Stakeholder Opinions: Melanoma

Content

• Chapter 1 Executive Summary
  • Datamonitor insight into the melanoma market
• Chapter 2 Disease Overview
  • Melanoma comprises just 5% of all skin cancers, but it is the most deadly
  • The skin has a role of functions, including protection against solar ultraviolet damage
  • Melanoma: a disease of melanocytes which have accumulated genetic defects
  • Four major subtypes of melanoma exist although they do not affect treatment decisions
  • Lentigo maligna melanoma (LMM) is associated with the elderly
  • Superficial spreading melanoma (SSM) is the commonest subtype of melanoma
  • Nodular melanoma (NM) is characterised by rapid growth
  • Acral-lentiginous melanoma (ALM) may be related to delayed diagnosis
  • The pathogenesis of melanoma is believed to involve defective cell cycle regulation
  • The incidence of melanoma continues to rise
  • A range of risk factors are associated with the development of melanoma
  • Excessive exposure to sunlight and severe sunburn is thought to be a major contributing factor for cutaneous melanoma
  • Although evidence finds that sun-beds emit harmful UV radiation, their use is increasing in the young
  • More research is required to determine a safe method to obtain the protective effects of vitamin D
  • The presence of nevi (moles) is associated with increased risk of developing melanoma
  • Individuals with fair hair, a pale complexion and freckling are at the greatest risk of developing melanoma
  • Melanocortin-1 receptor (MC1R) alleles may be linked with melanoma
  • Hereditary factors and family history accounts for 10% of all melanomas
  • Half of all melanomas are found in those aged over 50 years
  • Due to increased sun exposure, males are twice as likely to develop melanoma than women
  • Xeroderma pigmentosum is an inherited autosomal recessive disorder which renders individuals more susceptible to UV radiation
  • A melanoma risk model is available for US patients that could aid clinical trial recruitment
  • Symptoms of melanoma are typically linked with changes in the apperance of nevi
  • The use of sunscreen is inadequate
  • Screening is low among high-risk patients
  • As diagnosis of melanoma is usually made histologically, it is vital that the thickness of the tumor is accurately determined
  • Melanoma biomakers could improve screening, diagnosis and treatment of the disease
  • A number of staging systems exist for melanoma
  • The prognosis of stage IV melanoma is poor
  • Relapse among melanoma patients is common
• Chapter 3 Current Treatment Controversies
  • Melanoma treatment paradigms are tailored to suit individual patient needs
  • NCCN guidelines recommened clinical trials as a systemic therapy
  • Surgery forms the cornerstone of therapy for stage I–III melanoma
  • narrow versus wide excision margins: debate still continues as to which should be employed
  • Mohs's micrographic surgery is suitable for facial in situ melanomas
  • Lymph node dissection is only appropriate for stage III melanoma patients
  • The use of surgery at stage IV disease is extremely limited and serves only pallitative purposes
  • Radiotherapy is generally ineffective for melanoma
  • Radiotherapy resistance may be linked with DOPAchrome tautomerase (DCT) enzyme expression
  • Chemotherapeutic agents have limited activity in metastatic melanoma
  • Dacarbazine (Bayer's DTIC-Dome, now genericized) was FDA approved over thirty years ago, but it is still the most active agent within metastatic melanoma
  • Schering Plough's Temodar (temozolomide) is used off-label for melanoma that has metastasized to the brain
  • Isolated limb perfusion may be used to deliver chemotherapy to a specific extremity
  • Immunotherapy plays a significant role in the treatment of melanoma in the US market
  • Schering-Plough's Intron-A (interferon alpha-2b) is currently the only FDA-approved treatment for adjuvant melanoma
  • Pegylated INF-alpha monotherapy appears not to improve upon standard INF-alpha's efficacy or toxicity profile...
