Monday Night with Research To Practice: An 8-Part Live CME Webcast Series

1. Monday Night with Research To Practice: An 8-Part Live CME Webcast Series Part V: Central Nervous System CancersMonday, October 18, 20107:30 PM - 8:30 PM ET

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, MDModerator Research To PracticeMiami, 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

5. Disclosures for James J Vredenburgh, MD N/A = Not Applicable

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 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. 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.

15. 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 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. 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 Cloughesy T et al. Proc ASCO 2010;Abstract 2008.

20. BRAIN Study: Updated Safety Data Comparing Bevacizumab versus Bevacizumab plus Irinotecan in Recurrent GBM Cloughesy T et al. Proc ASCO 2010;Abstract 2008.

21. 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) Desjardins A et al. Proc ASCO 2010;Abstract 2045.

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

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

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

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

28. Erik Rupard, MDFort 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, MDFort 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. Clinical Features, Mechanisms, and Management of Pseudoprogression in Malignant Gliomas Brandsma D et al. Lancet Oncol 2008;9(5):453-61.

38. 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 Brandsma D et al. Lancet Oncol 2008;9(5):453-61.

39. 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. Current McDonald Criterion Wen PY et al. J Clin Oncol 2010;28(11):1963-72.

41. 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. Wen PY et al. J Clin Oncol 2010;28(11):1963-72.

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

43. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma Stupp R et al. N Engl J Med 2005;352(10):987-96.

44. 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 Temozolomidein GBM Temozolomide was administered at 75mg/m2 PO QD for up to seven weeks with RT Post-RT, temozolomide was administered at 150 mg/m2, days 1-5 cycle 1, and then temozolomide 150-200mg/m2 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 *Hazard ratio relative to MGMT unmethylated XRT Stupp R et al. Lancet Oncol 2009;10(5):459-66.

47. 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.

49. 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 Lai A et al. Proc ASCO 2009;Abstract 2000.