癌分子目標治療的最適化分析

本報告已在2011年07月19日停止出版。

簡介

目錄

Introduction

Cancer pharmacotherapy is on the cusp of a paradigm shift. The emergence of a richness of targets and developmental agents has resulted from a convergence of scientific advances. However, maximizing the chances of success and optimizing commercial rewards will require developers to mitigate several key scientific, clinical, regulatory and economic obstacles

Scope

• Overview of the clinical and developmental challenges facing players in the oncology sector
• Expert insight into strategies for improving patient selection and optimizing "go and no-go" decisions in progressing late stage clinical development
• Lifecycle management case studies of key targeted therapy agents
• Strategies to overcome pharmacoeconomic challenges hindering the uptake of targeted treatment

Report Highlights

Targeted treatment (TT) will not entirely replace traditional cytotoxic treatment and the latter will continue to form the cornerstone of cancer treatment. However, the co-administration of TT will allow the optimization of cytotoxic doses and so drive the market for both classes over the coming years

Lifecycle management in the era of TT is becoming increasingly more challenging. The key to future success will be intensified efforts to identify responsive patient populations at an earlier stage of the drug development process

Given the mechanistic differences between small molecules and antibodies a logical approach is to combine these two drug classes. While this is an area of active clinical research, key to the success of this economically challenging approach is to identify the best combination of drugs and the patients that will benefit most from treatment

Reasons to Purchase

• Understand clinical and strategic challenges to the commercialization of targeted treatments
• Assess opportunities and risks for the continued development of innovative developmental treatments
• Adopt knowledge from this report to drive strategic planning decisions in oncology drug development

ABOUT DATAMONITOR HEALTHCARE

CHAPTER 1 EXECUTIVE SUMMARY

CHAPTER 2 INTRODUCTION

• A dynamic and challenging oncology market offers significant commercial opportunity
• Growing patient population and significant unmet needs propel innovation in the cancer market
• Cancer epidemiology - an expanding patient base
• Cancer incidence and the aging global population
• Sales growth in the oncology sector will outstrip that in the CV and CNS therapy areas
• Oncology R&D has the most projects in clinical development
• The emergence of targeted treatment heralds a revolution in cancer pharmacotherapy
• MTTs will become an increasingly prominent therapy class
• Clinical, regulatory and economic challenges on the path to commercialization
• Datamonitors Oncology Foresight Seminar provides vehicle for analysts and key opinion leaders to share their perspectives on challenges to commercialization of MTTs

CHAPTER 3 MEETING EXISTING UNMET NEEDS

• Successful management of advanced disease is relatively limited
• Cytotoxic chemotherapy will continue to form the cornerstone of treatment approaches
• Improvements in symptom control, quality of life and, above all, cure rates should be the goals of MTT

CHAPTER 4 OPTIMIZING TREATMENT APPROACHES EMPLOYING MTTS

• Cancer pharmacotherapy is on the cusp of a paradigm shift
• Novartiss Gleevec (imatinib) provides a model for future developmental strategies
• A plethora of molecular targets offered by a greater understanding of signal transduction
• The signal transduction paradox: is less specificity better?
• Angiogenesis inhibitors offer greatest clinical benefit when administered in combination with chemotherapy
• Which targeted therapy class offers the greatest commercial potential?
• Monoclonal antibodies: an unprecedented success story
• Small molecule drugs: tumor shrinkage not consistently translated into improved survival
• Decision to use monotherapy or combinatorial approach is dependent on drug class
• Small molecule EGFR-TKIs have shown limited clinical benefit when administered as monotherapy
• OSI/Genentech/Roches Tarveca provides the only clear demonstration of clinical benefit with EGFR-TKI monotherapy
• Millenniums Velacde provides more of a broad-spectrum approach
• Development of Johnson & Johnsons Zarnestra will benefit from improved patient selection in clinical trials
• High-profile failures in combining small molecules with chemotherapy the result of poor patient selection?
• Clinical activity of MoAbs appears greatest when combined with chemotherapy
• Herceptin is set to revolutionize the treatment of HER-2 overexpressing breast cancer
• Rituxan has demonstrated activity both as monotherapy and in combination approaches with chemotherapy
• Erbitux proves the first example of success in combining a MTT with radiotherapy
• Dilemmas persist regarding the optimiziation of combination approaches employing MTTs
• The emerging richness of targets in oncology
• Combining two unapproved MTTs will raise complex legal issues

