Pipeline Insight: Breast Cancer - Recent approvals increase pressure on pipeline candidates

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the breast cancer market 4
Related reports 5
Upcoming reports 5

CHAPTER 2 PIPELINE OVERVIEW AND DYNAMICS 7
Pipeline overview 7
Products in late-phase development for breast cancer 7
Products in Phase II development for breast cancer 8
Products in Phase I development for breast cancer 13
Pipeline by development phase and therapy class 14
Molecular targeted therapies account for over 50% of all drugs in development for breast cancer 14
Pipeline by indication 17
Most trials of late-phase breast cancer drugs are in the metastatic setting 17
Pipeline by company 19
Biotech and small/mid pharma account for the majority of companies with drugs in clinical development for breast cancer 19
The majority of companies have a single drug in clinical development for breast cancer 19
The top four companies in terms of marketed and pipeline drugs for breast cancer are Novartis, AstraZeneca, Roche and Pfizer 22
Novartis 24
AstraZeneca 26
Pfizer 28
Roche 30
Key metrics 32
Datamonitor pipeline assessment summary 34

CHAPTER 3 BREAST CANCER - MARKET POTENTIAL 36
Definition of breast cancer 36
Anatomy of the breast 36
Histology of breast cancer 37
Segmentation of breast cancer 38
Staging of breast cancer 38
Predictive markers for breast cancer 40
Hormone receptor status used to predict benefit of hormonal therapy 40
HER-2 status is a well-established prognostic factor and is used to make therapeutic choices 41
Gene expression analysis will further subdivide the breast cancer population 42
Epidemiology of breast cancer 43
Incidence of breast cancer in the seven major markets 43
Incidence of female invasive breast cancer will total 455,000 in the seven major markets in 2008 43
Age distribution of breast cancer incidence rates 46
Mortality 47
Female mortality from breast cancer will total 118,000 in the seven major markets in 2008 47
Current breast cancer treatment options 49
Overview of drug therapies approved for breast cancer 50
Cytotoxic therapies, endocrine therapies and molecular targeted therapies form the mainstay of breast cancer drug therapy 50
Treatment options and treatment outcomes by disease stage 53
Early invasive and locally advanced disease is treated with surgery and adjuvant/neoadjuvant therapy 53
Metastatic breast cancer treated with intention of improving quality of life 56
Unmet needs in breast cancer 59
Agents capable of increasing overall survival are needed for metastatic breast cancer 59
More treatment options are needed for hormone receptor-negative and HER-2-negative patients 60
Treatment options for elderly patients are limited by small amount of data 60
More tolerable and more convenient drug therapies are needed 61

CHAPTER 4 R&D APPROACH 63
Classification of pipeline products 63
Cytotoxics 63
Endocrine therapies 64
Molecular targeted therapies 65
Single-target signal transduction inhibitors 66
Angiogenesis inhibitors 66
Apoptosis inducers 66
Cell cycle inhibitors 66
Multi-targeted inhibitors 67
Epigenetic modulators 67
Immunotherapeutic agents 68
Optimizing clinical trial design in breast cancer 68
Patient selection is important for successful development of targeted therapies in breast cancer 68
Clinical trial endpoints in breast cancer 70
Survival: progression-free survival is commonly-used as a primary endpoint for metastatic breast cancer 70

CHAPTER 5 CYTOTOXIC THERAPIES ANALYSIS AND FORECASTS 71
Overview of cytotoxic therapies 71
Pipeline summary 71
Late-phase pipeline of cytotoxic therapies 73
Phase II pipeline of cytotoxic therapies 73
Phase I pipeline of cytotoxic therapies 75
Comparative forecasts 76
Definition of current comparator therapy 77
Taxotere (docetaxel; Sanofi-Aventis) 77
Eribulin (E7389; Eisai) 79
Drug overview 79
Key historical events 79
Clinical development in breast cancer 80
Two Phase III studies are to evaluate eribulin in relapsed locally advanced and metastatic breast cancer 81
Phase II results show some activity and relatively low toxicity in a heavily pretreated refractory breast cancer patient population 82
Datamonitor comments 83
Eribulin will need to demonstrate considerable efficacy or toxicity benefits in the face of strong competition 83
Eisai could benefit from help of company with more experience of the breast cancer market 84
Forecasts to 2017 85
Larotaxel (XRP-9881; Sanofi-Aventis) 87
Drug overview 87
Key historical events 88
Clinical development in breast cancer 88
Phase III trial shows that larotaxel has no superiority over Xeloda in terms of response rate in progressive metastatic breast cancer 89
Larotaxel confers a 19% response rate in taxane-resistant metastatic breast cancer in a Phase II study 90
Earlier Phase II results show larotaxel confers greater activity in taxane non-resistant patients, but at the expense of high toxicity 90
Datamonitor comments 91
Failure to show superiority over Xeloda has dented prospects of larotaxel as a single agent 91
Too early to predict clinical potential of combinations of larotaxel 92
Genericization of taxanes will further limit larotaxel's commercial potential 92

