Abstract
Overview
Introduction
Non-Hodgkin' s lymphoma (NHL) is the most common hematological malignancy and is comprised of around 30 different disease subtypes. Each of these present with a distinct set histological, genetic and clinical characteristics. Treatment options in NHL include chemotherapy, targeted therapies, stem cell transplantation and radiotherapy.
Scope
- NHL background and epidemiology, including forecast incidence of the major subtypes in the seven major markets
- Treatment of NHL by subtype and line of therapy, including major treatment controversies and areas of unmet need
- Examination of pipeline activity including profiles of late-phase pipeline drugs
- Stakeholder opinions based on qualitative interviews with opinion leaders from the US and Europe
Highlights
Rituxan-based regimens constitute the mainstay of first-line treatment options in several NHL subtypes. Uptake of Rituxan in the maintenance setting for follicular lymphoma (FL) has allowed the drug to achieve further market penetration.
There is a lack of consensus over the treatment of relapsed and refractory disease in most NHL subtypes. Refractory patients are poorly served by currently available treatment options. Other unmet needs include detection of patients with aggressive lymphoma at high risk of relapse and an efficacious maintenance therapy for these patients.
The NHL late-phase pipeline is relatively active, with 10 Phase IIII drugs and 46 Phase II drugs. Monoclonal antibodies are among those agents that continue to demonstrate promising signs of clinical and commercial potential. However, Rituxan' s status as market leader is unlikely to be challenged within the next 510 years.
Reasons to Purchase
- Understand current epidemiological trends in non-Hodgkin' s lymphoma and ongoing treatment options
- Identify limitations of therapy currently available to non-Hodgkin' s lymphoma patients and the potential of future therapy
- Identify the key products in late-phase development for NHL. Consider, assess and react to opportunities and risks influencing their future potential
Table of Contents
- ABOUT DATAMONITOR HEALTHCARE
- About the Oncology pharmaceutical analysis team
- Andrew Paramore - Oncology Lead Analyst & Head of Product Development
- About the Oncology pharmaceutical analysis team
- CHAPTER 1 EXECUTIVE SUMMARY
- Scope of analysis
- Datamonitor insight into the non-Hodgkin' s lymphoma market
- Related reports
- Upcoming reports
- CHAPTER 2 NON-HODGKIN' S LYMPHOMA: DISEASE BACKGROUND
- Chapter summary
- Disease overview and classification
- Disease overview
- Disease classification
- NHL is classified under the WHO classification system
- Immunophenotype differs between NHL subtypes
- Several genetic abnormalities linked to NHL
- NHL can follow an aggressive or indolent disease course
- Diagnosis, staging and prognosis in NHL
- Diagnosis of NHL
- Ann Arbor staging system
- Ann Arbor classification used for staging NHL but of limited prognostic use
- Determining prognosis for NHL
- International Prognostic Factor Index for aggressive NHL
- International Prognostic Factor Index for FL
- Molecular profiling in NHL
- Epidemiology
- Incidence of NHL in the seven major markets
- NHL is the most commonly occurring hematological malignancy in the seven major markets
- NHL incidence will total 122,000 in the seven major markets in 2007
- Incidence of NHL by subtype in the seven major markets
- Distribution of NHL subtypes varies considerably across the seven major markets
- DLBCL and FL account for over 50% of new NHL diagnoses
- Age distribution of NHL incidence rate
- Mortality
- NHL mortality will reach 47,000 in the seven major markets in 2007
- Incidence of NHL in the seven major markets
- Etiology
- Immunodeficiency and immunosuppression as risk factors for NHL
- Acquired immunodeficiency syndrome (AIDS)
- Congenital immunodeficiency
- Immunosuppressive drugs
- Autoimmune disorders
- Infections as risk factors for NHL
- Human T-cell lymphotrophic virus (HTLV-1)
- Epstein-Barr virus (EBV)
- Helicobacter pylori
- Hepatitis C
- Occupational, environmental and lifestyle risk factors
- Pesticides
- Hair dyes
- Lifestyle factors
- Immunodeficiency and immunosuppression as risk factors for NHL
- CHAPTER 3 CURRENT TREATMENT OPTIONS FOR NON-HODGKIN' S LYMPHOMA
- Chapter summary