CHAPTER 5 INCREASED PATIENT SELECTION AND MARKET SEGMENTATION IN THE ERA OF MTT

• Issues regarding patient selection are now far more complex
• Efficient and accurate assessment of biologically relevant target is often elusive
• Patient selection for Herceptin treatment is the archetype
• Fundamental to pursuing targeted patient selection are pharmacoeconomic considerations
• Improved patient selection: what tumor-specific features can be evaluated?
• Gene amplification, gene expression and somatic mutation can help predict clinical benefit derived from MTT
• Molecular characterization of EGFR correlates to treatment response with EGFR TKIs
• Mutated EGFR requires lower ligand concentrations for activation
• Patient selection for anti-angiogenic therapy

CHAPTER 6 OPTIMIZATION OF GO/NO-GO DECISIONS NECESSARY TO MITIGATE HIGH ATTRITION RATES

• Early development of diagnostic for biologically relevant target is critical
• Proof of concept paradigm shift
• The randomized discontinuation trial: a novel, innovative Phase II design
• Conventially recognized definitions of response need to be re-evaluated in the age of MTT

CHAPTER 7 MTTS TARGETING MULTIPLE ONCOGENIC SIGNALS IS AN AREA OF INTENSE R&D ACTIVITY

• Pfizer and Bayer/Onxy sprint to the finish line in the race to commercialize a multi-targeted TKI
• Renal cell carcinoma particulary susceptible to anti-angiogenic approaches
• Inhibition of multiple mission critical pathways is the key to success
• 17-AAGs anti-tumor activity results from its ability to inhibit the molecular chaperone, HSP-90

CHAPTER 8 MTT AND DRUG RESISTANCE

• De novo resistance to MTTs is almost inevitable
• Using MTTs to overcome chemotherapy resistant clones
• The population-based risk assessment with empiric treatment needs to evolve to a more personalized approach

CHAPTER 9 CHANGING THE PARADIGM: CANCER AS A CHRONIC DISEASE?

• Evolving maintenance therapy to prevent tumor recurrence and improve progression-free survival
• Long-term toxicities following chronic administration of MTTs
• Long-term cardiac toxicity of Herceptin falls within the range of acceptability
• MTTs may have unique toxicity profiles

CHAPTER 10 HOW WILL LIFECYCLE MANAGEMENT STRATEGIES CHANGE WITH THE INTRODUCTION OF TARGETED TREATMENTS?

• Herceptins logical and stepwise approach to indication expansion
• Moving from the metastatic to adjuvant setting requires a tremendous committment of human and financial resources
• Ground-breaking results support clinical benefit of Herceptin in the adjuvant setting
• Ongoing LCM strategy evaluates Herceptin use in combination with antihormonals
• Herceptin: the archetypal approach to LCM for novel MTT?
• Rituxan indication expansion from a niche tumor to the backbone of treatment for B-cell malignancies
• Off-label use in the US responsible for a significant sales growth
• Maintenance therapy indication the next goal for Genentech/Roche
• Rituxan indication expansion into non-malignant disease is unprecedented in the MTT era, but it should not be unique
• Avastin LCM based on data derived from randomized Phase II studies
• Randomized Phase II approach contrasts with that of Novartiss PTK-787 (valatanib)
• Early disappointment from results of Avastin in combination with Xeloda tempered by Horowitz trial data
• Indication expansion beyond CRC into other tumor-types proves fruitful
• Randomized Phase II study demonstrates Avastin activity in NSCLC and mBC

CHAPTER 11 THE PHARMACOECONOMIC CHALLENGE

• Pharamcoeconomic contraints will become increasingly more challenging
• The rising costs of mCRC pharmacotherapy are disproportionate in relation to improvements in survival
• Improved pharmacoeconomic analysis will be required to communicate the value of novel MTTs

