1. Copyright © 2010, Research To Practice, All rights reserved. Part V: Central Nervous System Cancers Monday, October 18, 2010 7:30 PM - 8:30 PM ET Monday Night with Research To Practice: An 8-Part Live CME Webcast Series

2. Tracy Batchelor, MD, MPH Executive Director Stephen E and Catherine Pappas Center for Neuro-Oncology Associate Professor of Neurology, Harvard Medical School Associate Neurologist, Massachusetts General Hospital Boston, Massachusetts James J Vredenburgh, MD Professor of Medicine Preston Robert Tisch Brain Tumor Center Duke University Medical Center Durham, North Carolina Neil Love, MD Moderator Research To Practice Miami, Florida

3. Disclosures for Moderator Neil Love, MD Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abraxis BioScience, Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, Lilly USA LLC, Millennium Pharmaceuticals Inc, Myriad Genetics, Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi- Aventis and Spectrum Pharmaceuticals Inc.

4. Disclosures for Tracy Batchelor, MD, MPH Consulting Agreements Roche Laboratories Inc, Schering-Plough Corporation Research Support AstraZeneca Pharmaceuticals LP, Millennium Pharmaceuticals Inc.

5. Disclosures for James J Vredenburgh, MD N/A = Not Applicable Advisory Committee and Consulting Agreements Genentech BioOncology Paid ResearchN/A Speakers BureauN/A

6. Case History: Dr Batchelor A 37 year old man presents with a generalized seizure Left fronto-parietal mass deemed unresectable Biopsy: Anaplastic astrocytoma

7. WHO Grading of Astrocytic Tumors of the CNS Grade I Subependymal giant cell astrocytoma Pilocytic astrocytoma Grade II Pilomyxoid astrocytoma Diffuse astrocytoma Pleomorphic xanthoastrocytoma Grade IIIAnaplastic astrocytoma Grade IV Glioblastoma Giant cell glioblastoma Gliosarcoma Louis DN et al. Acta Neuropathol 2007;114(2):97-109.

8. 1) What treatment would you recommend for this patient? Radiation therapy Temozolomide Radiation therapy plus temozolomide Other

9. Case History: Dr Batchelor (continued) Received radiation therapy/temozolomide on RTOG 98-13 Follow-up MRI 9 months after diagnosis revealed increased size of the mass Biopsy: GBM

10. 2) What treatment would you recommend for this patient? Bevacizumab Chemo/bevacizumab Temozolomide Nitrosourea Combination PCV Cyclophosphamide Platinum-based regimen Other

11. Case History: Dr Batchelor (continued) Phase II study with cilengitide monotherapy, with radiographic partial response After > 1 year on cilengitide, nodular enhancement outside the radiation field Cediranib x 4 months with initial tumor reduction followed by progression of FLAIR signal abnormality

12. Copyright © 2010, Research To Practice, All rights reserved. Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma Stupp R et al. J Clin Oncol 2010;28(16):2712-8.

13. Hypothesized Mechanisms of Action of Cilengitide With permission from Stupp R et al. Presentation. ASCO 2010;Abstract TPS152.

14. Survival Outcomes of Cilengitide Combined with Temozolomide and Radiation Therapy Stupp R et al. J Clin Oncol 2010;28(16):2712-8. Overall (n = 52) Methylated MGMT Promoter (n = 23) Unmethylated MGMT Promoter (n = 22) Median progression-free survival (PFS) 8.0 mo13.4 mo3.4 mo PFS rate at 24 mo15%28%5% Median overall survival (OS)16.1 mo23.2 mo13.1 mo OS rate at 24 mo35%46%20%

15. Copyright © 2010, Research To Practice, All rights reserved. Phase II Study of Cediranib, an Oral Pan-vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma Batchelor TT et al. J Clin Oncol 2010;28(17):2817-23.

16. Efficacy of Cediranib for Recurrent GBM Volumetric criteria Partial response by MRI 3-D measurement (n = 30)56.7% Minor response (n = 30)20.0% Macdonald criteria Partial response (n = 30)26.6% Alive and progression-free at 6 months (n = 31)25.8% Progression-free survival117 days Overall survival227 days Batchelor TT et al. J Clin Oncol 2010;28(17):2817-23.

17. Case History: Dr Batchelor (continued) Received bevacizumab/irinotecan (9 months) and bevacizumab/carboplatin (2 months) with stability of FLAIR until significant clinical decline Death 3 years after initial diagnosis Autopsy: extensive tumor infiltration throughout the left hemisphere, basal ganglia, splenium of the corpus callosum and right parietal and occipital lobes

18. Copyright © 2010, Research To Practice, All rights reserved. Updated Safety and Survival of Patients with Relapsed Glioblastoma Treated with Bevacizumab in the BRAIN Study Cloughesy T et al. Proc ASCO 2010;Abstract 2008.

