Renal Cell Carcinoma - Novel Targeted Treatments to Fill the Void

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Publication Date: 2005-12-22

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A meager 20% of metastatic RCC tumors respond to standard cytokine therapy, thus rendering 80% of advanced RCC patients without any effective treatment. Further, with up to 50% of stage one to three patients relapsing following nephrectomy and an increasing incidence of this disease, RCC represents a lucrative commercial opportunity for the developers of novel, effective pharmacotherapy.

Scope

Overview of disease including epidemiology, biology of RCC, staging and prognostic variables

Review of current treatment controversies and physician opinion of existing and future treatment strategies

Examination of unmet needs in RCC treatment and market opportunities for drug developers

Profile of the four major novel molecular targeted therapies including their therapeutic and commercial potential

Report Highlights
The high existing unmet need in the treatment of RCC is reflected by the poor prognosis of patients with advanced stage disease, five- year survival rates with existing cytokine therapy being less than 20% in this patient cohort.

The identification of biomarkers is set to revolutionize patient staging and prognosis by individualizing patient treatments and creating novel drug targets. Establishing the context in which innovative therapeutics are to be integrated into existing practice will dramatically alter RCC treatment paradigms.

Nexavar and Sutent, both indicated for metastatic RCC, look set to compete well to the end of the decade. With Nexavar's first to market advantage and Sutent's purported superior efficacy, revenue margins will lie extremely close. Datamonitor forecasts Nexavar's 2010 revenues will reach $122 million and Sutent's $179 million.

Reasons to Purchase

Assess the impact on the market of the launch of four new RCC drugs, the first new therapeutics for this indication in 10 years

Identify opportunities for individualized patient treatment and novel drug targets

Plan strategic planning and product development, based on an understanding of how novel therapeutics will alter current RCC treatment paradigms

About Datamonitor - page 2
About the Oncology pharmaceutical analysis team - page 2

