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Introduction

The close association with hepatitis means that hepatocellular carcinoma (HCC) is common in developing countries where hepatitis B and C infections are endemic. However, the increasing prevalence of hepatitis in the West means that incidence of HCC in the US and Europe is expected to increase significantly over the coming years.

Scope

Overview of hepatocellular carcinoma, including epidemiology, staging, prognosis and unmet needs Review of current treatment modalities and physician opinion of existing and future treatment strategies Evaluation of key drugs currently used in the treatment of hepatocellular carcinoma Review of late-phase drugs in development for hepatocellular carcinoma including key opinion leaders' view on their potential

Highlights

Typically a disease of the developing countries, incidence of HCC is increasing in the West due to increasing cases of hepatitis infection, thus representing a revenue opportunity for pharmaceutical and biotechnology companies with targeted therapies. HCC patients are poorly served by existing treatment options, with only a small proportion amenable to curative therapy such as surgical resection and liver transplantation. Prognosis is poor for unresectable patients, and there remains no standard drug therapy for advanced HCC. Given the lack of standard of care, R&D interest in HCC is relatively high, with 37 compounds in clinical development. The majority consist of targeted therapies, with Bayer-Schering/Onyx's Nexavar, Genentech/Roche's Avastin and OSI/Genentech/Roche's Tarceva considered to have the highest clinical and commercial potential.

Reasons to Purchase

Evaluate opportunities and risks in the HCC market by analyzing the clinical and commercial potential of key pipeline drugs Review critical factors that drive the HCC market to assess the potential of existing and pipeline drugs for the disease Understand current and future competitive dynamics of HCC to determine the attractiveness of the market