CHAPTER 12 APPENDIX

• Research methodology
• Disclaimer
• List of Figures
• Figure 1: Increasing combined incidence for breast, lung, prostate and colorectal cancer with increasing age
• Figure 2: Predicted rise in global population aged 60 years and over
• Figure 3: Global oncology sales, 2002-09
• Figure 4: Focus of R&D by therapy area
• Figure 5: Predicted sales growth by therapy class, 2003-08
• Figure 6: Colorectal cancer developmental agents, 2004
• Figure 7: Unmet needs in cancer
• Figure 8: The targets in signal transduction
• Figure 9: The antiangiogenesis approach
• Figure 10: Monoclonal antibodies in oncology
• Figure 11: Small molecule drugs in oncology
• Figure 12: Monotherapy with small molecule MTTs
• Figure 13: Combination therapy with small molecule MTTs
• Figure 14: Combination treatment with MoAbs, Part I
• Figure 15: Combination treatment with MoAbs, Part II
• Figure 16: Conclusions and persisting dilemmas to novel approaches with MTTs
• Figure 17: The richness of targets in oncology
• Figure 18: Challenges to the development of novel treatment combinations
• Figure 19: Novel MTT combinations in solid tumors
• Figure 20: Patient selection for Herceptin treatment
• Figure 21: Patient selection according to molecular characteristics
• Figure 22: EGFR mutations and response to EGFR-TKIs
• Figure 23: Frequency of EGFR mutations and NSCLC, Part I
• Figure 24: Frequency of EGFR mutations and NSCLC, Part II
• Figure 25: Molecular characteristics of EGFR and response to treatment
• Figure 26: EGFR mutations and response to EGFR-TKIs
• Figure 27: Improved patient selection for anti-angiogenic treatment
• Figure 28: Optimization of go/no go decisions
• Figure 29: The Proof of Concept paradigm shift
• Figure 30: The RDT schematic
• Figure 31: RDT of sorafenib (BAY 43-9006)
• Figure 32: BAY 43-9006 targets both signal transduction and angiogenesis
• Figure 33: Sorafenib (BAY 43-9006) RDT results
• Figure 34: PFS for sorafenib (BAY 43-9006) in the RDT
• Figure 35: Multi-targeted TKIs
• Figure 36: How to treat cancers targeted by multiple genomic aberrations?
• Figure 37: 17-AAG inhibits multiple mission critical pathways
• Figure 38: Resistance to novel MTTs
• Figure 39: Chemotherapy-induced acquired drug resistance
• Figure 40: MTTs and drug resistance
• Figure 41: Changing the paradigm - cancer to become a chromic disease?
• Figure 42: Cardiotoxicity of Herceptin in the adjuvant setting
• Figure 43: LCM for Herceptin
• Figure 44: Herceptin and docetaxel in mBC
• Figure 45: Adjuvant Herceptin in breast cancer
• Figure 46: Adjuvant Herceptin and improvements in DFS
• Figure 47: Adjuvant Herceptin and improvements in OS
• Figure 48: LCM for Rituxan
• Figure 49: Rituxan - GELA trial results
• Figure 50: Rituxan - Mint trial results
• Figure 51: Rituxan in combination with CVP for indolent NHL
• Figure 52: Maintenance Rituxan (MabThera) in indolent NHL
• Figure 53: Avastin in combination with IFL improves OS in mCRC
• Figure 54: Avastin improves survival in first-line treatment of NSCLC
• Figure 55: Avastin improves PFS in first-line treatment of mBC
• Figure 56: Avastin improves OS in first-line treatment of mBC
• Figure 57: LCM of Avastin - future tumor targets
• Figure 58: Improved survival in mCRC
• Figure 59: The cost of mCRC treatment regimens
• Figure 60: Cost evaluation study of rituximab plus MCP in follicular lymphoma
• Figure 61: Conclusions from cost evaluation study of rituximab plus MCP in follicular lymphoma

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