CHAPTER 1 EXECUTIVE SUMMARY - page 3
- Datamonitor insight into the renal cell cancer market - page 3
  - Significant rise in disease incidence without clear risk factors - page 3
  - RCC is dominated by clear cell subtype where prognosis remains poor for advanced disease - page 4
  - Current treatment options are limited - page 5
  - High unmet needs require new treatment approaches - page 6
  - Significant market impact of the major newcomers - page 8
  - Further pipeline products emerging - page 10
CHAPTER 2 DISEASE OVERVIEW - page 19
- Renal cell carcinomas account for 85% of renal tumors - page 19
- RCC: a heterogenous group of renal tubular diseases - page 19
- RCC subtype can determine prognosis and treatment paradigm - page 21
- There are at least five hereditary syndromes linked to RCC - page 21
- Clear-cell RCC pathophysiology is thought to involve overexpression of hypoxia-related genes - page 21
- Spontaneous remission in RCC is believed to have an immunological basis, forming the rationale for immunotherapy - page 23
- RCC subtypes possess their own distinctive epidemiological profile - page 24
- A wide range of risk factors are linked to RCC - page 29
- RCC is relatively asymptomatic, making early diagnosis difficult - page 31
- Up to 40% of RCC cancer diagnoses are as a result of incidental findings - page 31
- The TNM staging system is extensively used for RCC - page 32
- The prognosis of metastatic RCC is very poor - page 34
- Tumor stage, nuclear grade and performance status currently provide the most reliable prognostic information - page 35
- Molecular markers are set to revolutionize RCC staging and prognostication - page 37
CHAPTER 3 CURRENT TREATMENT CONTROVERSIES - page 39
- Stage I-III RCCs follow similar treatment paradigms - page 39
- RCC treatment approaches are individualized - page 40
  - Surgery remains the standard treatment of early-stage RCC - page 40
    - Radical nephrectomy remains the treatment of choice for RCC greater than T1 - page 40
    - Nephron-sparing surgery is appropriate for tumors smaller than 4cm in size - page 40
    - RN offers a survival advantage in RCC patients with lesions greater than T1 - page 41
    - Laparoscopic nephrectomy: an emerging advance in the surgical treatment of RCC - page 41
  - Transarterial embolization can aid nephrectomies - page 42
  - Radiofrequency ablation is effective as surgery at four years in RCCs smaller than 5cm - page 43
  - External beam radiotherapy is used to provide symptomatic relief only - page 44
  - Cytoxic chemotherapy: conflicting advice is creating confusion - page 45
- Immunotherapy: the standard systemic treatment of metastatic RCC is poorly tolerated - page 45
  - Chiron's Proleukin (aldesleukin) is the sole FDA-approved drug for metastatic RCC - page 46
    - High-dose IL-2 monotherapy is associated with significant toxicity, cost and low response rates - page 46
    - High-dose IL-2 offers no survival advantage over low-dose IL-2 - page 47
    - The addition of GM-CSF to LD IL-2 may interfere with the latter's therapeutic potential and increase adverse effects - page 49
    - Subcutaneous administration may improve the toxicity profile of IL-2 - page 50
  - INF-alfa improves RCC survival in small number of RCC patients - page 51
    - INF-alfa monotherapy overall response rate is just 15% - page 52
    - IFN-alfa has fewer adverse effects than IL-2, although they can be dose limiting - page 52
    - Pegylated INF-alfa decreases dosing frequency but fails to improve response rate of non-pegylated INF-alfa - page 53
  - Combination immunotherapy regimens: the recent focus of RCC cytokine treatment - page 54
    - INF-alfa and IL-2 in combination improves response rate but fails to prolong overall survival - page 54
    - Cytokine/chemotherapy combinations may confer improved clinical benefit - page 56
    - Addition of both 5-FU and VBL to cytokines associated with three-year survival rates of almost 90% - page 58
- Adjuvant immuno-chemotherapy fails to improve overall survival or remission - page 59
- Allogeneic peripheral-blood stem-cell transplantation found to improve patient long-term survival in RCC - page 59
CHAPTER 4 UNMET NEEDS IN RCC - page 61
- RCC patients represent a hugely underserved patient pool - page 61
- Modest cytokine response provides market opportunity - page 61
- High unmet need means that any incremental survival benefit including disease stabilization would be welcomed by prescribers - page 62
- The toxicity of cytokines renders a large majority of RCC patients unsuitable for treatment - page 63
- Lack of adjuvant therapy provides huge market opportunity - page 64
- Stage III patients are an ideal target for novel therapeutics - page 65
- Non-clear cell RCC subtypes must be the focus of future therapies - page 66
- With the emergence of novel targeted treatments, the optimal role and duration of cytokine treatment needs greater definition - page 67
CHAPTER 5 MARKET IMPACT OF THE MAJOR NEWCOMERS - page 69
- EMEA approval of Bayer/Onyx's Nexavar (sorafenib) is pending - page 70
  - Nexavar: a novel orally active multi-kinase inhibitor - page 70
  - Phase III study reveals that Nexavar doubles progression-free survival to 24 weeks - page 70
  - Nexavar's Phase II results also demonstrate improved progression-free survival at 24 weeks - page 75
  - The randomized discontinuation trial: a novel, innovative Phase II design - page 75
  - Nexavar's randomized discontinuation trial design considered appropriate by interviewed physicians - page 76
  - Nexavar could be used in chronic RCC management thanks to disease stabilization capabilities - page 77
  - Physicians regard Nexavar's toxicity profile as acceptable - page 78
  - There are a number of ongoing Nexavar clinical trials - page 79
- Pfizer's Sutent (sunitinib) is hot on the heels of Nexavar - page 80
  - Development is ongoing in a variety of tumors due to wide applicability of use - page 80
  - Phase III RCC Sutent trial is ongoing at over 100 sites worldwide - page 81
  - Phase II studies show second-line Sutent delays disease progression by 8.7 months - page 81
  - Sutent has an acceptable toxicity profile, with most adverse effects mild in nature - page 82
  - Patient reported outcomes study reports Sutent leads to reversible fatigue - page 82
  - Sutent's intended dosing regimen may lead to patient relapse - page 83
  - Further Phase II trials investigating Sutent in RCC are ongoing - page 83
- Expert RCC physicians view Sutent's objective response rate superior to Nexavar's - page 84
- Physicians percieve Sutent and Nexavar to have different toxicity profiles - page 85
- Differentiating between Sutent and Nexavar provides a challenge to physicians due to the absence of Phase III data for the former - page 85
- Genentech/Roche's Avastin (bevacizumab): the first VEGF inhibitor to receive FDA approval for cancer - page 86
  - Avastin in combination with INF-alfa is under Phase III RCC investigation - page 86
  - Phase II monotherapy study shows Avastin improves progression-free survival to 4.8 months - page 87
  - Initial Phase II study sugget that the addition of Genentech/Roche/OSI's Tarceva (erlotinib) to Avastin may improve survival - page 88
  - Preliminary results from a second Phase II Avastin/Tarceva trial appear to contradict initial promise of the combination approach - page 88
  - The addition of Novartis's Gleevec (imatinib) to Avastin/Tarceva is in ongoing Phase II studies - page 90
  - Seven additional Avastin clinical trials are currently recruiting metastatic RCC patients - page 90
- Pfizer's AG-013736 is placed on hold for RCC development - page 91
  - AG-013736 shows substantial antitumor activity in cytokine-refractory metastatic RCC - page 92
- Summary of clinical trial data for the four major potential newcomers - page 93
- Datamonitor assessment of the major four newcomers' RCC market impact - page 94
  - Availability of Phase III survival data for Nexavar gives Bayer/Onxy a distinct advantage - page 94
CHAPTER 6 THE RCC PIPELINE IS BUSY - page 102
- Review of Phase III RCC pipeline drugs - page 108
  - Antigenics' Oncophage (vitespen; HSPCC-96) 'personalized' vaccine - page 108
    - HSP: a unique technology that stimulates the immune system - page 108
    - Oncophage's production may limit its target patient population - page 109
    - Nephrectomized patients to receive Oncophage within eight weeks of surgery - page 109
    - Oncophage Phase III trial is the largest adjuvant RCC and 'personalized' treatment clinical trial to date but is behind schedule - page 110
    - Phase II results demonstrate Oncophage leads to 18 weeks PFS - page 111
    - Regulatory, manufacturing and economic challenges cloud the path to commercialization - page 111
  - Wilex AG/Esteve SA's Rencarex (WX-G250) - page 113
    - Phase III clinical trials target adjuvant non-metastatic RCC patients - page 115
    - Phase II Rencarex data shows improvement in median survial to 15 months - page 115
    - Lack of Phase II data in the adjuvant setting raises questions regarding Phase III design - page 117
  - Wyeth's Temsirolimus (CCI-779) - page 118
    - Phase III data is expected during 2006 - page 119
    - Phase II trials - page 119
    - The focus of poor-risk patients in the Phase III trial raises concerns - page 120
CHAPTER 7 KEY OPINION LEADER TRANSCRIPTS - page 124
- Contributing experts - page 124
  - Opinion leader 1 - page 125
  - Opinion leader 2 - page 137
  - Opinion leader 3 - page 146
  - Opinion leader 4 - page 157
  - Opinion leader 5 - page 167
APPENDIX A - page 176
- Forecasts for pipeline drugs - page 176
- Datamonitor drug assessment methodology - page 176
APPENDIX B - page 180
- Bibliography - page 180
- List of tables - page 194
- List of figures - page 196
- ABOUT DATAMONITOR - page 198
  - About Datamonitor Healthcare - page 198
  - Datamonitor Healthcare's research and analysis methodologies - page 199
  - Datamonitor Healthcare's therapy area capabilities - page 199
  - About the Oncology analysis team - page 200

