1. Optimal Treatment of Ovarian Cancer Jan B Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium Masterclass, Ermatingen, Switzerland, April 4, 2011

4. Epithelial Ovarian Cancer: Recurrent Disease Case #2 A 62 year old post-menopausal woman presents with bulky pelvic and abdominal recurrence of her epithelial ovarian cancer. 10 months previously she achieved a complete response after treatment with carboplatin- paclitaxel x 6 cycles. She still suffers some peripheral neuropathy (grade 1). Her ECOG performance status is 1. The patient would like to receive aggressive treatment for her recurrent disease.

5. Epithelial Ovarian Cancer: Recurrent Disease Case #2 Should this patient have debulking surgery? Yes/No What chemotherapy would you give this patient? Carboplatin-paclitaxel (Taxol) Carboplatin-gemcitabine (Gemsar) Carboplatin-PLD (Caelyx) PLD-trabectedin (Yondelis) Carboplatin monotherapy PLD (Caelyx) Topotecan (Hycamtin) Gemcitabine Other

9. Five-year Survival in Ovarian Cancer 30 years of experience Vol. Year Cases Ia IV Overall (n) % 16 1963-68 4588 66.7 5.0 27.3 19 1976-78 6724 72.3 4.5 29.8 21 1982-86 10912 82.3 8.0 35.0 23 1990-92 7059 83.5 11.1 41.6 25 1996-98 4116 89.3 13.4 46.4 26* 1999-01 4911 89.3 18.6 49.7 Int. J Gynecol Obstet 2006 (Suppl 1)

11. Epithelial Ovarian Cancer Milestones http://ctep.cancer.gov/resources/gcig/index.html

14. Biologic Characteristics of Tumor vs Aggressiveness of Surgery in ADOVCA A basis for NACT? Chemosensitive Successful Debulking Survival

17. Vergote et al, N Engl J Med 2010; 363: 943-953

18. Vergote et al, N Engl J Med 2010; 363: 943-953

20. Front-line Trials in Advanced Ovarian Cancer Adding a third drug* Lead Group Arm I Arm II Accrual Outcome AGO TC TC + epirubicin 1282 no benefit NSGO TC TC + epirubicin 887 no benefit AGO TC TC -> TPT 1308 no benefit GOG TC TC + GEM 4312 no benefit TC + LPD GEM + C -> TC TPT + C -> TC NCIC-CTG TC TPT + P -> TC 819 no benefit AGO TC TC + GEM 1742 no benefit * GCIG trials

21. Consolidation/Maintenance Therapies Cytotoxic therapy Study Patients Randomization Results Scarfone ’02 n=162 III-IV, SSL, pCR Pt-Tax based Epirubicin x 4 vs observation OS NS Pfisterer (2003) n=1308 IIb-IV Tax-Carbo Topotecan x 4 vs observation PFS NS OS NS De Placido (2004) n=273 III-IV, SSL, pCR < 2 cm, Pt-based Topotecan x 4 vs observation PFS NS OS NS Markman ’03 N=277 III-IV Tax-Carbo, cCR Paclitaxel 3 or 12 cycles PFS 21 mo vs 28 mo P < 0.005

22. Markman et al, JCO 2003; 21: 2460-2465

23. Schema New Ovarian Elaborate Trial: NOVEL Trial Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube cancer FIGO Stage II-IV Conventional TC (c-TC) Paclitaxel 180mg/m 2 , day 1 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80mg/m 2 , days 1,8,15 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles Randomization Stratification; Residual disease: < 1cm, > 1cm FIGO Stage ： II vs. III vs. IV Histology ： clear cell/mucinous vs.serous/others Isohishi et al, ASCO 2008 (abstract #5506) Katsumata et al, Lancet 2009: 374: 1331-1338