CHAPTER 6 ENDOCRINE THERAPIES ANALYSIS AND FORECASTS 93
Overview of endocrine therapies 93
Pipeline summary 93
Late-phase pipeline of endocrine therapies 93
Phase II pipeline of endocrine therapies 94
Phase I pipeline of endocrine therapies 94
Arzoxifene (LY-353381; Eli Lilly) 95
Drug overview 95
Key historical events 95
Clinical development in breast cancer 95
Arzoxifene has inferior efficacy to tamoxifen in Phase III study 95
Datamonitor comments 97
Disappointing Phase III trial results mean that arzoxifene is unlikely to reach the market as a breast cancer treatment 97

CHAPTER 7 MOLECULAR TARGETED THERAPIES ANALYSIS AND FORECASTS 98
Overview of molecular targeted therapies 98
Pipeline summary 98
Late-phase pipeline of molecular targeted therapies 100
Phase II pipeline of molecular targeted therapies 100
Phase I pipeline of molecular targeted therapies 104
Comparative forecasts 105
Definition of current comparator therapy 107
Herceptin (trastuzumab; Genentech/Roche/Chugai) 107
Armala (pazopanib; GlaxoSmithKline) 109
Drug overview 109
Key historical events 109
Clinical development in breast cancer 110
Phase III study will evaluate combination of Armala and Tykerb as a second-line therapy in HER-2-positive inflammatory breast cancer patients 111
Datamonitor comments 112
Armala could satisfy significant unmet need in inflammatory breast cancer, but this indication has a very limited patient potential 112
Lack of Phase II data makes it difficult to comment on activity of Armala in breast cancer 113
The combination of Armala and Tykerb could be too costly for some healthcare markets 113
Forecasts to 2017 113
Certican (Everolimus, RAD-001; Novartis) 115
Drug overview 115
Key historical events 116
Clinical development in breast cancer 117
Phase III study will evaluate Certican and paclitaxel as one of six regimens in the neoadjuvant setting 120
Combination of Certican and Femara shows promise in the neoadjuvant setting for ER-positive breast cancer 120
Early Phase II data show that Certican has some activity as a single agent in metastatic breast cancer 121
Datamonitor comments 122
Certican will have to significantly improve treatment outcomes in order to ensure uptake in the neoadjuvant setting 122
Limited amount of Phase II data makes it difficult to assess clinical potential of Certican in metastatic breast cancer 123
Novartis's oncology marketing presence and experience of the breast cancer market will increase Certican's chances of success 123
Forecasts to 2017 124
Omnitarg (pertuzumab; Genentech/Roche/Chugai) 126
Drug overview 126
Key historical events 126
Clinical development in breast cancer 127
Phase III study is evaluating the combination of Omnitarg, Herceptin and Taxotere as a first-line treatment for HER-2-positive metastatic breast cancer 128
Phase II study suggests that combination of Herceptin plus Omnitarg has activity in progressive metastatic breast cancer previously treated with Herceptin 128
Omnitarg has limited activity as a single agent in metastatic breast cancer with low HER-2 expression 129
Datamonitor comments 130
Clinical benefit will have to outweigh increased cost of adding Omnitarg to Herceptin 130
Uncertain whether Omnitarg will be developed for HER-2-negative population 131
Forecasts to 2017 132
Sutent (sunitinib; Pfizer) 134
Drug overview 134
Key historical events 134
Clinical development in breast cancer 135
Extensive development program shows Pfizer's bold ambitions for Sutent in the breast cancer market 135
Four ongoing Phase III trials are evaluating Sutent as a treatment for metastatic breast cancer 137
Single-agent Sutent is active in heavily pretreated metastatic breast cancer patients 141
Datamonitor comments 143
Sutent will compete with Avastin in the HER-2-negative metastatic breast cancer population 143
Sutent could have a competitive edge over other small-molecule targeted therapies in the late-phase breast cancer pipeline 144
Forecasts to 2017 145
Axitinib (AG-013736; Pfizer) 148
Drug overview 148
Key historical events 148
Clinical development in breast cancer 148
Randomized Phase II trial suggests combination of axitinib and Taxotere has promising efficacy in metastatic breast cancer 149
Datamonitor comments 150
Axitinib could struggle to compete against Avastin but may have significant potential in subset of patients previously treated with adjuvant therapy 150
Pfizer appears to be prioritizing the development of Sutent over the development of axitinib in breast cancer 150

CHAPTER 8 IMMUNOTHERAPIES AND GENE THERAPIES 151
Overview of Immunotherapies and gene therapies 151
Pipeline summary 151
Phase II pipeline of immunotherapies and gene therapies 151
Phase I pipeline immunotherapies therapies 153

APPENDIX 155
Bibliography 155
List of figures 165
List of abbreviations 166
Methodology 168
Datamonitor forecast methodology 168
Epidemiology forecasts 168
Product forecasts 168
About Datamonitor 171
About Datamonitor Healthcare 171
Datamonitor Healthcare's therapy area capabilities 172
About the Disease Analysis Team 172
Disclaimer 174

