Table of Contents
- About Datamonitor
- About the Oncology pharmaceutical analysis team
- CHAPTER 1 EXECUTIVE SUMMARY
- Datamonitor insight into the renal cell cancer market
- Significant rise in disease incidence without clear risk factors
- RCC is dominated by clear cell subtype where prognosis remains poor
for advanced disease
- Current treatment options are limited
- High unmet needs require new treatment approaches
- Significant market impact of the major newcomers
- Further pipeline products emerging
- CHAPTER 2 DISEASE OVERVIEW
- Renal cell carcinomas account for 85% of renal tumors
- RCC: a heterogenous group of renal tubular diseases
- RCC subtype can determine prognosis and treatment paradigm
- There are at least five hereditary syndromes linked to RCC
- Clear-cell RCC pathophysiology is thought to involve overexpression of
hypoxia-related genes
- Spontaneous remission in RCC is believed to have an immunological basis,
forming the rationale for immunotherapy
- RCC subtypes possess their own distinctive epidemiological profile
- A wide range of risk factors are linked to RCC
- RCC is relatively asymptomatic, making early diagnosis difficult
- Up to 40% of RCC cancer diagnoses are as a result of incidental findings
- The TNM staging system is extensively used for RCC
- The prognosis of metastatic RCC is very poor
- Tumor stage, nuclear grade and performance status currently provide the
most reliable prognostic information
- Molecular markers are set to revolutionize RCC staging and
prognostication
- CHAPTER 3 CURRENT TREATMENT CONTROVERSIES
- Stage I-III RCCs follow similar treatment paradigms
- RCC treatment approaches are individualized
- Surgery remains the standard treatment of early-stage RCC
- Radical nephrectomy remains the treatment of choice for RCC greater
than T1
- Nephron-sparing surgery is appropriate for tumors smaller than 4cm
in size
- RN offers a survival advantage in RCC patients with lesions greater
than T1
- Laparoscopic nephrectomy: an emerging advance in the surgical
treatment of RCC
- Transarterial embolization can aid nephrectomies
- Radiofrequency ablation is effective as surgery at four years in RCCs
smaller than 5cm
- External beam radiotherapy is used to provide symptomatic relief only
- Cytoxic chemotherapy: conflicting advice is creating confusion
- Immunotherapy: the standard systemic treatment of metastatic RCC is
poorly tolerated
- Chiron's Proleukin (aldesleukin) is the sole FDA-approved drug for
metastatic RCC
- High-dose IL-2 monotherapy is associated with significant toxicity,
cost and low response rates
- High-dose IL-2 offers no survival advantage over low-dose IL-2
- The addition of GM-CSF to LD IL-2 may interfere with the latter's
therapeutic potential and increase adverse effects
- Subcutaneous administration may improve the toxicity profile of IL-2
- INF-alfa improves RCC survival in small number of RCC patients
- INF-alfa monotherapy overall response rate is just 15%
- IFN-alfa has fewer adverse effects than IL-2, although they can be
dose limiting
- Pegylated INF-alfa decreases dosing frequency but fails to improve
response rate of non-pegylated INF-alfa
- Combination immunotherapy regimens: the recent focus of RCC cytokine
treatment
- INF-alfa and IL-2 in combination improves response rate but fails to
prolong overall survival
- Cytokine/chemotherapy combinations may confer improved clinical
benefit
- Addition of both 5-FU and VBL to cytokines associated with
three-year survival rates of almost 90%
- Adjuvant immuno-chemotherapy fails to improve overall survival or
remission
- Allogeneic peripheral-blood stem-cell transplantation found to improve
patient long-term survival in RCC
- CHAPTER 4 UNMET NEEDS IN RCC
- RCC patients represent a hugely underserved patient pool
- Modest cytokine response provides market opportunity
- High unmet need means that any incremental survival benefit including
disease stabilization would be welcomed by prescribers
- The toxicity of cytokines renders a large majority of RCC patients
unsuitable for treatment