  • ...however, pegylated INF-alpha in combination with Temodar shows promise
  • Chiron's Proleukin (aldesleukin) was the last agent to gain FDA approval for metastatic melanoma in 1998
  • Combinational systemic therapy has been intensively investigated
  • The future role of biochemotherapy within melanoma is unclear
  • Use of systemic therapeutics across the five major European markets finds interferon dominates early-stage melanoma, while dacarbazine is favored for stage IV patients
• Chapter 4 Unmet Needs In Melanoma
  • Melanoma patients represent a hugely underserved patient population
  • Current melanoma therapeutics have a high risk to benefit ratio
  • Over the past three decades there have been few significant advances in pharmacotherapy for metastatic disease
  • Early diagnosis is the key to curative treatment
  • Gene profiling will help individualize treatment approaches
• Chapter 5 Pipeline Analysis
  • Genta's Genasense (oblimersen) remains in development despite termination of agreement with Sanofi-Aventis
  • Genasense is under review with the EMEA despite failure to gain FDA approval for melanoma in 2004
  • Two-year follow-up data used for Genasense's MAA finds the trial missed its overall survival primary endpoint
  • Normal serum lactate dehydrogenase (LDH) levels may be associated with improved overall survival
  • The combination of Genasense and dacarbazine is associated with increased toxicity
  • Approval of Genasense in combination with dacarbazine viewed as unlikely
  • Phase I study initiated to investigate Genasense in combination with Schering-Plough's Temodar (temozolomide) and Abraxis Oncology's Abraxane
  • Termination of agreement with Sanofi-Aventis is a major setback for Genta
  • Bayer/Onyx's Nexavar (sorafenib): an orally active multi-kinase inhibitor stimulates stakeholder interest
  • Initial results from a Phase III melanoma study are disappointing
  • Phase II study shows Nexavar monotherapy has poor activity
  • The addition of carboplatin and paclitaxel to Nexavar improves progression-free survival over Nexavar monotherapy
  • Preliminary results from a randomized Phase II study of a Temodar and Nexavar combination shows promise
  • Nexavar with dacarbazine is well tolerated and is currently in Phase II development
  • The future of Nexavar in advanced melanoma looks uncertain following failure of the Phase III PRISM trial
  • Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibodies show promise in the management of melanoma
  • Medarex/Bristol-Myers Squibb's ipilimumab (MDX-010, BMS-734016) has been awarded Fast Track status in melanoma
  • Pfizer hopes to file ticilimumab (CP-675,206) with the FDA in 2007 for melanoma
  • Distinguishing between ipilimumab and ticilimumab proves challenging
  • Melanoma vaccines: augmenting anti-tumor immunity
  • AVAX Technologies' M-Vax is an autologous vaccine that has been launched in Switzerland
  • Financial constraints trouble M-Vax's initial approval in Australia
  • M-Vax re-enters Phase III development in October 2006
  • Multiple hurdles challenge M-Vax's future success
  • Improved second-generation formulation facilitates use in early-stage disease
  • Oncophage's Phase III results prompt further investigation
  • Personalized nature could work in Oncophage's favor
  • Lack of cost-effectiveness, clinical benefit and marketing experience will pose significant strategic challenges for Antigenics
  • If encouraging, results from an ongoing Phase III clinical trial will support a BLA
  • Phase II results demonstrate complete or partial responses for the MDX-1379 and ipilimumab combination in melanoma
  • Partnership with Bristol-Myers Squibb will put Medarex at a significant advantage
  • Vical/AnGes's Allovectin-7: a gene transfer product involving a Dna plasmid/lipid complex
  • Phase III melanoma development continues despite suffering a major setback
  • Phase II data shows Allovectin-7 leads to durable responses lasting over six months
  • A further Phase II Allovectin-7 study demonstrates median overall survival of over 21 months
  • The market impact of Allovectin-7 still looks doubtful
• Chapter 6 Appendix
  • Contributing experts
  • Opinion leader interview transcripts
  • Bibliography
• List of tables
• List of figures
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