List of Tables
Table 1: Late-phase pipeline for breast cancer, 2008 7
Table 2: Phase II pipeline for breast cancer, 2008 8
Table 3: Phase I pipeline for breast cancer, 2008 13
Table 4: Number of pipeline drugs for breast cancer by therapy class and phase of development, 2008 15
Table 5: Treatment settings under investigation in ongoing Phase I-III clinical trials of drugs in late-phase development for breast cancer, 2008 17
Table 6: Companies with three or more drugs in clinical development for breast cancer, 2008 21
Table 7: Novartis's marketed cancer portfolio, 2008 24
Table 8: Novartis's portfolio of marketed and pipeline drugs for breast cancer, 2008 25
Table 9: AstraZeneca's marketed cancer portfolio, 2008 26
Table 10: AstraZeneca's portfolio of marketed and pipeline drugs for breast cancer, 2008 27
Table 11: Pfizer's marketed cancer portfolio, 2008 28
Table 12: Pfizer's portfolio of marketed and pipeline drugs for breast cancer, 2008 29
Table 13: Roche's marketed oncology portfolio, 2008 30
Table 14: Roche's portfolio of marketed and pipeline drugs for breast cancer, 2008 31
Table 15: Late-phase breast cancer products sales forecasts in the seven major markets ($m), 2008-2017 32
Table 16: Crude female invasive breast cancer incidence rates (per 100,000 persons) in the seven major markets, 2002 44
Table 17: Forecast incidence of invasive female breast cancer in the seven major markets, 2002-17 45
Table 18: Crude female breast cancer mortality rates (per 100,000 persons) in the seven major markets, 2002 47
Table 19: Forecast mortality from breast cancer in the seven major markets, 2002 and 2008 48
Table 20: Approved cytotoxic therapies for breast cancer in the seven major markets, March 2008 51
Table 21: Approved endocrine therapies for breast cancer in the seven major markets, March 2008 52
Table 22: Approved molecular targeted therapies for breast cancer in the seven major markets, March 2008 53
Table 23: Summary of treatment outcomes for adjuvant drug regimens in Stage I-III breast cancer 55
Table 24: Summary of treatment outcomes for neoadjuvant drug regimens in Stage I-III breast cancer 56
Table 25: Summary of treatment outcomes for drug regimens in Stage IV breast cancer 57
Table 26: Late-phase pipeline cytotoxic therapies in breast cancer, 2008 73
Table 27: Phase II pipeline cytotoxic therapies in breast cancer, 2008 73
Table 28: Phase I pipeline cytotoxic therapies in breast cancer, 2008 75
Table 29: Forecasting assumptions for late-phase cytotoxic therapies in the seven major pharmaceutical markets, 2008 76
Table 30: Taxotere: key facts 78
Table 31: Eribulin: key historical events 79
Table 32: Ongoing clinical trials involving eribulin in breast cancer, 2008 80
Table 33: Eisai's oncology portfolio, 2008 85
Table 34: Forecasting assumptions for Eribulin in the seven major pharmaceutical markets, 2008 (1 of 2) 85
Table 35: Forecasting assumptions for Eribulin in the seven major pharmaceutical markets, 2008 (2 of 2) 86
Table 36: Eribulin sales forecast for third-line therapy in locally recurrent and metastatic breast cancer in the seven major pharmaceutical markets ($m), 2008-2017 86
Table 37: Larotaxel: key historical events 88
Table 38: Ongoing clinical trials involving larotaxel in breast cancer, 2008 89
Table 39: Late-phase endocrine therapies in breast cancer, 2008 93
Table 40: Phase II endocrine therapies in breast cancer, 2008 94
Table 41: Phase I endocrine therapies in breast cancer, 2008 94
Table 42: Arzoxifene: Key historical events 95
Table 43: Late-phase molecular targeted therapies in breast cancer, 2008 100
Table 44: Phase II molecular targeted therapies in breast cancer, 2008 100
Table 45: Phase I molecular targeted therapies in breast cancer, 2008 104
Table 46: Forecasting assumptions for MTTs in the seven major pharmaceutical markets, 2008 (1 of 2) 105
Table 47: Forecasting assumptions for MTTs in the seven major pharmaceutical markets, 2008 (2 of 2) 106
Table 48: Herceptin: key facts 108
Table 49: Armala: Key historical events 109
Table 50: Ongoing clinical trials involving Armala in breast cancer, 2008 110
Table 51: Forecasting assumptions for Armala in the seven major pharmaceutical markets, 2008 (1 of 2) 113
Table 52: Forecasting assumptions for Armala in the seven major pharmaceutical markets, 2008 (2 of 2) 114
Table 53: Armala sales forecast in second-line, HER-2-positive inflammatory breast cancer in the seven major pharmaceutical markets ($m), 2008-2017 114
Table 54: Certican: Key historical events 116
Table 55: Ongoing clinical trials involving Certican in breast cancer, 2008 117
Table 56: Forecasting assumptions for Certican in the seven major pharmaceutical markets, 2008 (1 of 2) 124