19. BRAIN Study: Updated Survival Data Comparing Bevacizumab versus Bevacizumab plus Irinotecan in Recurrent GBM Bevacizumab (n = 85) Bevacizumab + Irinotecan (n = 82) 12-months survival38% 18-months survival24%18% 24-months survival16%17% 30-months survival11%16% Cloughesy T et al. Proc ASCO 2010;Abstract 2008.

20. BRAIN Study: Updated Safety Data Comparing Bevacizumab versus Bevacizumab plus Irinotecan in Recurrent GBM Grade > 3Bevacizumab Bevacizumab + Irinotecan Hypertension10.7%3.8% Cerebral Hemorrhage0%1.3% Venous Thromboembolism3.6%10.1% Arterial Thromboembolism3.6%2.5% GI Perforation0%2.5% Cloughesy T et al. Proc ASCO 2010;Abstract 2008.

21. Copyright © 2010, Research To Practice, All rights reserved. Long-Term Survival from the Initial Trial of Bevacizumab and Irinotecan Desjardins A et al. Proc ASCO 2010;Abstract 2045.

22. Efficacy and Safety of Bevacizumab plus Irinotecan in Recurrent GBM (N = 35) Partial Response Median Overall Survival 6-Month Survival 4-Year Survival 57%9.7 months46%8.6% Desjardins A et al. Proc ASCO 2010;Abstract 2045. Adverse events Thromboembolic events11% Grade 2 fatigue11% >Grade 3 GI toxicity11% Grade 2 proteinuria6% CNS hemorrhage3%

23. In the past year, how many new patients with GBM have you managed? Patterns of Care Survey of US-Based Medical Oncologists (n = 100) Patients Median = 4 patients 12% 47% 26% 15% >5 3-5 1-2 0

24. In the past year, how many patients with recurrent GBM have you treated with bevacizumab? Patterns of Care Survey of US-Based Medical Oncologists (n = 85) Median = 1 patient 18% 22% 35% 25% >2 2 1 0 Patients

25. Have you observed a clinically meaningful antitumor response to bevacizumab? Patterns of Care Survey of US-Based Medical Oncologists (n = 85) 62%Yes

26. What type of antitumor response to bevacizumab have observed in a patient with GBM? Patterns of Care Survey of US-Based Medical Oncologists (n = 53) 22% 12% 13% 25% 37% Other improvements Partial response Near complete response Stable disease Tumor shrinkage

28. —Erik Rupard, MD Fort Gordon, GA I have a patient in his early 60s with an unresectable, infratentorial Grade II astrocytoma with cerebellar involvement. Generally, we treat patients who have low grade disease with radiation therapy alone. Is there a role for adding in temozolomide for a patient like this man?

29. —Frank Rodriguez, MD Fort Myers, FL I am treating a 27-year-old woman with a resected anaplastic astrocytoma. She is receiving radiation therapy/temozolomide and tolerating therapy well. Would the thought leaders consider adding bevacizumab to temozolomide in an off-protocol setting, given her age, after she finishes chemo/radiation?

30. Case History: Dr Vredenburgh A 46 year old man with GBM Radiation therapy/temozolomide followed by temozolomide x 8 before progression Tumor EGFRv3-positive, PTEN-normal

31. 3) What treatment would you generally recommend? Bevacizumab Chemo/bevacizumab Temozolomide Nitrosourea Combination PCV Cyclophosphamide Platinum-based regimen Other

32. Case History: Dr Vredenburgh (continued) Received bevacizumab/erlotinib x 8 months, with response and clinical improvement Developed 1+, 2+, 3+ proteinuria

33. Case History: Dr Vredenburgh (continued) Patient continues receiving bevacizumab 5 mg/kg plus erlotinib for 19 months

34. MRI at Diagnosis

35. MRI at Progression

36. MRI Post-bevacizumab/erlotinib

37. Copyright © 2010, Research To Practice, All rights reserved. Clinical Features, Mechanisms, and Management of Pseudoprogression in Malignant Gliomas Brandsma D et al. Lancet Oncol 2008;9(5):453-61.

38. Brandsma D et al. Lancet Oncol 2008;9(5):453-61. Clinical Features of Pseudoprogression Discordance between the radiologic findings and the clinical status — most patients are asymptomatic Lesions decrease in size or stabilize without additional treatments Can occur in up to 20% of patients who have been treated with temozolomide plus radiation therapy Can explain ~ 50% of all cases of MRI-progression Adjuvant temozolomide should be continued

39. Copyright © 2010, Research To Practice, All rights reserved. Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro- Oncology (RANO) Working Group Wen PY et al. J Clin Oncol 2010;28(11):1963-72.

