1. Best of ASCO in Gyn Oncology Adnan R Munkarah

2. Biologics in Recurrent Ovarian Ca Cediranib- highly selective and potent oral TK inhibitor of VEGFR1, VEGFR2, VEGFR3 and c- Kit(Matulanis #5501, Hirte#5521) Cediranib- highly selective and potent oral TK inhibitor of VEGFR1, VEGFR2, VEGFR3 and c- Kit(Matulanis #5501, Hirte#5521) Sunitinib- multitargeted RTK inhibitor (Biagi #5522) Sunitinib- multitargeted RTK inhibitor (Biagi #5522) Pertuzumab- monoclonal ab prevents HER2 dimerization + CBDCA (Kaye #5520, Lalla #5550) Pertuzumab- monoclonal ab prevents HER2 dimerization + CBDCA (Kaye #5520, Lalla #5550) Sorafenib- oral TKI targeting raf & VEGFR, PDGFR, Flt3, c-kit ( Matei D, GOG #5537) Sorafenib- oral TKI targeting raf & VEGFR, PDGFR, Flt3, c-kit ( Matei D, GOG #5537)

3. Folate Receptor  FR  Overexpressed in majority of EOC, absent in nomrla tissues Overexpressed in majority of EOC, absent in nomrla tissues MORAb-003 humanized monoclonal ab to FRA MORAb-003 humanized monoclonal ab to FRA Armstrong D #5500 Armstrong D #5500 52 patients with platinum sensitive EOC in first relapse 52 patients with platinum sensitive EOC in first relapse Asymptomatic patients treated with single agent ab (SA) Asymptomatic patients treated with single agent ab (SA) Symptomatic patients or those with progression on SA receive ab with platinum & Taxane Symptomatic patients or those with progression on SA receive ab with platinum & Taxane MOAb-003 significantly increased overall response and duration of response MOAb-003 significantly increased overall response and duration of response

4. Folate Receptor  FR  Bell-McGuinn #5517 Bell-McGuinn #5517 Phase I trrial in platinum resistant EOC patients Phase I trrial in platinum resistant EOC patients Well tolerated Well tolerated + response + response

5. Belinostat Histone deacetylase inhibitor Histone deacetylase inhibitor Preclinical studies Preclinical studies Synergy with carboplatinum and taxol Synergy with carboplatinum and taxol Effect in platinum resistant and sensitive EOC Effect in platinum resistant and sensitive EOC Well tolerated in combination with taxol/carbo and clinical benefit in heavily pretreated patients (Finkler #5519) Well tolerated in combination with taxol/carbo and clinical benefit in heavily pretreated patients (Finkler #5519) Promising activity in LMP ovarian tumors (Mackay # 5518) Promising activity in LMP ovarian tumors (Mackay # 5518)

6. Seiji Isonishi, 1 Makoto Yasuda, 1 Fumiaki Takahashi, 2 Noriyuki Katsumata, 3 Eizo Kimura, 1 Daisuke Aoki, 4 Toshiko Jobo, 5 Fumitoshi Terauchi, 6 Hiroshi Tsuda, 4 Toru Sugiyama 7 1.The jikei University School of Medicine, 2. Kitasato University,3. National Cancer Center Hospital, 3. Kousei General Hospital, 4. Keio University School of Medicine, 5. Social Insurance Sagamino Hospital, 6. Tokyo Medical University, 7. Iwate Medical University School of Medicine j gog0606@jgog.gr.jp j gog0606@jgog.gr.jp

7. Conventional administration of paclitaxel and carboplatin (c-TC) every 21 days is a standard therapy for advanced epithelial ovarian cancer. Conventional administration of paclitaxel and carboplatin (c-TC) every 21 days is a standard therapy for advanced epithelial ovarian cancer. Several phase II clinical trials of dose-dense weekly administration of paclitaxel and carboplatin (dd-TC) in ovarian cancer have demonstrated promising efficacy and favorable tolerability Several phase II clinical trials of dose-dense weekly administration of paclitaxel and carboplatin (dd-TC) in ovarian cancer have demonstrated promising efficacy and favorable tolerability (Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243). (Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243). Recent randomized phase III trials for breast cancer demonstrated weekly paclitaxel improved survival (NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649). Recent randomized phase III trials for breast cancer demonstrated weekly paclitaxel improved survival (NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649). Conventional administration of paclitaxel and carboplatin (c-TC) every 21 days is a standard therapy for advanced epithelial ovarian cancer. Conventional administration of paclitaxel and carboplatin (c-TC) every 21 days is a standard therapy for advanced epithelial ovarian cancer. Several phase II clinical trials of dose-dense weekly administration of paclitaxel and carboplatin (dd-TC) in ovarian cancer have demonstrated promising efficacy and favorable tolerability Several phase II clinical trials of dose-dense weekly administration of paclitaxel and carboplatin (dd-TC) in ovarian cancer have demonstrated promising efficacy and favorable tolerability (Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243). (Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243). Recent randomized phase III trials for breast cancer demonstrated weekly paclitaxel improved survival (NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649). Recent randomized phase III trials for breast cancer demonstrated weekly paclitaxel improved survival (NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649).

8. Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube cancer FIGO Stage II-IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube cancer FIGO Stage II-IV Conventional TC (c-TC) Paclitaxel 180mg/m 2, day 1 Paclitaxel 180mg/m 2, day 1 Carboplatin AUC 6.0, day 1 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles every 21 days for 6-9 cycles Conventional TC (c-TC) Paclitaxel 180mg/m 2, day 1 Paclitaxel 180mg/m 2, day 1 Carboplatin AUC 6.0, day 1 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80mg/m 2, days 1,8,15 Paclitaxel 80mg/m 2, days 1,8,15 Carboplatin AUC 6.0, day 1 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80mg/m 2, days 1,8,15 Paclitaxel 80mg/m 2, days 1,8,15 Carboplatin AUC 6.0, day 1 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles every 21 days for 6-9 cycles Randomization Stratification; Residual disease: 1cm FIGO Stage ： II vs. III vs. IV Histology ： clear cell/mucinous vs.serous/others New Ovarian Elaborate trial: NOVEL trial

9. I.Histologically or cytologically* confirmed stage II-IV ovarian epithelial, primary peritoneal, or fallopian tube cancer II.No prior chemotherapy III.Age: 20 and more IV.Performance status: ECOG 0-3 V.1) Absolute neutrophil count at least 1,500/mm 3 2) Platelet count at least 100,000/mm 3 3) Bilirubin less than 1.5mg/dL 4) SGOT less than 100 IU/l 5) Serum creatinine less than 1.5mg/dL VI. Written informed consent I.Histologically or cytologically* confirmed stage II-IV ovarian epithelial, primary peritoneal, or fallopian tube cancer II.No prior chemotherapy III.Age: 20 and more IV.Performance status: ECOG 0-3 V.1) Absolute neutrophil count at least 1,500/mm 3 2) Platelet count at least 100,000/mm 3 3) Bilirubin less than 1.5mg/dL 4) SGOT less than 100 IU/l 5) Serum creatinine less than 1.5mg/dL VI. Written informed consent *CA125/CEA >25, and GI cancer should be ruled out

10. Primary endpoint: Primary endpoint: Progression-free Survival Secondary endpoints: Secondary endpoints: Overall survival (OS) Response rate Adverse events Quality of life (FACT) Primary endpoint: Primary endpoint: Progression-free Survival Secondary endpoints: Secondary endpoints: Overall survival (OS) Response rate Adverse events Quality of life (FACT)

11. Hypothesis:5 months improvement in median PFS (from 16 to 21 months) Hypothesis:5 months improvement in median PFS (from 16 to 21 months) Statistical test:2 sided log-rank with α=0.05, β=0.2 Statistical test:2 sided log-rank with α=0.05, β=0.2 Sample size:380 patients initially on Apr. 2003 Sample size:380 patients initially on Apr. 2003 600 patients with one interim analysis after amendment on Jan. 2005 Progression defined as: Progression defined as: appearance of any measurable or evaluable lesion OR CA125 level > 2 times UNL or nadir for 2 consecutive measurements at least 1 week apart Hypothesis:5 months improvement in median PFS (from 16 to 21 months) Hypothesis:5 months improvement in median PFS (from 16 to 21 months) Statistical test:2 sided log-rank with α=0.05, β=0.2 Statistical test:2 sided log-rank with α=0.05, β=0.2 Sample size:380 patients initially on Apr. 2003 Sample size:380 patients initially on Apr. 2003 600 patients with one interim analysis after amendment on Jan. 2005 Progression defined as: Progression defined as: appearance of any measurable or evaluable lesion OR CA125 level > 2 times UNL or nadir for 2 consecutive measurements at least 1 week apart

12. 637 Patients enrolled and randomly assigned 320 Assigned to c-TC dd-TC 317 Assigned to dd-TC 319 Eligible Patients 312 Eligible Patients 1 Ineligible 5 Ineligible 6 cycles of treatment Additional 3 cycles should be given if clinical responses were observed. Interval or secondary debulking surgery were allowed. 319 Primary intention to treat efficacy analysis 314 Safety analysis 312 Primary intention to treat efficacy analysis 312 Safety analysis

13. Characteristic Conventional TC (n = 319) Dose-dense TC (n = 312) Median age (range) 57 (25-84) 57 (25-87) FIGO stage, % IIIIIIV176716206515 ECOG PS, % 0 or 1 2390649072 Disease, % Ovarian Fallopian tube Primary peritoneal 876883512

