Contents:

ABOUT US HEALTHCARE 2 About the Oncology pharmaceutical analysis team 2 CHAPTER 1 EXECUTIVE SUMMARY 3 Scope of the analysis 3 Datamonitor insight into the NSCLC market 3 Related reports 5 Upcoming reports 5 CHAPTER 2 PIPELINE OVERVIEW AND DYNAMICS 7 Pipeline overview 7 Drugs in late-phase development for NSCLC 7 Drugs in Phase II development for NSCLC 8 Drugs in Phase I development for NSCLC 12 Pipeline by development phase and therapy class 12 There are over 100 drugs in the NSCLC pipeline, more than half of which are molecular targeted therapies 12 Pipeline by mode of action 15 Pipeline drugs have diverse modes of action 15 Pipeline by indication 17 The majority of drugs are being investigated in the first-line treatment of advanced disease 17 Pipeline by company 18 Nearly 100 different companies or institutions are involved in the NSCLC pipeline 18 Merck Serono is the only company with two drugs in Phase III development for NSCLC 19 Top three companies in terms of the number of NSCLC pipeline candidates are Pfizer, Novartis and Bristol-Myers Squibb 21 Pfizer 21 Novartis 23 Bristol Myers Squibb 25 Key metrics 26 Datamonitor pipeline assessment summary 30 CHAPTER 3 NON-SMALL CELL LUNG CANCER - MARKET POTENTIAL 34 Definition of NSCLC 34 Non-small cell lung cancer accounts for about 80% of all lung cancers 34 Three major types of NSCLC exist 35 Staging of NSCLC is usually based on the AJCC Tumor Node Metastases (TNM) staging system 36 A revised staging system may have treatment implications in the future 37 The NSCLC market is segmented according to disease stage 37 Risk factors in the development of NSCLC 38 Overview of NSCLC treatment 38 The treatment of early-stage disease (Stages I-IIIA) 40 The management of early-stage disease is largely based on surgery 40 Adjuvant chemotherapy may benefit a subset of patients with early-stage disease 41 Radiotherapy has a central role in the treatment of unresectable early-stage disease 42 The treatment of advanced disease (Stages IIIB-IV) 42 Chemoradiotherapy is the standard of care in patients with unresectable Stage IIIB disease 43 A recent trial has generated controversy regarding the use of consolidation chemotherapy in unresectable Stage III disease 43 Systemic platinum-based chemotherapy has a central role in the management of advanced disease 44 The addition of Avastin may offer an added advantage for a subset of patients 44 A number of options are available for previously-treated patients 45 The role of targeted therapies in the treatment of NSCLC 46 Avastin is extensively used in the first-line setting, but only a subset of patients is eligible for treatment 46 Off-label use of Tarceva is taking place in the first-line setting 49 AstraZeneca will be seeking EU approval for Iressa in the second-line setting 51 Targeted therapies may find an application in a number of settings in NSCLC 53 The treatment of NSCLC is moving into an era of individualized medicine 53 The epidemiology of NSCLC 55 There will be more than 380,000 new cases of NSCLC in the seven major markets in 2017 55 Mortality from NSCLC is high 55 NSCLC is predominantly a disease of the elderly 56 Adenocarcinoma has become the most common histological subtype of NSCLC 56 Asia will face a major epidemic of lung cancer in the future 57 NSCLC incidence and mortality rates are still increasing in women 57 NSCLC in never-smokers may become more prevalent in the future 57 Increased detection by screening is unlikely to affect NSCLC incidence 58 NSCLC is an attractive market for new product development 58 Unmet need in NSCLC 60 Effective treatments are required for both advanced and early-stage disease 60 NSCLC needs to be recognized as a heterogeneous disease 60 Less toxic treatments for poor performance status patients are required 61 The treatment of NSCLC is in