Stakeholder Opinions: Bladder Cancer - New drugs needed to challenge ineffective 20-year old drugs

Stakeholder Opinions: Bladder Cancer - New drugs needed to challenge ineffective 20-year old drugs
ABOUT DATAMONITOR HEALTHCARE 2

About the Oncology pharmaceutical analysis team 2

CHAPTER 1 EXECUTIVE SUMMARY 3

Scope of analysis 3

Datamonitor insight into the bladder cancer market 3

Related reports 4

Upcoming reports 4

CHAPTER 2 DISEASE OVERVIEW 6

Introduction 6

Disease overview 6

Insufficient treatment options for advanced stages of disease 6

The recurring nature of non-invasive tumors leads to a great economic burden 6

Anatomy of the bladder 7

Bladder cancer 8

Definition 8

Pathology/histology 8

Transitional cell carcinoma is the most common cancer type in developed countries 9

Squamous cell carcinoma accounts for 75% of bladder tumors in developing countries 9

Adenocarcinoma is common in patients with exstrophy 10

Uncommon bladder cancer types 10

Clinical classifications 11

Epidemiology 11

Aging population contributes to rising incidence rates 11

Rising mortality rates highlight the need for better treatment options 13

Risk factors 15

Older age 15

Active and passive smokers are more likely to develop bladder cancer 15

Chemical industry employees are at greater risk 16

Medical risk factors and prior cyclophosphamide-based chemotherapy increases chances of developing bladder cancer 16

Urinary tract infections are directly related to invasive SCC 16

Greater incidence in men than women 16

Ethnicity and geographical location affect prognosis and risk of developing disease 17

Genetic factors also affect the chances of developing bladder cancer 17

Symptoms 18

All cases of hematuria should be investigated for bladder cancer 18

Screening 18

Urinary markers have not been embraced for bladder cancer screening 18

Diagnosis 19

Cystoscopy is the most widely used test for bladder cancer 19

Staging 20

The TNM system is the more descriptive method of staging 20

The World Health Organization (WHO) offers a modified grading system 21

75% of tumors are non-invasive at the time of diagnosis 22

Prognosis and survival 23

High-grade tumors have the worst prognosis as progression is more likely to occur 23

Growth factor receptors may serve as prognostic markers and therapy targets 23

Prevention 24

Lifestyle changes are advised to prevent bladder cancer. 24

CHAPTER 3 CURRENT TREATMENT OPTIONS AND CONTROVERSIES 25

Introduction 25

Treatment guidelines 25

National Comprehensive Cancer Network treatment guidelines 25

Transurethral resection followed by intravesical BCG is the standard treatment for non-invasive tumors and CIS in the US 25

Radical cystectomy is the preferred treatment for continually recurring tumors 27

European treatment guidelines 28

EU clinicians use BCG therapy less than clinicians in the US 28

Japanese treatment guidelines 29

Cystectomy is the main treatment used for bladder cancer in Japan 29

Treatment by stage 30

Non-invasive bladder cancer 30

Recurrence and progression must be prevented by surgery and adjuvant intravesical therapy if long-term survival is to be achieved 30

TURBT is an appropriate primary treatment because it eliminates visible tumors 31

Immunotherapy is preferred to chemotherapy as an adjuvant to TURBT 32

Few options are available for BCG-refractory patients 33

Combination chemotherapy is more effective than single-agent chemotherapy 34

Invasive bladder cancer 36

Cystectomy is the standard therapy for invasive tumors... 36

...however, only 50% of patients will survive past 5 years unless adjuvant chemotherapy is administered 37

Metastatic bladder cancer 39

Bladder-removing surgery remains the best life-saving strategy as adequate treatment has yet to be identified 39

Neoadjuvant chemotherapy is recommended for metastatic tumors 39

Cisplatin-based combination chemotherapy forms the cornerstone of first-line therapy for metastatic bladder cancer 40

Patients with a poor performance history receive radiotherapy 42

Recurrent tumors 42

CHAPTER 4 UNMET NEEDS 43

Introduction 43

Unmet needs 43

No treatment available to prevent recurrent tumors in non-invasive bladder cancer 43

Limited treatment options for patients who are unfit for current treatment options 44

BCG-refractory patients usually fail to respond to chemotherapy 44

Patients who are unfit for cystectomy receive substandard treatment due to a lack of options 45

Metastatic disease treatment is not effective 45

No standard treatment schedule is available for adjuvant therapy with immunotherapy or chemotherapy 46

Better routes of administration than intravesically may lead to longer exposure time and better drug absorption 46

More sensitive detection methods as well as prognostic markers are needed to combat the high cost of follow-up 47