- Overview of NHL treatment options
- Chemotherapy
- Targeted therapies
- Rituxan has made a large impact on NHL treatment outcomes
- Radioimmunotherapies combine a monoclonal antibody and radioactive component
- Drug developers aiming for widened indications for approved targeted therapies
- Other drug classes
- Combination regimens
- Radiotherapy
- Myeloablative therapy and stem cell transplantation
- Treatment outcome measurements for NHL
- Treatment of DLBCL
- DLBCL overview
- Induction therapy in DLBCL
- R-CHOP established as standard of care for induction therapy in DLBCL
- Treatment of refractory and relapsed DLBCL
- Debate remains over second-line chemotherapy combinations and whether to add Rituxan in relapsed patients
- Consolidation myeloablative therapy and ASCT recommended where possible in relapsed DLBCL
- Lack of viable treatment of options in refractory patients
- Improving treatment outcomes in DLBCL
- Increasing the R-CHOP dose frequency may improve treatment outcomes in elderly patients
- Rituxan use unlikely to extend to first-line maintenance therapy in DLBCL
- Treatment of FL
- FL overview
- First-line therapy in FL
- Initial treatment may be delayed for several years in some cases
- Localized, non-bulky FL treated with radiotherapy
- No established standard of care for patients with advanced FL
- Addition of Rituxan to first-line chemotherapy improves treatment outcomes in FL
- Radioimmunotherapy rarely used in first-line treatment of FL
- Consolidation therapy in FL
- Myeloablative therapy and ASCT superseded by Rituxan maintenance as a consolidation therapy in FL
- Radioimmunotherapy may experience limited uptake as a consolidation therapy in FL despite promising data
- Treatment of relapsed and refractory FL
- Single-agent Rituxan or Rituxan-based regimens commonly used as second-line regimens in FL.
- Limited use of radioimmunotherapy in relapsed or refractory FL despite promising evidence of efficacy
- Benefit of myeloablative therapy and ASCT in treatment of relapsed or refractory FL uncertain
- Rituxan maintenance in FL
- Rituxan maintenance after first-line therapy and after second-line therapy improves PFS and overall survival in FL compared to observation
- Unclear whether Rituxan maintenance adds clinical benefit after first-line Rituxan-containing regimen
- Should Rituxan maintenance be used after induction therapy and after first relapse?
- Optimal dosing schedule remains to be determined
- Treatment of MALT lymphomas
- Gastric MALT lymphoma
- Localized gastric MALT lymphoma treated according to H. pylori status
- Advanced gastric MALT lymphoma treated in a similar fashion to FL
- Non-gastric MALT lymphoma
- Gastric MALT lymphoma
- Treatment of MCL
- First-line therapy in MCL
- Rituxan increases efficacy of chemotherapy regimens used as induction therapy for MCL
- Myeloablative therapy and ASCT used as consolidation therapy after induction therapy
- Second-line therapy in MCL
- Velcade is the first FDA-approved treatment option for relapsed MCL
- First-line therapy in MCL
- Treatment of SLL
- SLL treated in a similar fashion to indolent lymphomas
- Treatment of T-Cell Lymphoma (PTCL/CTCL)
- Treatment options in PTCL of unspecified subtype
- Lack of efficacious regimens in PTCL
- Treatment of CTCL
- Treatment options in PTCL of unspecified subtype
- Unmet needs in NHL
- CHAPTER 4 PIPELINE ANALYSIS
- Chapter summary
- Pipeline overview
- Phase III NHL product pipeline
- Phase II NHL product pipeline
- Pixantrone (Cell Therapeutics)
- Drug overview
- Pixantrone intended to be a more efficacious, less cardiotoxic alternative to traditional anthracyclines
- Overview of ongoing clinical trials and clinical trial data
- Phase III trials of pixantrone are ongoing in aggressive and indolent NHL
- Phase II data reported in aggressive NHL
- Phase II trials of pixantrone in indolent NHL
- Datamonitor comments
- Problems associated with trying to replace genericized drugs must be overcome
- Physician awareness and patient recruitment may be challenging
- Pixantrone set to benefit from co-licensing agreement with Novartis
- Drug overview
- Avastin (bevacizumab; Genentech/Roche)
- Drug overview
- VEGF is a promising target in NHL
- Overview of ongoing clinical trials and clinical trial data
- Phase III trial of Avastin with R-CHOP in first-line DLBCL underway