need of an overall refinement 61 CHAPTER 4 R&D APPROACH 63 Classification of pipeline products 63 Cytotoxic therapies 63 Molecular targeted therapies 64 Single-target signal transduction inhibitors 65 Angiogenesis inhibitors 65 Apoptosis inducers 65 Cell cycle inhibitors 65 Multi-targeted inhibitors 66 Epigenetic modulators 66 Immunotherapeutic agents 66 Evolution in NSCLC clinical trial design 67 The heterogeneity of NSCLC makes patient selection a critical issue 67 Targeted trial designs utilizing biomarkers are increasingly used 68 Early-phase clinical trials and endpoints may need redefining 69 Barriers may still exist to the accrual of patients to NSCLC trials 70 NSCLC trials may not be very representative of the clinical setting 71 CHAPTER 5 MOLECULAR TARGETED THERAPIES ANALYSIS AND FORECASTS 72 Overview of molecular targeted therapies 72 Pipeline summary 72 Late-phase pipeline of molecular targeted therapies 74 Phase II pipeline of molecular targeted therapies 74 Phase I pipeline of molecular targeted therapies 77 Comparative forecasts 77 Definition of current comparator therapy 78 Avastin (bevacizumab Genentech/Roche/Chugai) 78 Erbitux (cetuximab; ImClone/Merck Serono/Bristol-Myers Squibb) 79 Drug overview 79 Key historical events 80 Clinical development in NSCLC 82 Phase III study of Erbitux with cisplatin and vinorelbine meets its primary endpoint of improved survival 84 Phase III study of Erbitux with carboplatin and a taxane fails to meet its primary endpoint 86 A number of other trials have evaluated Erbitux in NSCLC 89 A combination of chemotherapy, Erbitux, and Avastin is being evaluated 91 Erbitux may enhance the efficacy of chemoradiotherapy in the treatment of unresectable, locally advanced disease 91 Datamonitor comments 93 Erbitux may become the first EGFR inhibitor to show a survival improvement in combination with chemotherapy in the first-line setting 93 The extent to which US physicians will adopt the cisplatin/vinorelbine regimen may affect Erbituxs uptake 93 Erbitux may achieve a higher uptake in patients who are not eligible for Avastin treatment 94 Erbitux could find additional application in the treatment of locally advanced, unresectable NSCLC 95 Forecasts to 2017 95 Nexavar (sorafenib; Bayer Schering) 97 Drug overview 97 Key historical events 97 Clinical development in NSCLC 98 The combination of Nexavar with platinum-based chemotherapy fails to improve overall survival in a Phase III study 100 Nexavar monotherapy results in disease stabilization in the second and third-line settings 101 An additional study has evaluated Nexavar monotherapy in the second-line setting 103 Datamonitor comments 104 Nexavars potential in NSCLC now significantly limited 104 Nexavar joins the growing number of TKIs that have failed in the first-line setting 104 Bayer Schering has adopted a conservative strategy for Nexavars Phase III trial with Gemzar and cisplatin 105 Forecasts to 2017 106 Recentin (cediranib; AstraZeneca) 108 Drug overview 108 Key historical events 109 Clinical development in NSCLC 110 Two Phase I trials have evaluated Recentin in the first-line treatment of advanced NSCLC 111 Datamonitor comments 112 Recentin fails to progress into Phase III in advanced NSCLC 112 Sutent (sunitinib; Pfizer) 112 Drug overview 112 Key historical events 113 Clinical development in NSCLC 113 Sutent monotherapy shows moderate clinical activity in the second- and third-line setting of advanced NSCLC 115 The combination of Sutent with Gemzar and cisplatin is safe and tolerable 116 Datamonitor comments 117 The toxicity and cost of adding Sutent to Tarceva will need to be justified 117 Targeting the second-line setting may be a successful strategy for Sutent 118 Forecasts to 2017 118 Zactima (vandetanib; AstraZeneca) 120 Drug overview 120 Key historical events 121 Clinical