New drugs required for non-urothelial cell tumor treatment 48

Summary of unmet needs 48

CHAPTER 5 PIPELINE ANALYSIS 50

Pipeline overview 50

The bladder cancer pipeline 50

Phase III pipeline 50

Phase II pipeline 51

Targeted therapy strives for a place in the bladder cancer market 52

Phase III drug profiles 52

EOquin (apaziquone; Spectrum Pharmaceuticals) 52

Drug overview 52

Key historical events 53

Clinical development in bladder cancer 53

Datamonitor comments 58

Iressa (gefitinib; AstraZeneca) 58

Drug overview 58

Key historical events 59

Clinical development in bladder cancer 60

Datamonitor comments 62

Urocidin (MCC; Bioniche Life Science) 64

Drug overview 64

Key historical events 64

Clinical development in bladder cancer 64

Datamonitor comments 68

Valstar (valrubicin; Indevus) 69

Drug overview 69

Key historical events 69

Clinical development in bladder cancer 70

Datamonitor comments 70

Larotaxel (XRP9881; Sanofi-Aventis) 71

Drug overview 71

Key historical events 71

Clinical development in bladder cancer 72

Datamonitor comments 73

CHAPTER 6 KEY OPINION LEADER INTERVIEW TRANSCRIPTS 75

Contributing experts 75

Key opinion leader interview transcripts 75

APPENDIX 76

Bibliography 76

List of tables 86

List of figures 87

About Datamonitor 88

About Datamonitor Healthcare 88

About the Oncology analysis team 89

Disclaimer 90

List of Tables

Table 1: Clinical subtypes of bladder cancer 11

Table 2: Crude incidence rates for bladder cancer (per 100,000 persons) in the seven major markets, 2002 12

Table 3: Forecast incidence of bladder cancer in the seven major markets, 2002-2017 12

Table 4: Crude mortality rates for bladder cancer in the seven major markets, 2002 14

Table 5: Risk factors associated with bladder cancer 15

Table 6: Diagnostic tests for bladder cancer 19

Table 7: TNM and Jewett staging systems for primary bladder tumors 20

Table 8: Lymph node classifications in the TNM staging system 21

Table 9: Distant metastasis classification in the TNM staging system 21

Table 10: World Health Organization grading system for non-invasive bladder tumors 22

Table 11: Rate of progression and survival of non-invasive tumors in bladder cancer 23

Table 12: National Comprehensive Cancer Network (NCCN) guidelines for primary bladder cancer treatment in the US, 2008 26

Table 13: National Comprehensive Cancer Network (NCCN) guidelines for recurrent bladder cancer treatment in the US, 2008 28

Table 14: European treatment guidelines for bladder cancer, 2008 28

Table 15: Japanese treatment guidelines for bladder cancer 29

Table 16: Late-phase bladder cancer pipeline, 2008 50

Table 17: Phase II bladder cancer pipeline, 2008 51

Table 18: EOquin: key historical events, 2007-08 53

Table 19: Ongoing clinical trials involving EOquin, 2008 54

Table 20: Iressa: key historical events, 2002-08 59

Table 21: Ongoing clinical trials involving Iressa, 2008 60

Table 22: Cost of TICE BCG and Iressa per week based on price of drugs alone 62

Table 23: Ongoing trials in the metastatic transitional cell carcinoma (TCC) setting 63

Table 24: Urocidin: key historical events, 2006-08 64

Table 25: Ongoing clinical trials involving Urocidin, 2008 65

Table 26: Valstar: key historical events, 1998-2007 69

Table 27: Larotaxel: key historical events, 2004-08 71

Table 28: Ongoing clinical trials involving larotaxel, 2008 72

List of Figures

Figure 1: Anatomy of the bladder 7

Figure 2: Bladder tumor histology and their abundance in the US, 2008 8

Figure 3: Forecast incidence of bladder cancer in the seven major markets, 2002-2017 13

Figure 4: Incidence and mortality of bladder cancer in the seven major markets, 2008 and 2017 14

Figure 5: Stage of bladder cancer at diagnosis 22

Figure 6: Phase III trial demonstrating that GC is less toxic than MVAC in metastatic bladder cancer patients 27

Figure 7: Phase III trial of neoadjuvant MVAC combination therapy in invasive transitional cell carcinoma (TCC) 38

Figure 8: Phase III trial comparing CG and MVAC combination chemotherapy in metastatic bladder cancer 41

Figure 9: Summary of unmet needs in bladder cancer, 2008 49

Figure 10: Phase III study design of EOquin in low-grade papillary tumors 55

Figure 11: Phase II 'marker' tumor trial of EOquin in non-invasive bladder cancer 56

Figure 12: Phase I trial to demonstrate safety of EOquin following surgery 57

Figure 13: Phase III trial of Iressa in patients with high-risk non-invasive transitional cell carcinoma (TCC) 61

Figure 14: Phase III trial of Urocidin monotherapy in BCG-refractory non-invasive transitional cell carcinoma (TCC) 65

Figure 15: Phase II study investigating Urocidin in high-risk non-invasive bladder cancer 66

Figure 16: Phase I/II study of Urocidin monotherapy in patients with carcinoma in situ (CIS) tumors 67

Figure 17: Phase III study design for larotaxel in combination with cisplatin in metastatic transitional cell carcinoma (TCC) 73

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