24. Dose-dense TC (weekly T, 3-weekly C) ASCO 2008 * /Lancet 2009 PFS dd-TC vs c-TC: HR 0.714 p=0.0015 OS dd-TC vs C-TC: HR 0.735 p=0.0496 *Isohishi et al for JGOG, Katsumata et al. Lancet 2009; 374:1331-8

26. IP Chemotherapy in ADOVCA “Recognition at last” Vermorken JB. Ann Oncol 2006; 17 (suppl. 10): x241-x246

27. IPCT vs IVCT in Advanced Ovarian Cancer Overall survival Investigators No. of Overall survival (mo) year published pts Control arm Exp. Arm Alberts et al, 1996 546 41 49 1 Polyzos et al, 1999 90 25 26 Gadducci et al, 2000 113 51 67 Markman et al, 2001 462 52 63 2 Yen et al, 2001 118 48 43 Armstrong et al, 2006 415 50 66 3 1 p = 0.02; 2 p = 0.05; 3 p = 0.03

28. Pooled Data (all cisplatin studies) HR 0.79 (95% CI : 0.70, 0.89)

31. Targeted Therapies in Ovarian Cancer Target Drug(s) ErbB kinases Gefitinib, erlotinib, lapatinib, canertinib, cetuximab, pertuzumab, matuzumab, trastuzumab MUC1 / PEM Pemtumomab MUC16 (CA 125) Oregovomab mTOR / AKT Temsirolimus, everolimus, deforolimus Apoptosis pathway AEG35156, OGX-011 Angiogenesis Bevacizumab, sunitinib, sorafenib, pazopanib, cediranib, vatalanib Endothelial cells Combretastatin, Oxi4503 Matrix metalloproteinases BAY 12-9566, marimastat

32. Summary of Completed OC Trials with Bevacizumab (B) Trial Rec/Prim Regimen Outcome Toxicity Burger et al 2007 Rec B 15 mg/kg RR 21%, PFS 4.7 mo G 3/4 GI G3 RR  , G4 Prot Cannistra et al 2008 Rec B 15 mg/kg RR 15.9%, PFS 4.4 mo OS 10.7 GIP 11% ATE 6.8% G3 RR  9.1% Micha et al 2007 Prim B 15 mg/kg + TC RR 80% G 3/4 ANC 48.3% G3 RR  11% DVT 11%

36. Recurrent Ovarian Cancer Vermorken JB. Second line randomized trials in epithelial ovarian cancer; Int J Gynecol Cancer 2008; vol. 18 (suppl. 1): 59-66

38. Patient VBH (°1944): CA-125 Levels Vermorken JB. Int J Gynecol Cancer 2008; vol. 18 (suppl. 1): 59-66 04/1997: ADOVCA IIIc CAPx3  IDS  CAPx4 05/1999: 1st relapse TCx6  CR 02/2002: 2nd relapse GVPx6  CR 10/2003: 3rd relapse DIPx5  SD 01/2006: PD Caelyxx7  PR 01/2005: PD TPTx4  PR 08/2006: PD GPd1+8 (low dose) Normal range

41. Proportion of Patients Relapsing at Various Time Points Modified from Piccart et al, J Natl Cancer Inst. 2000; 92: 699-708 OV-10: Randomized Intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in advanced ovarian cancer 8% 20% 50%

43. When to Treat? Harries and Gore, 2002

44. Early Treatment of Relapsed Ovarian Cancer Based on CA125 Level Alone versus Delayed Treatment Based on Conventional Clinical Indicators Results of the Randomized MRC OV05 and EORTC 55955 Trials Gordon Rustin (Mount Vernon Cancer Centre) and Maria van der Burg On behalf of all OV05 and 55955 Collaborators 31 st May 2009

45. Trial Design Ovarian cancer in complete remission after first-line platinum based chemotherapy and a normal CA125 CA125>2 x upper limit of normal RANDOMIZED Early treatment Clinician and patient informed Delayed treatment Clinician not informed , treatment delayed until clinically indicated REGISTER Blinded CA125 measured every 3 months Rustin GJ et al, Lancet 2010; vol 376: 1155-1163

