Abstract
Overview
Introduction
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
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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