- Limited clinical trial data available to date
- Datamonitor comments
- Difficult to predict clinical benefit of Avastin in DLBCL at this stage
- Use of Avastin in DLBCL could significantly add to cost of treatment
- Genentech and Roche' s marketing power will be essential in driving uptake of Avastin in NHL
- Drug overview
- Enzastaurin (LY317615; Eli Lilly)
- Drug overview
- Enzastaurin is an orally administered multi-targeted kinase inhibitor
- Ongoing clinical trials and clinical trial data
- Phase III trial of enzastaurin as a maintenance therapy in DLBCL
- Phase II data reported for enzastaurin as a second-line DLBCL therapy
- Enzastaurin holding promise as a maintenance therapy in MCL
- Datamonitor comments
- Eli Lilly has adopted a risky strategy for enzastaurin in DLBCL with potentially high financial reward
- Termination of Phase III trial for enzastaurin in glioma may hamper its potential in other indications
- Drug overview
- Galiximab (Anti-CD80 MAb; Biogen Idec)
- Drug overview
- Galiximab is a primatized monoclonal antibody targeting CD80
- Overview of ongoing clinical trials and clinical trial data
- Randomized Phase III trial and single-arm Phase III retreatment trial initiated in relapsed or refractory FL patients
- Phase II results show galiximab and Rituxan can be safely combined and produce promising response rates in follicular NHL patients
- Datamonitor comments
- Biogen Idec in a strong position to successfully market galiximab alone
- Lack of standard-of-care for second-line treatment of FL will aid galiximab' s approval prospects
- Biogen Idec will need to effectively demonstrate the value of a combination of galiximab and Rituxan to payers
- Drug overview
- Ofatumumab (HuMax-CD20; Genmab/GlaxoSmithKline)
- Drug overview
- Ofatumumab is a fully human CD20-directed monoclonal antibody intended to show superior efficacy to Rituxan
- Overview of ongoing clinical trials and clinical trial data
- Genmab has initiated a pivotal Phase III trial in FL
- Phase I/II data reported in relapsed/refractory FL
- Datamonitor comments
- Ofatumumab may offer hope for Rituxan-insensitive patients
- Approval of other monoclonal antibodies being developed for NHL may restrict ofatumumab' s potential even further
- GlaxoSmithKline will offer invaluable experience to Genmab and aid commercialization of ofatumumab
- Drug overview
- Torisel (temsirolimus; Wyeth)
- Drug overview
- Torisel inhibits a key pathway in tumor cell proliferation
- Overview of ongoing clinical trials and clinical trial data
- Wyeth has initiated a Phase III trial for Torisel in MCL
- Promising Phase II data reported for Torisel in MCL
- Torisel also making headway in other NHL subtypes
- Datamonitor comments
- Torisel will have to compete with Velcade in the MCL market
- Prior commercialization of Mylotarg, Neumega and launch of Torisel for RCC will provide Wyeth with valuable insight into the oncology market
- Drug overview
- Zanolimumab (HuMax-CD4; Genmab)
- Drug overview
- Zanolimumab is a fully human monoclonal antibody targeting CD4
- Overview of ongoing clinical trials and clinical trial data
- Zanolimumab in Phase III trial for CTCL
- Positive Phase II results in CTCL presented
- Zanolimumab may also hold promise for non-cutaneous PTCL patients
- Datamonitor comments
- The T-cell lymphoma market offers zanolimumab a limited commercial potential
- Depletion of CD4+ T-cells by zanolimumab may render the patient susceptible to infections
- Drug overview
- BiovaxID (Accentia Biopharmaceuticals)
- Drug overview
- BiovaxID is an autologous vaccine combining a tumor-specific idiotype protein and a protein carrier
- Overview of ongoing clinical trials and clinical trial data
- Phase III trial of BiovaxID initiated in February 2000 in FL patients in first complete remission
- BiovaxID inches closer to approval in the US and European markets for FL
- Possible association between a specific negative chromosomal translocation following vaccination and disease-free survival in FL
- Phase II results of BiovaxID in MCL are promising
- Datamonitor comments
- BiovaxID competing with Specifid and MyVax for first-to-market status
- BiovaxID' s price should reflect the anticipated competition and current treatment costs
- Drug overview
- Specifid (FavId; Id-KLH; Favrille)