46. Overall Survival HR=1.00 (95%CI 0.82-1.22) p=0.98 Early Delayed Abs diff at 2 years= 0.1% (95% CI diff= -6.8, 6.3%) Rustin GJ et al, Lancet 2010; vol 376: 1155-1163

47. Time from Randomisation to First Deterioration in Global Health Score (or death) Proportion alive without deterioration in GHS Number at risk Rustin GJ et al, Lancet 2010; vol 376: 1155-1163

50. Single Agent Chemotherapy in ROC Relationship with platinum sensitivity Agent Response rates (%; range) Refractory Resistant Sensitive Platinum < 10 27-34 59-77 Paclitaxel 3-22 11-37 22-55 Topotecan 6-11 15-18 19-33 Gemcitabine 15-20 19-27 34 Epirubicin 11 a 14 36 Liposomal dox 11 9-15 18-37 Vinorelbine 15-30 21-33 29 Etoposide 27 27 34 Altretamine 10-14 40 Trabectedin 7 37 Conte PF, 2000; Vermorken JB 2000 ( a PFI < 3 mo) Johnston & Gore 2001, Stebbing & Gaya 2002 Monk et al, 2008

53. Progression-Free Survival (ITT) Pujade-Lauraine et al, J Clin Oncol 2010; 28: 3323-3329

54. CALYPSO study: Toxicity Toxicity (G3/4); % CD (n=466) CP (n=501) P Value Neutropenia 35 46 <0.01 Thrombocytopenia 16 6 <0.001 Severe HTOX - Leading to TRT disc 28 6 39 15 <0.01 <0.001 Alopecia (≥ G2; %) 7 84 <0.001 HSR 6 19 <0.001 Sensory neuropathie 5 27 <0.001 HSF (G2-3) 12 2 <0.001 Nausea 35 24 <0.001 Mucositis 14 7 <0.001 Pujade-Lauraine et al, J Clin Oncol 2010; 28: 3323-3329

58. OS in the Partially Platinum-Sensitive Population Poveda et al. Annals of Oncology 2010 ; doi:10.1093/annonc/mdq352

59. Safety Profile Selected Grade 3-4 Clinically Relevant AEs PLD n=330 n (%) Trabectedin + PLD n=333 n (%) Hand-foot syndrome 65 (20) 13 (4) Mucosal Inflammation 19 (6) 7 (2) Stomatitis 17 (5) 3 (1) Monk BJ et al. J Clin Oncol 28:3107-3114 (EPAR). Yondelis H-773-II-08 Assessment Report. European Medicines Agency (EMEA), January 2010

60. Mean ALT Among All Patients During Treatment With Trabectedin + PLD 0 1 2 3 4 5 6 Cycle Mean ALT/ULN 1 2 3 4 5 6 7 8 n= 333 309 271 230 205 169 125 105 ALT elevation leading to: Dose Reduction: 18 (5%) Dose Delay: 12 (4%)

65. Radiotherapy after Induction Chemotherapy in ADOVCA for Consolidation During 1988-1993: 742 patients with stage III EOC received 4 cycles of AP or EP Those will cCR or cPRor NED  second look At SL 3 groups: pCR, pPR, sPR 172 could be randomized: 98 in pCR group Whole abdominal radiotherapy  Rec.n=16; 50%* 6 cycles of AP or EP  Rec.n=25; 71%* no further therapy  Rec.n=23; 74%* Sorbe B, 2003 (* p=0.027)