40. ResponseCriterion Complete ResponseComplete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically Partial Response≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no new lesions; stable or reduced corticosteroid dose; and stable or improved clinically Stable DiseaseDoes not qualify for complete response, partial response, or progression; and stable clinically Progression≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration Wen PY et al. J Clin Oncol 2010;28(11):1963-72. Current McDonald Criterion

41. Wen PY et al. J Clin Oncol 2010;28(11):1963-72. Select RANO Criterion Progression within 12 weeks after completion of chemoradiotherapy can only be defined using diagnostic imaging if there is a new enhancement outside of the radiation field or if there is viable tumor on histology.

42. In the past year, how many patients with GBM in your practice experienced “pseudoprogression”? Patterns of Care Survey of US-Based Medical Oncologists (n = 85) 7% 24% 25% 15% >2 2 1 0 Not familiar with pseudoprogression Patients 29%

43. Copyright © 2010, Research To Practice, All rights reserved. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma Stupp R et al. N Engl J Med 2005;352(10):987-96.

44. Copyright © 2010, Research To Practice, All rights reserved. Effects of Radiotherapy with Concomitant and Adjuvant Temozolomide versus Radiotherapy Alone on Survival in Glioblastoma in a Randomised Phase III Study: 5-year Analysis of the EORTC-NCIC Trial Stupp R et al. Lancet Oncol 2009;10(5):459-66.

45. Survival Benefit of Adjuvant Temozolomide in GBM Radiation Alone Radiation- Temozolomide 1 Hazard Ratiop-value Overall Survival (Median) 12.1 months14.6 months0.63< 0.001 2-Year Survival10.4%26.5% Not Reported Not reported PFS (Median)5.0 months6.9 months0.54< 0.001 Temozolomide was administered at 75mg/m 2 PO QD for up to seven weeks with RT Post-RT, temozolomide was administered at 150 mg/m 2, days 1-5 cycle 1, and then temozolomide 150-200mg/m 2 q 28 days in cycles 2-6 Stupp R et al. N Engl J Med 2005;352(10):987-96.

46. Phase III Trial of Radiation Therapy with or without Temozolomide for Newly Diagnosed GBM: Five-Year Survival Analysis Stupp R et al. Lancet Oncol 2009;10(5):459-66. Hazard ratio Median survival Two years Five years Overall XRT XRT + T 1.0 0.6 12.1 mo 14.6 mo 10.9% 27.2% 1.9% 9.8% MGMT unmethylated XRT XRT + T 1.0 0.6 11.8 mo 12.6 mo 1.8% 14.8% 0% 8.3% MGMT methylated* XRT XRT + T 0.5 0.3 15.3 mo 23.4 mo 23.9% 48.9% 5.2% 13.8% * Hazard ratio relative to MGMT unmethylated XRT

47. Copyright © 2010, Research To Practice, All rights reserved. Bevacizumab (BEV) in Combination With Temozolomide (TMZ) and Radiation Therapy (XRT) Followed by BEV, TMZ, and Irinotecan for Newly Diagnosed Glioblastoma Multiforme (GBM) Vredenburgh JJ et al. Proc ASCO 2010;Abstract 2023.

48. Survival Outcomes of Bevacizumab, Temozolomide and Radiation Therapy Vredenburgh JJ et al. Proc ASCO 2010;Abstract 2023. Efficacy data (n = 75)Outcome Median progression-free survival (PFS)14.2 months Two-year PFS13.3% Median overall survival (OS)21.2 months Two-year OS45%

49. Copyright © 2010, Research To Practice, All rights reserved. Phase II trial of Bevacizumab in Combination with Temozolomide and Regional Radiation Therapy for Up-front Treatment of Patients with Newly Diagnosed Glioblastoma Multiforme Lai A et al. Proc ASCO 2009;Abstract 2000.

50. Bevacizumab in Combination with Radiation and Temozolomide in Up-front Management of GBM Bevacizumab- Radiation- Temozolomide (n = 70) Radiation- Temozolomide (Matched Control- Group)p-value Progression-Free Survival 13.0 months8.1 months0.0395 Overall Survival25.0 months21.1 months0.4 Lai A et al. Proc ASCO 2009;Abstract 2000.

51. RTOG-0825: Phase III Trial Evaluating the Role of Bevacizumab in the Up-Front Management of GBM Target Accrual: 720 Radiation therapy Temozolomide Placebo Radiation therapy Temozolomide Bevacizumab Newly diagnosed GBM Partial or complete surgical resection within 3-5 weeks R www.clinicaltrials.gov, October 2010.

