Stakeholder Opinions: Renal Cell Carcinoma - Novel Targeted Treatments to Fill the Void

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