- Lack of adjuvant therapy provides huge market opportunity
- Stage III patients are an ideal target for novel therapeutics
- Non-clear cell RCC subtypes must be the focus of future therapies
- With the emergence of novel targeted treatments, the optimal role and
duration of cytokine treatment needs greater definition
- CHAPTER 5 MARKET IMPACT OF THE MAJOR NEWCOMERS
- EMEA approval of Bayer/Onyx's Nexavar (sorafenib) is pending
- Nexavar: a novel orally active multi-kinase inhibitor
- Phase III study reveals that Nexavar doubles progression-free survival
to 24 weeks
- Nexavar's Phase II results also demonstrate improved progression-free
survival at 24 weeks
- The randomized discontinuation trial: a novel, innovative Phase II
design
- Nexavar's randomized discontinuation trial design considered
appropriate by interviewed physicians
- Nexavar could be used in chronic RCC management thanks to disease
stabilization capabilities
- Physicians regard Nexavar's toxicity profile as acceptable
- There are a number of ongoing Nexavar clinical trials
- Pfizer's Sutent (sunitinib) is hot on the heels of Nexavar
- Development is ongoing in a variety of tumors due to wide
applicability of use
- Phase III RCC Sutent trial is ongoing at over 100 sites worldwide
- Phase II studies show second-line Sutent delays disease progression by
8.7 months
- Sutent has an acceptable toxicity profile, with most adverse effects
mild in nature
- Patient reported outcomes study reports Sutent leads to reversible
fatigue
- Sutent's intended dosing regimen may lead to patient relapse
- Further Phase II trials investigating Sutent in RCC are ongoing
- Expert RCC physicians view Sutent's objective response rate superior to
Nexavar's
- Physicians percieve Sutent and Nexavar to have different toxicity
profiles
- Differentiating between Sutent and Nexavar provides a challenge to
physicians due to the absence of Phase III data for the former
- Genentech/Roche's Avastin (bevacizumab): the first VEGF inhibitor to
receive FDA approval for cancer
- Avastin in combination with INF-alfa is under Phase III RCC
investigation
- Phase II monotherapy study shows Avastin improves progression-free
survival to 4.8 months
- Initial Phase II study sugget that the addition of
Genentech/Roche/OSI's Tarceva (erlotinib) to Avastin may improve survival
- Preliminary results from a second Phase II Avastin/Tarceva trial
appear to contradict initial promise of the combination approach
- The addition of Novartis's Gleevec (imatinib) to Avastin/Tarceva is in
ongoing Phase II studies
- Seven additional Avastin clinical trials are currently recruiting
metastatic RCC patients
- Pfizer's AG-013736 is placed on hold for RCC development
- AG-013736 shows substantial antitumor activity in cytokine-refractory
metastatic RCC
- Summary of clinical trial data for the four major potential newcomers
- Datamonitor assessment of the major four newcomers' RCC market impact
- Availability of Phase III survival data for Nexavar gives Bayer/Onxy a
distinct advantage
- CHAPTER 6 THE RCC PIPELINE IS BUSY
- Review of Phase III RCC pipeline drugs
- Antigenics' Oncophage (vitespen; HSPCC-96) 'personalized' vaccine
- HSP: a unique technology that stimulates the immune system
- Oncophage's production may limit its target patient population
- Nephrectomized patients to receive Oncophage within eight weeks of
surgery
- Oncophage Phase III trial is the largest adjuvant RCC and
'personalized' treatment clinical trial to date but is behind schedule
- Phase II results demonstrate Oncophage leads to 18 weeks PFS
- Regulatory, manufacturing and economic challenges cloud the path to
commercialization
- Wilex AG/Esteve SA's Rencarex (WX-G250)
- Phase III clinical trials target adjuvant non-metastatic RCC patients
- Phase II Rencarex data shows improvement in median survial to 15
months
- Lack of Phase II data in the adjuvant setting raises questions
regarding Phase III design
- Wyeth's Temsirolimus (CCI-779)
- Phase III data is expected during 2006
- Phase II trials
- The focus of poor-risk patients in the Phase III trial raises
concerns
