肝細胞癌：新興治療方法

Abstract

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.

• 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

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.

• 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

Table of Contents

• About the Oncology pharmaceutical analysis team
  • Andrew Paramore - Oncology Lead Analyst & Head of Product Development

Chapter 1 EXECUTIVE SUMMARY

• Scope of analysis
• Datamonitor insight into the hepatocellular carcinoma market

Chapter 2 HCC OVERVIEW

• Liver function
  • The damaged liver and its implications
• Hepatocellular carcinoma
• Epidemiology
  • Increasing incidence in the West
• Poor prognosis but improving
• Risk factors
  • Increasing hepatitis infection attributed to rising HCC incidence
    • Hepatitis B infection
    • Hepatitis C infection
  • Liver cirrhosis is a major risk factor for HCC
  • Aflatoxin exposure increases HCC risk
• Diagnosis and screening
  • Diagnostic criteria
  • Diagnostic procedures
    • Biopsy
    • Ultrasound
    • Computerized tomography
    • Magnetic resonance imaging
    • Angiography
    • Alpha-fetoprotein
• Staging
  • AJCC TNM staging system
  • Child-Pugh classification
  • Okuda staging system
  • The Cancer of the Liver Italian Program (CLIP)
  • BCLC classification

Chapter 3 CURRENT TREATMENT OPTIONS

• Introduction
• Treatment modalities
  • Surgical resection remains the mainstay of treatment for HCC
  • Liver transplantation is an option for patients with localized disease
  • Radiofrequency ablation may be as effective as surgery in selected patient cohorts
    • Opportunity for immunotherapy?
  • Use of percutaneous ethanol injection remains marginal
  • High complication rate of cryosurgery may limit its applicability
  • Transcatheter arterial chemoembolization (TACE) offers a survival improvement
  • Randomized study will be required to fully define role of hepatic arterial pumps

Chapter 4 CHEMOTHERAPY REGIMENS IN UNRESECTABLE HCC

• Introduction
• Compromised liver function may restrict use of chemotherapy
  • Single agents used in the management of HCC offer limited benefit
    • Doxorubicin
    • Doxil/Caelyx/Myocet (pegylated liposomal doxorubicin - Ortho Biotech/Schering-Plough/Cephalon/Sopherion)
    • Cisplatin
    • Gemzar (gemcitabine - Eli Lilly)
    • Xeloda (capecitabine - Roche)
    • Epirubicin
    • Tamoxifen
    • Intron A/Roferon A (interferon-alpha - Schering-Plough/Roche)
  • Combination regimens fail to demonstrate any significant efficacy advantage
  • Cisplatin and doxorubicin
  • Cisplatin, interferon-alpha, doxorubicin and 5-FU (PIAF)
  • Cisplatin, doxorubicin and Xeloda
  • Cisplatin and Gemzar
  • Cisplatin, epirubicin, UFT and leucovorin
  • Cisplatin, mitoxantrone and 5-FU
  • Gemzar and oxaliplatin
  • Liposomal doxorubicin plus Gemzar
  • Liposomal doxorubicin plus Xeloda or Gemzar
  • Interferon combinations

Chapter 5 UNMET NEEDS

• Unmet needs
  • Curbing the increasing incidence of HCC
  • Lack of effective treatment
  • Poor clinical trial designs
  • Relatively modest R&D interest

Chapter 6 HCC PIPELINE ANALYSIS

• Pipeline drugs for HCC
  • Pipeline drugs by phase
  • Pipeline drugs by drug class
  • Pipeline drugs by phase and drug class
• Pipeline drugs in Phase III development
  • Talaporfin (LS11) - Light Sciences Oncology
    • Minimal toxicity is the key for talaporfin
  • Nexavar (sorafenib) - Onyx Pharmaceuticals /Bayer Schering
    • Phase III trial results indicate a 44% overall survival benefit associated with Nexavar
    • Phase II trial suggests Nexavar' s potential to significantly improve median survival offered by doxorubicin
    • Ongoing Phase II combination trial will give better indication of Nexavar' s worth
    • Nexavar does not have overlapping toxicities with doxorubicin
    • First-to-market status and collaboration will ensure Nexavar is the leading multi-kinase inhibitor in HCC
  • Thado (thalidomide) - TTY BioPharm
    • Phase II trial results do not support the use of thalidomide in HCC
    • Additional Phase II trial does not support use of thalidomide in HCC
    • Response in some patients may be due to etiology
    • Thalidomide unlikely to make its mark on the HCC market
  • AMT-2003 - Auron Healthcare
    • Dearth of data for AMT-2003
• Key pipeline drugs in Phase II development
  • Avastin (bevacizumab) - Genentech/Roche/Chugai
  • Erbitux (cetuximab) - ImClone/Bristol-Myers Squibb/Merck Serono
  • Tarceva (erlotinib) - OSI Pharmaceuticals/Genentech/Roche/Chugai
  • Iressa (gefitinib) - AstraZeneca
  • Recentin (AZD2171/cediranib) - AstraZeneca
  • Velcade (bortezomib) - Millennium Pharmaceuticals/Ortho Biotech
  • Tykerb/Tycerb (lapatinib) - GlaxoSmithKline
  • Sutent (sunitinib) - Pfizer

• Contributing experts
• UN Population Data
• Bibliography
• List of tables
• List of figures
• About Datamonitor
  • About Datamonitor Healthcare
  • About the Oncology analysis team
  • Disclaimer

• Table 1: Incidence of HCC in the seven major markets, 2007-2016
• Table 2: Prevalence of HBV in various areas worldwide
• Table 3: AJCC TNM staging for liver tumors (including intrahepatic bile ducts)
• Table 4: Child-Pugh classification
• Table 5: Okuda staging system
• Table 6: CLIP scoring for HCC
• Table 7: Barcelona Clinic Liver Cancer classification
• Table 8: Reported outcomes of surgical resection for HCC
• Table 9: Improvement in five-year survival rates in HCC patients undergoing liver transplantation
• Table 10: Comparison of RFA and surgical resection in terms of recurrence rates and overall survival
• Table 11: Comparison of RFA in HCC patients with Child-Pugh class A and class B
• Table 12: Arterial embolization or chemoembolization compared to systemic treatment for HCC
• Table 13: Summary results of commonly used cytotoxic monotherapy in first-line unresectable HCC
• Table 14: Summary results of commonly used cytotoxic combinations in first-line unresectable HCC
• Table 15: Combining doxorubicin with cisplatin does not increase response rate
• Table 16: Drugs in clinical development for HCC, 2007
• Table 17: Ongoing clinical trials of Avastin in HCC
• Table 18: Results of Phase II studies for unresectable HCC, 2007
• Table 19: UN Population Data, 2002-2016

• Figure 1: Liver anatomy
• Figure 2: Incidence of HCC in the seven major markets, 2007-2016
• Figure 3: Five-year survival rates for liver and intrahepatic bile duct cancer, 1975-1998
• Figure 4: Association between HBV/HCV prevalence and HCC incidence
• Figure 5: HCV disease progression leading to HCC
• Figure 6: Treatment algorithm for HCC
• Figure 7: Summary results of commonly used cytotoxic monotherapy in first-line unresectable HCC
• Figure 8: Summary results of commonly used cytotoxic combinations in first-line unresectable HCC
• Figure 9: Pipeline drugs for HCC by phase, 2007
• Figure 10: Pipeline drugs for HCC by class, 2007
• Figure 11: Pipeline drugs for HCC by phase and class, 2007
• Figure 12: Results of Phase II studies for unresectable HCC, 2007