Stakeholder Opinions: Sarcomas

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of analysis 3
Datamonitor insight into sarcomas 3
Related reports 4
Upcoming reports 4

CHAPTER 2 SARCOMA OVERVIEW 7
Introduction 7
Sarcomas are a diverse group of rare neoplasms 7
Anatomy of the connective tissues 8
Sarcoma classification 9
Soft tissue sarcomas are the commonest form of sarcomas 9
Leiomyosarcoma 10
Malignant fibrous histiocytoma (MFH) 10
Liposarcoma 10
Synovial sarcoma 11
Rhabdomyosarcoma 11
Gastrointestinal stromal tumor (GIST) 11
Kaposi's sarcoma 11
Bone sarcomas make up less than 0.2% of all cancers 12
Primary bone cancers are sarcomas 12
Osteosarcoma 12
Ewing's sarcoma 13
Chondrosarcoma 13
Epidemiology 14
The diversity and rarity of sarcomas makes it difficult to determine the actual incidence 14
Soft tissue sarcomas comprise around 70% of all sarcomas 15
GIST 16
Osteosarcoma 17
Etiology of sarcomas 17
A variety of environmental and genetic factors may increase the risk of developing sarcomas 17
Sarcoma symptoms and diagnosis 19
Site-specific symptoms can sometimes be difficult to detect 19
Diagnosis of sarcoma 20
Sarcomas are often detected at an advanced stage 20
Staging of sarcomas 22
Staging of soft tissue sarcomas 22
Staging of bone sarcomas 23
Sarcoma patient survival 24
Around 10-20% of patients present with metastatic disease at diagnosis 24
Outlook for metastatic bone sarcoma patients is encouraging due to advances in treatment 24
Outlook for metastatic soft tissue sarcoma patients is poor 24

CHAPTER 3 CURRENT TREATMENT OPTIONS AND CONTROVERSIES 26
Treatment overview 26
Optimal sarcoma treatment is multidisciplinary 26
Soft tissue sarcomas 27
Bone sarcomas 28
Surgery forms the mainstay of treatment for sarcomas 29
Radiotherapy complements surgical resection 29
The use of preoperative and postoperative radiotherapy needs to be fully determined 30
Soft tissue sarcomas excluding GIST 30
Bone sarcomas 31
Chemotherapy for sarcomas 31
Patient outcomes for soft tissue sarcomas remain unsatisfactory despite the use of multiple chemotherapeutic agents 31
Chemotherapy is more commonly used to treat unresectable/metastatic soft tissue and bone sarcoma patients 33
Doxorubicin and ifosfamide are the most active single agents in metastatic sarcoma patients 33
Yondelis (trabectedin; PharmaMar/Johnson & Johnson) 38
Doxil (pegylated liposomal doxorubicin; Johnson & Johnson/Schering-Plough) 40
Combination chemotherapy regimens for unresectable/metastatic soft tissue sarcomas 40
Postoperative and preoperative chemotherapy proves more beneficial for bone sarcoma patients 41
The use of preoperative chemotherapy for resectable sarcomas remains undetermined 42
Preoperative chemotherapy for bone sarcomas improves local control but not survival 43
Molecular targeted therapy for GIST 44
Identification of specific mutations has permitted the use of molecular-targeted therapies for GIST 44
GIST may originate from the interstitial cells of Cajal in the gut 44
Two small molecule inhibitors are now approved for use in GIST 45
The approval of agents that specifically target c-kit has particularly improved the management of advanced/unresectable GIST as previously these patients were largely deemed untreatable. 45
Gleevec/Glivec (imatinib; Novartis) as first-line therapy for unresectable GIST 45
Sutent (sunitinib; Pfizer) as second-line therapy for GIST 50

CHAPTER 4 UNMET NEEDS IN SARCOMAS 54
Agents that improve survival of unresectable/metastatic sarcoma patients needed urgently 54
Effective treatment options required for resectable sarcoma patients 54
Better understanding of disease mechanisms needed to guide treatment 55
Small subtype populations make it difficult to perform appropriately powered studies 55
Summary of unmet needs 56

CHAPTER 5 PIPELINE ANALYSIS 57
Sarcoma pipeline overview 57
GIST serves as a model for the development of targeted therapies for sarcomas 60
Angiogenesis as a target for sarcoma therapy 61
Matrix metalloproteinase inhibitors for sarcoma therapy 62
Growth factor signaling inhibitors for sarcoma therapy 62
Phase III drug profiles 64
Avastin (bevacizumab; Genentech/Roche/Chugai) 64
Drug overview 64
Key historical events 65
Clinical trial data for Avastin 65
Ongoing clinical development of Avastin 66
Datamonitor comments 67
Deforolimus (ARIAD/Merck & Co) 68
Drug overview 68
Key historical events 69
Clinical trial data for deforolimus 70
Ongoing clinical development of deforolimus 73
Datamonitor comments 73
Ombrabulin (Sanofi-Aventis) 75
Drug overview 75
Key historical events 75
Clinical trial data for ombrabulin 75
Ongoing clinical development of ombrabulin 76
Datamonitor comments 76
Retaspimycin (Infinity/MedImmune) 77
Drug overview 77
Key historical events 78
Clinical trial data for retaspimycin 78
Ongoing clinical development of retaspimycin 80
Datamonitor comments 80
Tasigna (nilotinib; Novartis) 81
Drug overview 81
Key historical events 82
Clinical trial data for Tasigna 82
Ongoing clinical development of Tasigna 84
Datamonitor comments 84