- CHAPTER 7 KEY OPINION LEADER TRANSCRIPTS
- Contributing experts
- Opinion leader 1
- Opinion leader 2
- Opinion leader 3
- Opinion leader 4
- Opinion leader 5
- APPENDIX A
- Forecasts for pipeline drugs
- Datamonitor drug assessment methodology
- APPENDIX B
- Bibliography
- List of tables
- List of figures
- ABOUT DATAMONITOR
- About Datamonitor Healthcare
- Datamonitor Healthcare's research and analysis methodologies
- Datamonitor Healthcare's therapy area capabilities
- About the Oncology analysis team
- List of Tables
- Table 1: Heidelberg classification of RCC
- Table 2: Crude incidence rates of kidney cancer by gender (per
100,000) in the seven major markets, 2005
- Table 3: Kidney cancer (types C64-C66 & C68) incidence forecast in
the seven major markets, 2005-15
- Table 4: RCC incidence forecast in the seven major markets, 2005-15
- Table 5: RCC subtype incidence in the seven major markets, 2005-15
- Table 6: AJCC TNM classification of RCC
- Table 7: % of RCC patients by TNM stage
- Table 8: Decision box to determine the appropriate risk category of
patients with RCC
- Table 9: Estimated disease specific survival rates according to risk
group in patients with localized disease
- Table 10: Patient responses to high dose, low dose and s.c IL-2
- Table 11: Grade III/IV toxicities of high dose, low dose and s.c IL-2
- Table 12: Bolus IL-2 /GM-CSF versus c.i.v IL-2/GM-CSF: response rates
- Table 13: s.c IL-2 versus i.v IL-2: response rates
- Table 14: Summary of clinical trial results of PEG INF-alfa
- Table 15: IL-2/INF-alfa combination versus IL-2 or INF-alone: response
rate
- Table 16: Summary of cytokine chemotherapy results
- Table 17: Nexavar TARGETs Phase III trial results: objective responses
by independent review data
- Table 18: Nexavar Phase I/II studies recruiting patients, Dec 2005
- Table 19: Sutent Phase II studies recruiting patients, Dec 2005
- Table 20: Avastin Phase I/II studies recruiting patients, Dec 2005
- Table 21: Summary of completed clinical trial results for the four
major RCC newcomers
- Table 22: Forecast revenue ($m) of the major four market newcomers in
the seven major markets
- Table 23: Forecast methodology assumptions
- Table 24: Commercial/clinical success of the major four newcomers
- Table 25: Commercial and clinical attractiveness score summary of the
four major newcomers
- Table 26: Overview of RCC pipeline, Dec 2005
- Table 27: Ongoing Phase III and II RCC clinical trials, Dec 2005
- Table 28: Temsirolimus Phase II results according to WHO criteria
- Table 29: MSKCC Prognostication system for advanced RCC patients
- Table 30: Datamonitor drug assessment parameters
- List of Figures
- Figure 1: Proposed RCC pathophysiology
- Figure 2: Kidney cancer incidence in the seven major markets, 2005-15
- Figure 3: RCC incidence forecast in the seven major markets, 2005-15
- Figure 4: RCC subtype incidence in the seven major markets, 2005-15
- Figure 5: NCCN guidelines for the treatment of kidney cancer
- Figure 6: Mechanism of action of the four major market newcomers
- Figure 7: Nexavar TARGETs Phase III trial results: progression-free
survival benefit
- Figure 8: Nexavar TARGETs Phase III trial results: progression-free
survival across patient subgroups
- Figure 9: Nexavar TARGETs Phase III trial results: maximum % reduction
in tumor measurement
- Figure 10: Nexavar Phase II RDT: treatment schema and patient outcome
- Figure 11: Incorporation of Nexavar into the management of RCC
- Figure 12: ECOG Phase II randomized trial: proposed study schema
- Figure 13: Forecast revenue of the major four market newcomers in the
seven major markets
- Figure 14: Commercial/clinical attractiveness of the major four
newcomers
- Figure 15: The manufacture of Oncophage
- Figure 16: Rencarex's mechanism of action
- Figure 17: Rencarex Phase II results: median survival
- Figure 18: Rencarex Phase II results: overall median survival
- Figure 19: Example of Datamonitor drug assessment scorecard
- Figure 20: Example of Datamonitor drug assessment graph
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