development in NSCLC 122 The addition of Zactima to platinum-based chemotherapy improves progression-free survival in the first-line setting 123 The combination of Zactima with Taxotere and with Iressa improves progression-free survival in the second-line setting 124 Datamonitor comments 127 Zactimas multi-targeted nature could offer a competitive advantage 127 Zactima is targeting a broad population of previously-treated, advanced NSCLC patients 127 The head-to-head trial against Tarceva is a high-risk strategy 128 AstraZenecas strength in the oncology market will be key to Zactimas success 129 Forecasts to 2017 129 Zolinza (vorinostat; Merck & Co) 131 Drug overview 131 Key historical events 132 Clinical development in NSCLC 132 Zolinza shows moderate clinical activity as a second-line monotherapy in NSCLC 134 A Phase II trial of Zolinza with Tarceva in relapsed/refractory NSCLC was terminated 135 Zolinza shows preliminary evidence of clinical activity in combination with chemotherapy 135 Datamonitor comments 135 A different strategy may have improved Zolinzas chances of success in the NSCLC market 135 Forecasts to 2017 136 Aflibercept (VEGF-Trap; Sanofi Aventis/Regeneron) 138 Drug overview 138 Key historical events 138 Clinical development in NSCLC 139 Aflibercept shows manageable toxicity and some evidence of clinical activity in heavily pre-treated, advanced NSCLC patients 139 Datamonitor comments 140 The combination of aflibercept with Taxotere will have to demonstrate a favorable toxicity profile 140 Aflibercepts Phase III trial may not be accounting for the current standards of care 141 Aflibercepts Phase II trial results are interpreted using the modified RECIST criteria 141 Presence in oncology field will aid commercialization of aflibercept 142 Forecasts to 2017 142 BIBW 2992 (Boehringer Ingelheim) 144 Drug overview 144 Key historical events 144 Clinical development in NSCLC 145 Phase III study will evaluate BIBW 2992 in patients who have failed prior therapy with reversible EGFR inhibitors 145 BIBW 2992 shows preliminary evidence of activity in a Phase I study in solid malignancies 146 Datamonitor comments 147 Targeting patients who are Tarceva-refractory may be a successful entry strategy into the NSCLC market 147 Motesanib (AMG706; Amgen/Takeda Pharmaceutical) 148 Drug overview 148 Key historical events 148 Clinical development in NSCLC 148 The combination of motesanib with chemotherapy is safe and shows preliminary evidence of clinical activity 149 Datamonitor comments 150 Can motesanib succeed where other tyrosine kinase inhibitors have failed? 150 Amgen runs a high risk with the inclusion of squamous cell patients in motesanibs Phase III trial 151 Forecasts to 2017 151 CHAPTER 6 CYTOTOXIC THERAPIES ANALYSIS AND FORECASTS 154 Overview of cytotoxic therapies 154 Pipeline summary 154 Late-phase pipeline of cytotoxic therapies 155 Phase II pipeline of cytotoxic therapies 156 Phase I pipeline of cytotoxic therapies 157 Comparative forecasts 158 Definition of current comparator therapy 159 Taxotere (docetaxel; Sanofi-Aventis) 159 Abraxane (albumin-bound paclitaxel; Abraxis) 159 Drug overview 159 Key historical events 160 Clinical development in NSCLC 161 The combination of Abraxane with carboplatin and Avastin is well-tolerated 162 Abraxane shows clinical activity and a favorable toxicity profile as a first-line monotherapy in metastatic NSCLC 163 Datamonitor comments 164 A novel taxane with an improved toxicity profile could gain a share of the NSCLC market 164 There is a high chance of approval for Abraxane in NSCLC 165 Abraxanes sales growth in the breast cancer market may be indicative of an uptake in NSCLC 166 Forecasts to 2017 166 Glutoxim (NOV-002; Novelos) 168 Drug overview 168 Key historical events 168 Clinical development in NSCLC 169 Glutoxim has been evaluated