List of Tables
Table 1: Heidelberg classification of RCC - page 20
Table 2: Crude incidence rates of kidney cancer by gender (per 100,000) in the seven major markets, 2005 - page 25
Table 3: Kidney cancer (types C64-C66 & C68) incidence forecast in the seven major markets, 2005-15 - page 25
Table 4: RCC incidence forecast in the seven major markets, 2005-15 - page 27
Table 5: RCC subtype incidence in the seven major markets, 2005-15 - page 28
Table 6: AJCC TNM classification of RCC - page 33
Table 7: % of RCC patients by TNM stage - page 34
Table 8: Decision box to determine the appropriate risk category of patients with RCC - page 36
Table 9: Estimated disease specific survival rates according to risk group in patients with localized disease - page 36
Table 10: Patient responses to high dose, low dose and s.c IL-2 - page 48
Table 11: Grade III/IV toxicities of high dose, low dose and s.c IL-2 - page 48
Table 12: Bolus IL-2 /GM-CSF versus c.i.v IL-2/GM-CSF: response rates - page 50
Table 13: s.c IL-2 versus i.v IL-2: response rates - page 51
Table 14: Summary of clinical trial results of PEG INF-alfa - page 54
Table 15: IL-2/INF-alfa combination versus IL-2 or INF-alone: response rate - page 55
Table 16: Summary of cytokine chemotherapy results - page 57
Table 17: Nexavar TARGETs Phase III trial results: objective responses by independent review data - page 71
Table 18: Nexavar Phase I/II studies recruiting patients, Dec 2005 - page 79
Table 19: Sutent Phase II studies recruiting patients, Dec 2005 - page 83
Table 20: Avastin Phase I/II studies recruiting patients, Dec 2005 - page 91
Table 21: Summary of completed clinical trial results for the four major RCC newcomers - page 93
Table 22: Forecast revenue ($m) of the major four market newcomers in the seven major markets - page 98
Table 23: Forecast methodology assumptions - page 99
Table 24: Commercial/clinical success of the major four newcomers - page 99
Table 25: Commercial and clinical attractiveness score summary of the four major newcomers - page 100
Table 26: Overview of RCC pipeline, Dec 2005 - page 102
Table 27: Ongoing Phase III and II RCC clinical trials, Dec 2005 - page 105
Table 28: Temsirolimus Phase II results according to WHO criteria - page 120
Table 29: MSKCC Prognostication system for advanced RCC patients - page 121
Table 30: Datamonitor drug assessment parameters - page 177