52. In the past year, how many patients with GBM have you treated with bevacizumab + temozolomide + radiation after primary surgery? Patterns of Care Survey of US-Based Medical Oncologists (n = 85) Patients Median = 1 patient 4% 15% 20% 60% >3 2-3 1 0

53. —Richard Polkinghorn, MD Brunswick, ME Recently, I treated two men in their 40s who had GBMs with nearly complete resections and radiation therapy/temozolomide. I sent them to Duke and both were put on bevacizumab and continued temozolomide. That’s in variance with many of our consultants in Boston, who do not tend to use bevacizumab as initial adjuvant therapy. Any thoughts?

54. —Neal Fishbach, MD Fairfield, CT I was intrigued by reports at ASCO this year, which raised the issue of whether radiation therapy was indicated in elderly patients with GBM. What do the investigators think about that data? Treating patients with temozolomide alone would probably result in a big improvement in quality-of-life for some patients.

55. Case History: Dr Batchelor A 68-year-old man presents with a generalized seizure MRI: Right parietal mass Subtotal-resection of a pathologically-confirmed GBM

56. MRI at Diagnosis

57. 4) Which additional diagnostic tests would you obtain on this patient? MGMT methylation status of the tumor Chromosome 1p and 19q testing Spinal MRI to screen for extent of tumor dissemination None

58. Case History: Dr Batchelor (continued) Patient receives radiation and temozolomide Evidence of tumor progression at 26-months after initial diagnosis

59. MRI at Progression

60. 5) How would you manage the patient now? Hospice care Dose-dense temozolomide Bevacizumab monotherapy Bevacizumab + irinotecan Second course of radiation

61. Case History: Dr Batchelor (continued) Patient started on bevacizumab therapy with objective improvement Remains on bevacizumab therapy for 24 months with sustained disease control and mild fatigue

62. MRI Post-bevacizumab

63. 6) Would you continue bevacizumab? Yes No

64. Copyright © 2010, Research To Practice, All rights reserved. NOA-08 Randomized Phase III Trial of 1-week-on/1-week-off Temozolomide Versus Involved- Field Radiotherapy in Elderly (Older Than Age 65) Patients With Newly Diagnosed Anaplastic Astrocytoma or Glioblastoma (Methusalem) Wick W et al. Proc ASCO 2010;Abstract LBA 2001.

65. NOA-08 Phase III Trial Design Temozolomide 100 mg/m 2 daily x 7 q14d Radiotherapy daily 30 x 1.8-2 Gy Anaplastic astrocytoma or Glioblastoma Age > 65 R PD Radiotherapy daily 30 x 1.8-2 Gy Temozolomide 100 mg/m 2 daily x 7 q14d Wick W et al. Proc ASCO 2010;Abstract LBA 2001.

66. Survival Outcomes for Temozolomide versus Radiotherapy ITT Population (N = 373) Radiotherapy (n = 179) Temozolomide (n = 194) Median overall survival293 days245 day 12-month overall survival38.3%30.8% Hazard ratio (95% CI)1.24 (0.94-1.63) The rate of adverse and serious adverse events was higher in the temozolomide arm Wick W et al. Proc ASCO 2010;Abstract LBA 2001.

67. Copyright © 2010, Research To Practice, All rights reserved. Glioblastoma (GBM) in Elderly Patients: A Randomized Phase III Trial Comparing Survival in Patients Treated with 6-week Radiotherapy (RT) Versus Hypofractionated RT Over 2 Weeks versus Temozolomide Single- Agent Chemotherapy (TMZ) Malmstrom A et al. Proc ASCO 2010;Abstract LBA 2002.

68. Nordic Clinical Brain Tumor Study Group Phase III Trial Design Radiotherapy 60 Gy (2 Gy x 30) Radiotherapy 34 Gy (3.4 Gy x 10) Glioblastoma Age ≥ 60 Temozolomide x 6 (200 mg/m 2 d 1-5 q 28 d) R Malmstrom A et al. Proc ASCO 2010;Abstract LBA 2002.

69. Survival Outcomes with Radiation Therapy versus Temozolomide (TMZ) TMZ (n = 119) RT 60 Gy (n = 100) RT 34 Gy (n = 123) Median overall survival (ITT) 1 8.3 months6.0 months7.5 months 60-70 years old7.9 months7.6 months8.8 months >70 years old 2 8.0 months5.2 months7.1 months 1 ITT 60 Gy vs TMZ, p = 0.02 60 Gy vs 34 Gy, p = 0.32 34 Gy vs TMZ, p = 0.18 2 >70 years old 60 Gy vs TMZ, p < 0.001 60 Gy vs 34 Gy, p = 0.02 34 Gy vs TMZ, p = 0.17 Malmstrom A et al. Proc ASCO 2010;Abstract LBA 2002.

70. Is there data to support retreatment with bevacizumab in patients with progressive primary CNS tumors?

71. I’m interested in your comment regarding telling patients on bevacizumab to get out and exercise. I may have missed something, but is that to counter-act the fatigue that occurs with the drug? Sarasota, FL