ABOUT DATAMONITOR HEALTHCARE 2
About the Oncology pharmaceutical analysis team 2
Andrew Paramore - Oncology Lead Analyst & Head of Product Development 2
CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of analysis 3
Datamonitor insight into the hepatocellular carcinoma market 4
CHAPTER 2 HCC OVERVIEW 9
Liver function 9
The damaged liver and its implications 10
Hepatocellular carcinoma 11
Epidemiology 11
Increasing incidence in the West 12
Poor prognosis but improving 14
Risk factors 15
Increasing hepatitis infection attributed to rising HCC incidence 15
Hepatitis B infection 16
Hepatitis C infection 18
Liver cirrhosis is a major risk factor for HCC 20
Aflatoxin exposure increases HCC risk 20
Diagnosis and screening 20
Diagnostic criteria 21
Diagnostic procedures 22
Biopsy 22
Ultrasound 22
Computerized tomography 22
Magnetic resonance imaging 22
Angiography 23
Alpha-fetoprotein 23
Staging 23
AJCC TNM staging system 24
Child-Pugh classification 25
Okuda staging system 25
The Cancer of the Liver Italian Program (CLIP) 26
BCLC classification 27
CHAPTER 3 CURRENT TREATMENT OPTIONS 29
Introduction 29
Treatment modalities 30
Surgical resection remains the mainstay of treatment for HCC 30
Liver transplantation is an option for patients with localized disease 32
Radiofrequency ablation may be as effective as surgery in selected patient cohorts 35
Opportunity for immunotherapy? 38
Use of percutaneous ethanol injection remains marginal 38
High complication rate of cryosurgery may limit its applicability 39
Transcatheter arterial chemoembolization (TACE) offers a survival improvement 40
Randomized study will be required to fully define role of hepatic arterial pumps 43
CHAPTER 4 CHEMOTHERAPY REGIMENS IN UNRESECTABLE HCC 44
Introduction 44
Compromised liver function may restrict use of chemotherapy 45
Single agents used in the management of HCC offer limited benefit 45
Doxorubicin 46
Doxil/Caelyx/Myocet (pegylated liposomal doxorubicin - Ortho Biotech/Schering-Plough/Cephalon/Sopherion) 47
Cisplatin 47
Gemzar (gemcitabine - Eli Lilly) 48
Xeloda (capecitabine - Roche) 48
Epirubicin 49
Tamoxifen 49
Intron A/Roferon A (interferon-alpha - Schering-Plough/Roche) 50
Combination regimens fail to demonstrate any significant efficacy advantage 51
Cisplatin and doxorubicin 52
Cisplatin, interferon-alpha, doxorubicin and 5-FU (PIAF) 53
Cisplatin, doxorubicin and Xeloda 54
Cisplatin and Gemzar 54
Cisplatin, epirubicin, UFT and leucovorin 54
Cisplatin, mitoxantrone and 5-FU 54
Gemzar and oxaliplatin 55
Liposomal doxorubicin plus Gemzar 55
Liposomal doxorubicin plus Xeloda or Gemzar 55
Interferon combinations 56
CHAPTER 5 UNMET NEEDS 57
Unmet needs 57
Curbing the increasing incidence of HCC 57
Lack of effective treatment 57
Poor clinical trial designs 58
Relatively modest R&D interest 58
CHAPTER 6 HCC PIPELINE ANALYSIS 60
Pipeline drugs for HCC 60
Pipeline drugs by phase 62
Pipeline drugs by drug class 63
Pipeline drugs by phase and drug class 64
Pipeline drugs in Phase III development 64
Talaporfin (LS11) - Light Sciences Oncology 64
Minimal toxicity is the key for talaporfin 65
Nexavar (sorafenib) - Onyx Pharmaceuticals /Bayer Schering 66
Phase III trial results indicate a 44% overall survival benefit associated with Nexavar 67
Phase II trial suggests Nexavar's potential to significantly improve median survival offered by doxorubicin 68
Ongoing Phase II combination trial will give better indication of Nexavar's worth 68
Nexavar does not have overlapping toxicities with doxorubicin 68
First-to-market status and collaboration will ensure Nexavar is the leading multi-kinase inhibitor in HCC 69
Thado (thalidomide) - TTY BioPharm 69
Phase II trial results do not support the use of thalidomide in HCC 70
Additional Phase II trial does not support use of thalidomide in HCC 71
Response in some patients may be due to etiology 71
Thalidomide unlikely to make its mark on the HCC market 72
AMT-2003 - Auron Healthcare 73
Dearth of data for AMT-2003 73
Key pipeline drugs in Phase II development 73
Avastin (bevacizumab) - Genentech/Roche/Chugai 73
Erbitux (cetuximab) - ImClone/Bristol-Myers Squibb/Merck Serono 75
Tarceva (erlotinib) - OSI Pharmaceuticals/Genentech/Roche/Chugai 77
Iressa (gefitinib) - AstraZeneca 78
Recentin (AZD2171/cediranib) - AstraZeneca 80
Velcade (bortezomib) - Millennium Pharmaceuticals/Ortho Biotech 80
Tykerb/Tycerb (lapatinib) - GlaxoSmithKline 81
Sutent (sunitinib) - Pfizer 82
APPENDIX 87
Contributing experts 87
UN Population Data 87
Bibliography 88
List of tables 106
List of figures 107
About Datamonitor 108
About Datamonitor Healthcare 108
About the Oncology analysis team 109
Disclaimer 110
List of Tables
Table 1: Incidence of HCC in the seven major markets, 2007-2016 13
Table 2: Prevalence of HBV in various areas worldwide 17
Table 3: AJCC TNM staging for liver tumors (including intrahepatic bile ducts) 24
Table 4: Child-Pugh classification 25
Table 5: Okuda staging system 26
Table 6: CLIP scoring for HCC 27
Table 7: Barcelona Clinic Liver Cancer classification 28
Table 8: Reported outcomes of surgical resection for HCC 32
Table 9: Improvement in five-year survival rates in HCC patients undergoing liver transplantation 33
Table 10: Comparison of RFA and surgical resection in terms of recurrence rates and overall survival 36
Table 11: Comparison of RFA in HCC patients with Child-Pugh class A and class B 37
Table 12: Arterial embolization or chemoembolization compared to systemic treatment for HCC 41
Table 13: Summary results of commonly used cytotoxic monotherapy in first-line unresectable HCC 45
Table 14: Summary results of commonly used cytotoxic combinations in first-line unresectable HCC 51
Table 15: Combining doxorubicin with cisplatin does not increase response rate 53
Table 16: Drugs in clinical development for HCC, 2007 60
Table 17: Ongoing clinical trials of Avastin in HCC 74
Table 18: Results of Phase II studies for unresectable HCC, 2007 84
Table 19: UN Population Data, 2002-2016 87
List of Figures
Figure 1: Liver anatomy 9
Figure 2: Incidence of HCC in the seven major markets, 2007-2016 13
Figure 3: Five-year survival rates for liver and intrahepatic bile duct cancer, 1975-1998 14
Figure 4: Association between HBV/HCV prevalence and HCC incidence 16
Figure 5: HCV disease progression leading to HCC 19
Figure 6: Treatment algorithm for HCC 30
Figure 7: Summary results of commonly used cytotoxic monotherapy in first-line unresectable HCC 46
Figure 8: Summary results of commonly used cytotoxic combinations in first-line unresectable HCC 52
Figure 9: Pipeline drugs for HCC by phase, 2007 62
Figure 10: Pipeline drugs for HCC by class, 2007 63
Figure 11: Pipeline drugs for HCC by phase and class, 2007 64
Figure 12: Results of Phase II studies for unresectable HCC, 2007 85