List of Figures
Figure 1: Proposed RCC pathophysiology - page 23
Figure 2: Kidney cancer incidence in the seven major markets, 2005-15 - page 26
Figure 3: RCC incidence forecast in the seven major markets, 2005-15 - page 27
Figure 4: RCC subtype incidence in the seven major markets, 2005-15 - page 29
Figure 5: NCCN guidelines for the treatment of kidney cancer - page 39
Figure 6: Mechanism of action of the four major market newcomers - page 69
Figure 7: Nexavar TARGETs Phase III trial results: progression-free survival benefit - page 72
Figure 8: Nexavar TARGETs Phase III trial results: progression-free survival across patient subgroups - page 73
Figure 9: Nexavar TARGETs Phase III trial results: maximum % reduction in tumor measurement - page 74
Figure 10: Nexavar Phase II RDT: treatment schema and patient outcome - page 77
Figure 11: Incorporation of Nexavar into the management of RCC - page 78
Figure 12: ECOG Phase II randomized trial: proposed study schema - page 80
Figure 13: Forecast revenue of the major four market newcomers in the seven major markets - page 98
Figure 14: Commercial/clinical attractiveness of the major four newcomers - page 100
Figure 15: The manufacture of Oncophage - page 110
Figure 16: Rencarex's mechanism of action - page 115
Figure 17: Rencarex Phase II results: median survival - page 116
Figure 18: Rencarex Phase II results: overall median survival - page 117
Figure 19: Example of Datamonitor drug assessment scorecard - page 178
Figure 20: Example of Datamonitor drug assessment graph - page 179

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Renal Cell Carcinoma - Novel Targeted Treatments to Fill the Void

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