- Drug overview
- Overview of ongoing clinical trials and clinical trial data
- Phase III trial of Specifid in FL initiated in 2004
- Phase II clinical trials have shown prolongation of time to progression in FL
- Single-agent Specifid demonstrates an objective response in indolent B-cell NHL
- Favrille also intend to develop Specifid for DLBCL
- Datamonitor comments
- Specifid competing with BiovaxID and MyVax to reach the market first
- Favrille' s lack of commercial experience will be a barrier to optimizing market penetration
- MyVax (GTOP-99; Genitope)
- Drug overview
- Overview of ongoing clinical trials and clinical trial data
- MyVax received Fast Track status for FL while Phase III clinical trial approaches completion
- Phase II clinical trials show greater number of immune responses among previously untreated patients
- Follow-up Phase II data of MyVax in MCL and DLBCL warrants further investigation
- Datamonitor comments
- Despite competition from BiovaxID and Specifid, MyVax increases its commercial potential by targeting an earlier stage treatment
- Comparison of anti-idiotype vaccines
- APPENDIX
- Bibliography
- Abbreviations
- List of tables
- List of figures
- Contributing experts
- About Datamonitor
- About Datamonitor Healthcare
- About the Oncology analysis team
- Disclaimer
- List of Tables
- Table 1: Subtypes of NHL under the WHO classification and relative incidence, 1998
- Table 2: Characteristic immunophenotype of major NHL subtypes
- Table 3: Chromosomal translocations associated with NHL
- Table 4: Grading of FL according to proportion of large cells in lymphoma
- Table 5: International Prognostic Factor Index for aggressive NHL (IPI)
- Table 6: Survival rates for different risk groups in aggressive NHL classified by IPI
- Table 7: Age-adjusted IPI (aaIPI) for aggressive lymphomas and associated survival rates
- Table 8: International Prognostic Factor Index for FL (FLIPI)
- Table 9: Survival rates for different risk groups in FL classified by FLIPI
- Table 10: Crude NHL incidence rates (per 100,000 persons), seven major markets, 2002
- Table 11: Forecast incidence of NHL in the seven major markets, 2007-16
- Table 12: Relative distribution of NHL subtypes in the US, EU and Japan
- Table 13: Forecast incidence of the six most commonly diagnosed NHL subtypes in the seven major markets, 2007
- Table 14: Median age at diagnosis for the six major subtypes of NHL in the seven major markets, 1998
- Table 15: NHL mortality rates (per 100,000 persons) in the seven major markets, 2002
- Table 16: Forecast mortality from NHL in the seven major markets, 2002 and 2007
- Table 17: Overview of chemotherapy agents used in NHL, 2007
- Table 18: Overview of targeted therapies used in NHL, 2007
- Table 19: Selected ongoing Phase III trials for approved targeted therapies in NHL, 2007
- Table 20: Overview of drugs other than chemotherapy and targeted therapies used in NHL, 2007
- Table 21: Overview of combination regimens commonly used in NHL
- Table 22: Definition of response criteria and endpoints used in NHL
- Table 23: Summary of randomized trials showing PFS and overall survival benefit of Rituxan maintenance in FL
- Table 24: Summary of randomized Phase III trial comparing R-CHOP to CHOP in previously untreated MCL
- Table 25: Summary of results from single-arm study of Velcade in relapsed/refractory MCL - The PINNACLE trial
- Table 26: Overview of pipelines drugs in Phase III trials for NHL, November 2007
- Table 27: Overview of pipelines drugs in Phase II trials for NHL, November 2007
- Table 28: Interim Phase II results of pixantrone as part of the R-CPOP regimen vs. R-CHOP regimen for first-line DLBCL
- Table 29: Interim Phase II results of pixantrone as part of the CPOP regimen in relapsed aggressive NHL
- Table 30: Phase II results of pixantrone as part of the BSHAP regimen in aggressive NHL patients experiencing their first relapse
- Table 31: Phase I/II trial results of pixantrone as part of the FPD-R regimen, to replace mitoxantrone in FND-R in indolent NHL
- Table 32: Summary of Phase II results for single-agent Avastin in relapsed aggressive NHL
- Table 33: Phase II results of enzastaurin in relapsed DLBCL
- Table 34: Phase II study of galiximab in combination with Rituxan in relapsed/refractory FL