CHAPTER 6 KEY OPINION LEADERS INTERVIEWED 87
Key opinion leaders interviewed 87

APPENDIX 88
Bibliography 88
Journals 88
Websites 93
Other 94
Abbreviations 97
List of tables 99
List of figures 100
About Datamonitor 101
About Datamonitor Healthcare 101
About the Oncology analysis team 102
Disclaimer 103

List of Tables
Table 1: Soft tissue sarcoma subtypes 9
Table 2: Proportion of soft tissue sarcomas based on site of malignancy 10
Table 3: Bone sarcoma subtypes 12
Table 4: Estimated incidence of bone and soft tissue sarcomas in the seven major pharmaceutical markets, 2008-2018 14
Table 5: Estimated incidence of soft tissue sarcomas in the seven major pharmaceutical markets, 2008-2018 15
Table 6: Estimated incidence of gastrointestinal stromal tumor (GIST) in the seven major pharmaceutical markets, 2008-2018 16
Table 7: Estimated incidence of osteosarcoma in the seven major pharmaceutical markets, 2008-2018 17
Table 8: Stage grouping for soft tissue sarcomas† 22
Table 9: Stage grouping for bone cancer† 23
Table 10: Five-year survival rates for soft tissue sarcoma patients by disease stage 25
Table 11: Overview of chemotherapy agents used in sarcomas, 2008 32
Table 12: Overview of chemotherapy combination regimens used in sarcomas, 2008 33
Table 13: Dose-response study of doxorubicin in bone and soft tissue sarcoma patients 34
Table 14: Phase II trial results of ifosfamide in 182 metastatic soft tissue sarcoma patients 35
Table 15: Phase III trial results of doxorubicin versus two ifosfamide schedules in 326 patients with advanced/metastatic soft tissue sarcomas 36
Table 16: A randomized study of postoperative chemotherapy in nonmetastatic osteosarcoma patients 41
Table 17: Molecular targeted therapies approved for gastrointestinal stromal tumor (GIST), 2008 45
Table 18: Selected ongoing Phase III trials for Gleevec in gastrointestinal stromal tumor (GIST) 2008 49
Table 19: Selected ongoing Phase III trials for Sutent in gastrointestinal stromal tumor (GIST), 2008 52
Table 20: Pipeline drugs in development for sarcoma (excluding GIST), 2008 57
Table 21: Pipeline drugs in development for gastrointestinal stromal tumor (GIST) , 2008 60
Table 22: Avastin: key historical events, 2004-08 65
Table 23: Phase II trial results of Avastin and doxorubicin in 17 patients with metastatic soft tissue sarcomas 66
Table 24: Avastin: ongoing Phase III development in osteosarcoma and gastrointestinal stromal tumor (GIST) 67
Table 25: Deforolimus: key historical events, 2005-08 69
Table 26: Deforolimus: ongoing Phase III development in sarcoma 73
Table 27: Ombrabulin: key historical events, 2001-08 75
Table 28: Ombrabulin: ongoing Phase II/III development in soft tissue sarcomas 76
Table 29: Retaspimycin: key historical events, 2005-08 78
Table 30: Retaspimycin: Phase I trial results in gastrointestinal stromal tumor (GIST) and other soft tissue sarcomas 79
Table 31: Retaspimycin: ongoing Phase III development in gastrointestinal stromal tumor (GIST) 80
Table 32: Tasigna: key historical events, 2006-08 82
Table 33: Tasigna: ongoing Phase III development in gastrointestinal stromal tumor (GIST) 84
Table 34: Abbreviations used in Stakeholder Opinions: Sarcomas, 2008 97

List of Figures
Figure 1: Anatomical sites of sarcoma development 8
Figure 2: Etiologies of sarcoma 18
Figure 3: Symptoms associated with sarcoma 19
Figure 4: Soft tissue sarcoma (excluding GIST) treatment overview 27
Figure 5: Osteosarcoma treatment overview 28
Figure 6: Phase III trial results for the addition of ifosfamide and etoposide to standard chemotherapy in 518 patients with Ewing's sarcoma and PNET* of bone 37
Figure 7: A randomized Phase II trial of Yondelis in soft tissue sarcoma patients who have failed previous anthracyclines or ifosfamide therapy 39
Figure 8: Phase II trial results for Gleevec in unresectable and or metastatic gastrointestinal stromal tumor (GIST) patients 46
Figure 9: Phase III trial results for Gleevec in 946 advanced/metastatic gastrointestinal stromal tumor (GIST) patients 47
Figure 10: Phase III trial results for Sutent in unresectable, Gleevec-resistant gastrointestinal stromal tumor (GIST) patients 51
Figure 11: Unmet needs in sarcoma 56
Figure 12: Molecular targeted therapies for sarcomas 61
Figure 13: Deforolimus: Phase II results in unresectable/metastatic soft tissue and bone sarcoma patients 70
Figure 14: Phase I results of deforolimus in metastatic refractory solid tumors 72
Figure 15: Phase I trial investigating Tasigna alone or in combination with Gleevec in Gleevec-resistant gastrointestinal stromal tumor (GIST) patients 83