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 II: Ovarian CancerMonday, September 27, 20107:30 PM - 8:30 PM ET

2. Deborah K Armstrong, MD Associate Professor of Oncology, Gynecology and Obstetrics The Sidney Kimmel Comprehensive Cancer Center The Johns Hopkins University Baltimore, Maryland David R Spriggs, MD Head, Division of Solid Tumor Oncology Winthrop Rockefeller Chair of Medical Oncology Memorial Sloan-Kettering Cancer Center New York, New York 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, Genzyme Corporation, Lilly USA LLC, Millennium Pharmaceuticals Inc, Monogram BioSciences Inc, Myriad Genetics, Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi-Aventis and Spectrum Pharmaceuticals Inc.

4. Disclosures for Deborah K Armstrong, MD N/A = Not Applicable

5. Disclosures for David R Spriggs, MD N/A = Not Applicable

6. Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian CancerVergote I et al.N Engl J Med 2010;363(10):943-53.Phase III Trial of Bevacizumab (BEV) in the Primary Treatment of Advanced Epithelial Ovarian Cancer (EOC), Primary Peritoneal Cancer (PPC), or Fallopian Tube Cancer (FTC): A Gynecologic Oncology Group StudyBurger RA et al.Proc ASCO 2010;Abstract LBA1.Can We Define Tumors That Will Respond to PARP Inhibitors? A Phase II Correlative Study of Olaparib in Advanced Serous Ovarian Cancer and Triple-Negative Breast CancerGelmon KA et al.Proc ASCO 2010;Abstract 3002.

7. Case History: Dr Spriggs • A 53-year-old woman with symptomatic ascites and clinically suspected bulky Stage III ovarian cancer • Gyn exam and Pap smear 8 months ago were normal • A gynecologic oncologist consultant estimates a 50/50 probability of an optimal debulking surgery

8. 1) Would you generally recommend neoadjuvant chemotherapy? Yes No

9. Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer Vergote I et al. N Engl J Med 2010;363(10):943-53.

10. Neoadjuvant Chemotherapy with Interval Debulking Surgery versus Primary Debulking Surgery in Stage IIIC/IV Ovarian Cancer (N=632) Hazard Ratio for Death (Intention-to-Treat) NACT versus PDS HR = 0.98, p = 0.01 Vergote I et al. NEJM 2010;363(10):943-53.

11. Case History: Dr Spriggs (continued) • Patient elects primary surgery • Visible residual disease (0.5 cm with miliary pattern) on bowel surface • Surgeon leaves an intraperitoneal port

12. 2) The patient returns to your office three weeks after surgery. What is your recommendation for chemotherapy? IV paclitaxel, IP cisplatin and IP paclitaxel IV carboplatin, IV paclitaxel and bevacizumab IP carboplatin,IV paclitaxel Carboplatin, paclitaxel, gemcitabine

13. During the past year, approximately how many new patients with ovarian cancer have you treated with intraperitoneal chemotherapy? Number of Patients None 1-2 3-5 >5 68% 17% 8% 7% 0% 20% 40% 60% 80% National Patterns of Care Survey, September 2010 (n = 81)

14. How would you advise a younger (eg, age 55), healthy woman inquiring about the side effects and risks of intraperitoneal therapy compared to IV chemo? Likely to be quite tolerable Likely to be somewhat difficult Likely to be very difficult 23% 69% 8% 0% 20% 40% 60% 80% National Patterns of Care Survey, September 2010 (n = 26)

15. Survival Outcomes with IP Chemotherapy in Optimally Debulked Ovarian Cancer cis = cisplatin; carbo = carboplatin 1 Alberts DS et al. NEJM 1996;335:1950-1955. 2 Markman M et al. JCO 2001;19:1001-1007. 3 Armstrong DK et al. NEJM 2006;354:34-43.

16. Phase III Trial of Bevacizumab (BEV) in the Primary Treatment of Advanced Epithelial Ovarian Cancer (EOC), Primary Peritoneal Cancer (PPC), or Fallopian Tube Cancer (FTC): A Gynecologic Oncology Group Study Burger RA et al. Proc ASCO 2010;Abstract LBA1.

17. GOG-0218 Primary Endpoint: PFS 1.0 CP + Bev  Bev vs. CPHR = 0.717, p < 0.0001 0.9 0.8 Proportion surviving progression free 0.7 0.6 0.5 0.4 0.3 0.2 CP (Arm I) + Bev (Arm II) 0.1 + Bev  Bev maintenance (Arm III) 0 0 12 24 36 Months since randomization With permission from Burger RA et al. Proc ASCO 2010;Abstract LBA1.

18. GOG-0218: Select Adverse Events *GI events include perforation, fistula, necrosis and leak. Burger RA et al. ProcASCO 2010;Abstract LBA1.

19. Phase III Study of Adding Bevacizumab to Standard Chemotherapy Carbo + Paclitaxel R Carbo + Paclitaxel + Bev 7.5 mg/kg Protocol ID: MREC-ICON7 Bev 7.5 mg/kg q21 d x 12 mo Target Accrual: 1,520 www.clinicaltrials.gov, September 2010.