- Table 35: Retrospective comparison of galiximab plus Rituxan with Rituxan monotherapy in relapsed/refractory FL
- Table 36: Interim Phase I/II results of ofatumumab in relapsed/refractory FL
- Table 37: GlaxoSmithKline' s marketed oncology portfolio, 2007
- Table 38: Phase II results of low-dose Torisel in relapsed/refractory MCL patients
- Table 39: Phase II study of Torisel in relapsed NHL patients
- Table 40: Phase II results of zanolimumab in mycosis fungoides (MF) CTCL
- Table 41: Phase II results of zanolimumab in non-cutaneous PTCL patients
- Table 42: Interim results of Specifid monotherapy Phase III trial in FL: response to Rituxan
- Table 43: Four-year follow up data from Phase II trial for Specifid in FL
- Table 44: Phase II interim results of MyVax in MCL and DLBCL NHL patients, (1 of 2)
- Table 45: Phase II interim results of MyVax in MCL and DLBCL NHL patients, (2 of 2)
- Table 46: Comparisons of the late-phase anti-idiotype vaccines, 2007
- Table 47: Abbreviations used in Stakeholders Opinions: Non-Hodgkin' s Lymphoma
- List of Figures
- Figure 1: Characterization of disease course of major NHL subtypes
- Figure 2: Symptoms shown at presentation by NHL patients
- Figure 3: Ann Arbor staging system for NHL
- Figure 4: Incidence of hematological malignancies in the seven major markets, 2002
- Figure 5: Forecast incidence of NHL in the seven major markets, 2007-16
- Figure 6: Forecast incidence of the six most commonly diagnosed NHL subtypes in the seven major markets, 2007
- Figure 7: Distribution of NHL incidence rates by age group, US, 2000-04
- Figure 8: Forecast mortality from NHL in the seven major markets, 2002 and 2007
- Figure 9: Summary of results of randomized study comparing R-CHOP to CHOP in elderly DLBCL patients
- Figure 10: Summary of results of randomized study comparing Rituxan plus chemotherapy to chemotherapy alone in young, low risk DLBCL patients
- Figure 11: Results of randomized study comparing R-CHOP to CHOP in the first-line treatment of FL
- Figure 12: Results of randomized study comparing R-CVP to CVP in the first-line treatment of FL
- Figure 13: Results of a Phase II trial of Bexxar as a first-line therapy in FL
- Figure 14: Results of a Phase III trial comparing myeloablative therapy and ASCT to IFN( maintenance for FL patients in first remission
- Figure 15: Results of a Phase III trial comparing myeloablative therapy and ASCT to CHVP/IFN( for FL patients in first remission
- Figure 16: Results of a Phase III trial comparing myeloablative therapy and ASCT to CHVP/IFN( for FL patients in first remission
- Figure 17: Results from a randomized study of Zevalin consolidation therapy compared to observation after first-line therapy in FL
- Figure 18: Results of a Phase III trial comparing Zevalin to Rituxan for relapsed or refractory FL patients
- Figure 19: Summary of collated results from five clinical trials for Bexxar in relapsed/refractory/transformed FL
- Figure 20: Summary of persistent unmet needs in NHL, 2007
- Figure 21: Phase III trial design for pixantrone in relapsed aggressive NHL
- Figure 22: Phase III trial design for pixantrone in relapsed or refractory indolent NHL
- Figure 23: Phase III study design for Avastin in combination with R-CHOP in DLBCL
- Figure 24: Phase III trial design for enzastaurin as a maintenance therapy in DLBCL (the PRELUDE study)
- Figure 25: Outline of randomized Phase III trial for galiximab in combination with Rituxan in relapsed or refractory FL (study ID: 114-NH-301)
- Figure 26: Outline of single-arm Phase III trial for retreatment with galiximab in combination with Rituxan in relapsed or refractory FL (study ID: 114-NH-302)
- Figure 27: Phase III study design for ofatumumab in Rituxan-refractory FL
- Figure 28: Phase III trial design for Torisel in relapsed or refractory MCL
- Figure 29: Phase II trial of Torisel in combination with Rituxan in second-line MCL patients
- Figure 30: Phase III study design for zanolimumab in CTCL
- Figure 31: Preliminary results for the first stage of the Phase III study for zanolimumab in CTCL
- Figure 32: Summary of Phase III trial of BiovaxID in FL
- Figure 33: Phase III study design for Specifid in FL
- Figure 34: Trial design of Phase II study of Specifid in progressive NHL
- Figure 35: Genitope' s personalized immunotherapy (MyVax) production system