66. Sorbe B, 2003 (progression-free survival  , p=0.032)

67. Consolidation/Maintenance Therapies Non-cytotoxic therapy Reference Patients Randomization Results Hall ’04 n=300 Ic-IV, Pt-based cCR-SD INF-  x 3 wk -> PD vs observ. PFS NS OS NS Hirte ’01 n=243 NED or resp (<2cm) Post Pt/Tax BAY-129566 vs placebo PFS NS OS NS Ehlen ’02 n=345 III-IV cCR Ovarex vs placebo OS NS Immune resp. vs no resp. TTR > 2-fold (p < 0.001) Seiden ’04 n=447 pCR at 2nd look post Pt-based CT MUC1+, Ic-IV Y90-R1549X1 vs control PFS NS OS NS

68. Ovarian Carcinoma: FIGO nomenclature (Rio de Janeiro 1988) Stage I Growth limited to the ovaries (A, B or C) II Growth involving one or both ovaries with pelvic extension (A, B or C) III Growth involving on or both ovaries and histologically confirmed implants outside the pelvis a/o positive LN (A, B or C, depending on size of extrapelvic lesions and +/- LN IV Growth involving one or both ovaries with DM. In case of pleural effusion cytology should be positive

70. Randomized trials in Relapsed Ovarian Cancer Some drugs are better than others Patient Drug schedule No of Outcome Category patients Plat-Tax 1 leuprorelin 3.75 mg 78 DFS  (p<.05) Refr/resist treosulfan 7.0 g/m² with treo; OS ns Plat-Tax 2 treosulfan 7.0 mg/m² 357 PFS  (p<.0001) Pretreated topotecan 1.5 mg/m², d1-d5 with top; OS  * Platinum 3 PLD 50 mg/m², q.4 wks 474 OS  (p=.05) Pretreated topotecan 1.5 mg/m², d1-5, q.3 wks with PLD; 2-yr S 35 % vs 24 % Platinum 4 PLD 40 mg/m², q 4 wks 153 OS  p=.048 Pretreated Gemcitabine 1000 mg/m², d1, 8, 15 q 4 wks with PLD MS 56 vs 51 wks 1 du Bois et al, 2002; 2 Meier et al, 2004 (* p=.0068 in TFI > 6 mo), 3 Gordon et al, 2001/2004, 4 Ferrandina et al, 2008 q.4 weeks q.3 weeks

71. Differences in Safety Profiles of Therapies for Recurrent Ovarian Cancer Drug HTOX Non-hematologic Toxicity ANC PLT Alopecia N/V STOM NEURO PPE HEP Paclitaxel  -   -  - - Topotecan    -  - - - PLD (Caelyx)*      -  - Treosulfan     - - - - Etoposide  -  -  - - - Gemcitabine   - - - - -  Vinorelbine  -   -  - - Oxaliplatin -  -  -  - - Hexamethylmelanine  - -  -  - - Grade 3+4:  < 5%;  6 – 20%;  > 20%; * Dose 50 mg/m² Vermorken JB. Int J Gynecol Cancer 2008; vol. 18 (suppl. 1): 59-66

73. Overall Survival at 2 Years NOGGO GONO ARNO 96 Cantù ICON IV GEICO AGO OVAR Overall (95% CI) 0.065 1 15.173 Favours Combo Favours Mono Study Odds ratio (95% CI) % Weight Bolis 1.81 (0.51,6.42) 1.30 (0.88,1.92) 0.53 (0.29,0.96) 0.71 (0.40,1.26) 0.69 (0.30,1.60) 0.82 (0.62,1.08) 0.16 (0.07,0.39) 0.77 (0.50,1.21) 0.80 (0.68,0.95) 1.8 19.5 8.4 9.1 4.2 38.3 3.7 14.9 95% CI Odds Ratio P-value 0.676-0.952 0.802 0.012

75. PFS Final Analysis- Independent Oncology Radiological + Clinical (Intent to Treat population) Monk BJ et al. J Clin Oncol 2010; 28:3107-3114 PFS Events: 432 HR: 0.72 (0.60-0.88) p=0.0008 #censored: 239 Trabectedin+PLD Median=7.4 months PLD Median=5.6 months