20. Phase III Study of Bevacizumab and Intravenous or Intraperitoneal Chemotherapy in Stage II-IV Ovarian Epithelial, Fallopian Tube or Primary Peritoneal Cancer Protocol ID: GOG-0252 Target Accrual: 1,250 R Cycles 1-6 Paclitaxel IV Carbo IV Bev 15 mg/kg IV Paclitaxel IV Carbo IP Bev 15 mg/kg IV Paclitaxel IV Cis IP Paclitaxel IP Bev 15 mg/kg IV Bev 15 mg/kg IV to 22 cycles www.clinicaltrials.gov, September 2010.

21. Case History: Dr Spriggs (continued) • Patient treated with a regimen containing IV paclitaxel, IP cisplatin and IP paclitaxel • Clinical remission after three cycles of therapy • Normal CA125 • Negative CT • Course complicated by nausea and grade 2 painful neuropathy

22. Treatment options for this patient • Single-agent liposomal doxorubicin • IV docetaxel / IV carboplatin • Single-agent IP carboplatin • Continue IV paclitaxel, IP cisplatin and IP paclitaxel — this is curative intent therapy • No further treatment

24. 2010 Survey of 100 US-based Oncologists Estimated Number of New Cases Per Year (median) *2009 survey data

25. During the past year, approximately how many new patients with ovarian cancer have you treated with bevacizumab + chemotherapy for surgically resected Stage III or IV disease? Number of Patients None 1 2 >2 64% 11% 12% 13% 0% 20% 40% 60% 80% National Patterns of Care Survey, September 2010 (n = 81)

26. What would you tell a woman who has previously undergone uncomplicated debulking surgery without bowel resection is the excess risk for bowel perforation for receiving bevacizumab 1 year after completing chemotherapy? Percent excess risk ≤2% 3-5% 6-10% >10% 22% 46% 14% Median = 5% 18% 0% 10% 20% 30% 40% 50% National Patterns of Care Survey, September 2010 (n = 81)

28. Dr Armstrong, why hasn’t there been more uniformity in the field of gyn oncology for the use of IP therapy?

29. Case History: Dr Armstrong 60 yo woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Deemed unresectable by a gynecologic oncologist Neoadjuvant carbo/pac x 3 without response Topotecan x 3 without response Weekly paracentesis for palliation CA-125 = 6916

30. Commonly Utilized Regimens for Platinum- Resistant, Recurrent Ovarian Cancer Platinum Resistant (Relapse < 6 mo after chemo) • Docetaxel • Oral etoposide • Gemcitabine • PLD • Weekly paclitaxel • Pemetrexed • Topotecan Targeted therapy • Bevacizumab

31. Docetaxel 3) What would be your most likely treatment recommendation? Oral etoposide Gemcitabine PLD Weekly paclitaxel Pemetrexed Topotecan Bevacizumab

32. Case History: Dr Armstrong (continued) • Patient enrolled on GOG 170D with bevacizumab 15 mg/kg IV q 3 weeks • Resolution of ascites in 1 wk and all GI symptoms w/in 3 wks • Marked response by imaging but unpredictable by CA-125 • Remained on therapy for 21 months before progression

33. Single Agent Bevacizumab in Refractory Ovarian Cancer: GOG 170D Post-4 cycles Pre-Treatment

34. Bevacizumab in Recurrent Ovarian Cancer: GOG 170D 25000 Bevacizumab 20000 15000 CA-125 10000 5000 0 Day 1 18 Months

35. Bevacizumab Trials in Relapsed EOC 1Burger RA et al. J Clin Oncol 2007;25(33):5165-71.2Garcia A et al. J Clin Oncol 2008;26(1):76-82. 3Cannistra SA et al. J Clin Oncol 2007;25(33):5180-86.

36. A Randomized, Phase III Study of Carboplatin and Pegylated Liposomal Doxorubicin Versus Carboplatin and Paclitaxel in Relapsed Platinum-sensitive Ovarian Cancer (OC): CALYPSO Study of the Gynecologic Cancer Intergroup (GCIG) Pujade-Lauraine E et al. Proc ASCO 2009;Abstract LBA5509.

37. CALYPSO: Progression-Free Survival (PFS) with Carboplatin (C) and Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin and Paclitaxel (P) in Relapsed Platinum-Sensitive Ovarian Cancer With permission from Pujade-Lauraine E et al. Proc ASCO 2009;Abstract LBA5509.

38. Can We Define Tumors That Will Respond to PARP Inhibitors? A Phase II Correlative Study of Olaparib in Advanced Serous Ovarian Cancer and Triple-Negative Breast Cancer Gelmon KA et al. Proc ASCO 2010;Abstract 3002.

39. Objective Response Rates to Olaparib in Patients with Advanced OC or TNBC According to BRCA Mutation Status *BRCA mutation-negative patients in study were 46 patients with high-grade serous ovarian carcinoma and 15 patients with triple-negative breast cancer. Gelmon KA et al. ProcASCO 2010;Abstract 3002.

40. Change in Target Lesion Size by OC Tumor Type and BRCA Mutation Status 100 Serous OC/BRCA-positive Non-serous OC/BRCA-positive Serous OC/BRCA-negative Non-serous OC/BRCA-negative 80 60 40 20 Best % change from baseline 0 -20 -40 -60 -80 -100 The majority of patients with ovarian cancer had some tumor shrinking with olaparib irrespective of their BRCA mutation status. With permission from Gelmon KA et al. ProcASCO 2010;Abstract 3002.

41. What is the role of a second-look surgery in treatment plan

42. Would like to know about other late stage therapies in ovarian cancer targeting angiogenesis

43. Can we ever cure stage III or IV