Report: Optimizing Targeted Treatment in Cancer: Negotiating the Challenges to Success TOC

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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