1. Copyright © 2010, Research To Practice, All rights reserved. Part II: Ovarian Cancer Monday, September 27, 2010 7:30 PM - 8:30 PM ET Monday Night with Research To Practice: An 8-Part Live CME Webcast Series

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, 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, 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 Advisory Committee Abraxis BioScience, Amgen Inc, Boehringer Ingelheim Pharmaceuticals Inc, Genentech BioOncology Paid ResearchN/A Speakers BureauN/A

5. Disclosures for David R Spriggs, MD Advisory Committee AstraZeneca Pharmaceuticals LP, Johnson & Johnson Pharmaceuticals Paid ResearchGenentech BioOncology Speakers BureauN/A N/A = Not Applicable

6. Copyright © 2010, Research To Practice, All rights reserved. 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. 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. 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.

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. Copyright © 2010, Research To Practice, All rights reserved. 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) Vergote I et al. NEJM 2010;363(10):943-53. Hazard Ratio for Death (Intention-to-Treat) NACT versus PDS HR = 0.98, p = 0.01

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? 7% 8% 17% 68% 0%20%40%60%80% None 1-2 3-5 >5 Number of Patients 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? 8% 69% 23% 0%20%40%60%80% Likely to be quite tolerable Likely to be somewhat difficult Likely to be very difficult National Patterns of Care Survey, September 2010 (n = 26)

15. Survival Outcomes with IP Chemotherapy in Optimally Debulked Ovarian Cancer Phase III Study NRegimen Survival Outcome 1 GOG-104654 IP cis + IV cyclophosphamide IV cis + IV cyclophosphamide HR=0.76 2 GOG-114523 IP cis + IV paclitaxel + IV carbo IV cis + IV paclitaxel RR=0.81 3 GOG-172415 IP cis + IV paclitaxel + IP paclitaxel IV cis + IV paclitaxel RR=0.75 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. cis = cisplatin; carbo = carboplatin

16. Copyright © 2010, Research To Practice, All rights reserved. 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 With permission from Burger RA et al. Proc ASCO 2010;Abstract LBA1. 1.0 0 Proportion surviving progression free Months since randomization CP (Arm I) 123624 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 + Bev (Arm II) + Bev  Bev maintenance (Arm III) CP + Bev  Bev vs. CP HR = 0.717, p < 0.0001

18. GOG-0218: Select Adverse Events Adverse Event Arm I CP (n = 601) Arm II CP + Bev (n = 607) Arm III CP + Bev  Bev (n = 608) GI events (grade ≥2)* 1.2%2.8%2.6% HTN (grade ≥2)7.2%16.5%22.9% Proteinuria0.7% 1.6% Venous thromboembolic events5.8%5.3%6.7% Arterial thrombotic events0.8%0.7% CNS bleeding0% 0.3% Non-CNS bleeding0.8%1.3%2.1% Burger RA et al. Proc ASCO 2010;Abstract LBA1. *GI events include perforation, fistula, necrosis and leak.

19. Eligibility High-risk Stage I or IIA Any Stage IIB-IV Ovarian epithelial, fallopian tube and peritoneal cancer Protocol ID: MREC-ICON7 Target Accrual: 1,520 Phase III Study of Adding Bevacizumab to Standard Chemotherapy www.clinicaltrials.gov, September 2010. Carbo + Paclitaxel Carbo + Paclitaxel + Bev 7.5 mg/kg q21 d x 12 mo R

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

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 1.Single-agent liposomal doxorubicin 2.IV docetaxel / IV carboplatin 3.Single-agent IP carboplatin 4.Continue IV paclitaxel, IP cisplatin and IP paclitaxel — this is curative intent therapy 5.No further treatment

24. 2010 Survey of 100 US-based Oncologists Estimated Number of New Cases Per Year (median) Cancer TypeNew Cases per Year Ovarian5 Breast40 Non-small cell lung28 Colorectal25 Renal5 Follicular lymphoma15 Multiple myeloma10 Hepatocellular carcinoma5* *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? 13% 12% 11% 64% 0%20%40%60%80% None 1 2 >2 Number of Patients 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? 18% 14% 46% 22% 0%10%20%30%40%50% ≤2% 3-5% 6-10% >10% Percent excess risk National Patterns of Care Survey, September 2010 (n = 81) Median = 5%

28. Copyright © 2010, Research To Practice, All rights reserved. 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. 3) What would be your most likely treatment recommendation? Docetaxel 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 Pre-Treatment Post-4 cycles

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

35. Bevacizumab Trials in Relapsed EOC GOG 170-D 1 (N = 62) NCI 5789 2 (N = 90) Cannistra 3 (N = 44) Study Treatment Single agent BV 15 mg/kg q 3 wk BV 10 mg/kg q 2 wks + low dose oral cytoxan Single agent BV 15 mg/kg q 3 wk Prior Treatment Setting Relapsed, up to 2 prior regimens, 1 platinum-based Relapsed, prior platinum therapy for primary w/ post-platinum maximum of 2 regimens Platinum resistant, up to 3 regimens Efficacy Results ORR 6-mo PFS 21% 40% 24% 56% 16% 28% GI perforation02 (3%)5 (11%) 1 Burger RA et al. J Clin Oncol 2007;25(33):5165-71. 2 Garcia A et al. J Clin Oncol 2008;26(1):76-82. 3 Cannistra SA et al. J Clin Oncol 2007;25(33):5180-86.

36. Copyright © 2010, Research To Practice, All rights reserved. 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. Copyright © 2010, Research To Practice, All rights reserved. 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. BRCA Mutation-PositiveBRCA Mutation-Negative* Ovarian7/17 (41.2%)11/46 (23.9%) Breast0/8 (0)0/15 (0) 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. Proc ASCO 2010;Abstract 3002.

40. Best % change from baseline 100 80 60 40 20 0 -20 -40 -60 -80 -100 Change in Target Lesion Size by OC Tumor Type and BRCA Mutation Status 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. Proc ASCO 2010;Abstract 3002. Serous OC/BRCA-positive Non-serous OC/BRCA-positive Serous OC/BRCA-negative Non-serous OC/BRCA-negative

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