International Liver Cancer Association (ILCA) Third Annual Congress, Milan, Italy, 4–6th September 2009; (9) Joint 15th Congress of the European Cancer Organisation (ECCO) and 34th ESMO; Berlin, Germany, 20–24th September 2009; (10) AASLD 60th Annual Meeting; Boston, Massachusetts, USA, 30th October–2nd November2009; (11) 19th Conference of the APASL; Beijing, China, 25–28th March 2010; (12) ILCA Fourth Annual Congress, Montreal, Québec, Canada, 10–12th September 2010; (13) 35th Congress of the ESMO, Milan, Italy, 8–12th October 2010.

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