in the first-line treatment of advanced NSCLC 169 Datamonitor comments 170 Glutoxims clinical and commercial potential cannot be evaluated 170 Forecasts to 2017 171 Javlor (vinflunine; Pierre Fabre) 173 Drug overview 173 Key historical events 173 Clinical development in NSCLC 173 Javlor shows efficacy equivalent to that of Taxotere in a Phase III trial in advanced NSCLC 174 Datamonitor comments 176 Pierre Fabres intentions for Javlor in NSCLC are unclear 176 Javlor will face intense competition in the second-line setting 176 Javlor could increase its uptake with use in combination with radiotherapy 176 Forecasts to 2017 177 Lipoplatin (liposomal cisplatin; Regulon) 179 Drug overview 179 Key historical events 179 Clinical development in NSCLC 179 The combination of Lipoplatin with Gemzar is safe and shows evidence of clinical activity 180 Lipoplatin shows a better toxicity profile than cisplatin as part of a combination regimen with paclitaxel 181 Datamonitor comments 182 Favorable market conditions exist for novel cytotoxic agents such as Lipoplatin 182 A more experienced oncology player could improve Lipoplatins chances of success in the market 183 Forecasts to 2017 183 Taxoprexin (DHA paclitaxel; Luitpold) 185 Drug overview 185 Key historical events 185 Clinical development in NSCLC 186 Taxoprexin shows moderate clinical efficacy and an unfavorable toxicity profile in a Phase II trial 186 Datamonitor comments 187 Taxoprexins clinical results to date raise concerns regarding its future in the NSCLC market 187 Forecasts to 2017 188 Xyotax (paclitaxel polyglumex; Cell Therapeutics/Novartis) 190 Drug overview 190 Key historical events 191 Clinical development in NSCLC 191 Three Phase III trials failed to meet their primary endpoints of improved overall survival 192 Combined analysis of STELLAR 3 and STELLAR 4 showed a survival benefit in women 194 Datamonitor comments 195 Non-inferiority may grant Xyotax approval in an underserved patient population with poor prognosis 195 It is unclear whether Cell Therapeutics will achieve a return on Xyotaxs development costs 196 The use of a prognostic biomarker for the selection of patients could enhance Xyotaxs clinical results 196 Forecasts to 2017 196 CHAPTER 7 IMMUNOTHERAPIES ANALYSIS AND FORECASTS 199 Overview of immunotherapies 199 Pipeline summary 199 Late-phase pipeline of immunotherapies 200 Phase II pipeline of immunotherapies 201 Phase I pipeline of immunotherapies 202 Comparative forecasts 203 Definition of current comparator therapy 204 Stimuvax (BLP-25; Merck Serono) 204 Drug overview 204 Key historical events 205 Clinical development in NSCLC 205 Stimuvax shows evidence of a survival benefit in patients with Stage IIIB locoregional disease 206 Datamonitor comments 208 The need for a minimally toxic maintenance therapy may drive Stimuvaxs uptake 208 Stimuvax may have to overcome regulatory hurdles... 208 Forecasts to 2017 209 MAGE-A3 ASCI (GSK1572932A; GlaxoSmithKline) 211 Drug overview 211 Key historical events 212 Clinical development in NSCLC 212 MAGE-A3 ASCI decreases the risk of cancer recurrence after surgery in a Phase II trial 213 Datamonitor comments 214 An adjuvant therapy with a favorable toxicity profile would be welcome in the NSCLC market 214 Recruitment to the large Phase III trial may present challenges 215 MAGE-A3 needs to overcome regulatory and pharmacoeconomic obstacles 215 Forecasts to 2017 216 APPENDIX 218 Bibliography 218 List of tables 237 List of figures 238 List of abbreviations 239 Contributing experts 241 Methodology 241 Datamonitor forecast methodology 241 Epidemiology forecasts 241 Product forecasts 241 Datamonitor drug assessment summary 242 About Datamonitor 244 About Datamonitor Healthcare 245 Datamonitor Healthcares therapy area capabilities 245 About the Disease Analysis Team 246 Disclaimer 24