14. Characteristic Conventional TC (n = 319) Dose-dense TC (n = 312) Surgery, % Primary debulking Primary debulking Interval debulking Interval debulking Secondary/Second Look Secondary/Second Look89918891112 Residual disease, % < 1cm > 1cm 45554654 Histologic type, % Clear or Mucinous Serous or others 16841783

15. Measurable % of patients c-TC (n = 135) dd-TC (n = 147) Objective response CRPRNCPDNE531638317956203629312 P=0.72 Evaluated by WHO criteria Clinical Response

16. Adverse Event c-TC (n = 314) dd-TC (n = 312) P value no. (%) Neutropenia 276 (80) 286 (92) 0.15 Thrombocytopenia 120 (38) 136 (44) 0.19 Anemia 137 (44) 214 (69) < 0.0001 Febrile neutropenia 29 (9) 1.00 Neuropathy-motor 43 (14) 37 (12) 0.55 Neuropathy-sensory 86 (27) 71 (23) 0.20 Evaluated by NCI-CTC ver.2.0

17. c-TC (n = 319) dd-TC (n = 312) > 6 cycles (all patients) 9 cycles (responding patients) 231 (72%) 50 186 (60%) 37 Completed protocol therapy Discontinued protocol therapy progression/death progression/deathtoxicityhematologicneuropathyallergy patient refusal for toxicity others patient refusal other reasons Unknown 200 (63%) 117 (37%) 286930571213811 2 147 (47%) 165 (53%) 2811368341325617 0

18. TreatmentnEvent Median PFS P value HR95%CIc-TC319200 17.2 mos. dd-TC312160 28.0 mos. 0.00150.7140.581-0.879

19. TreatmentnEvent 2-yr survival P value HR95%CIc-TC3199577.7% dd-TC3127083.6%0.04960.7350.540-1.000

20. n PS 2-3 61 PS 0-1 570 Age > 60 368 Age < 60 263 Primary peritoneal 63 Fallopian tube 32 Ovarian536 Serous/Others527 Clear cell/Mucinous 104 FIGO stage IV 98 FIGO stage III 417 FIGO stage II 116 Residual disease > 1cm 342 Residual disease < 1cm 289 Overall631 dd-TC betterc-TC better 0.00.51.01.52.0

21. PFS was improved with dose-dense weekly TC compared to conventional TC in patients with advanced epithelial ovarian cancer. PFS was improved with dose-dense weekly TC compared to conventional TC in patients with advanced epithelial ovarian cancer. Analysis of overall survival is ongoing. Analysis of overall survival is ongoing. Hematologic toxicity was increased in dose-dense TC. Hematologic toxicity was increased in dose-dense TC. Neurotoxicity was similar in both groups. Neurotoxicity was similar in both groups. PFS was improved with dose-dense weekly TC compared to conventional TC in patients with advanced epithelial ovarian cancer. PFS was improved with dose-dense weekly TC compared to conventional TC in patients with advanced epithelial ovarian cancer. Analysis of overall survival is ongoing. Analysis of overall survival is ongoing. Hematologic toxicity was increased in dose-dense TC. Hematologic toxicity was increased in dose-dense TC. Neurotoxicity was similar in both groups. Neurotoxicity was similar in both groups.

22. AZD2281 (KU-0059436), a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study Peter C Fong 1, David S Boss 2, Craig P Carden 1, Marja Mergui-Roelvink 2, Jacques De Greve 3, Charles M Gourley 4, James Carmichael 5, Johann S de Bono 1, Jan H Schellens 2, Stan B Kaye 1 1 The Royal Marsden Hospital and The Institute of Cancer Research, UK, 2 The Netherlands Cancer Institute, The Netherlands, 3 UZ Brussel Oncologisch Centrum, Belgium, 4 Edinburgh Cancer Research Centre, UK, 5 KuDOS Pharmaceuticals/AstraZeneca, UK

23. PARP Poly(ADP-ribose) polymerase-1- member of PARP enzymes Poly(ADP-ribose) polymerase-1- member of PARP enzymes Abundant nuclear protein Abundant nuclear protein Binds to DNA breaks Binds to DNA breaks Activated PARP cleaves NAD+ into nictoinamide and ADP-ribose and polymerizes the latter onto nuclear receptor proteins including histones, transcription factors and PARP itself Activated PARP cleaves NAD+ into nictoinamide and ADP-ribose and polymerizes the latter onto nuclear receptor proteins including histones, transcription factors and PARP itself Contributes to repair of single strand breaks in DNA Contributes to repair of single strand breaks in DNA

24. Poly ADP-Ribose Polymerase (PARP)

25. PARP inhibitors & BRCA

26. BRCA2 -/- BRCA2 +/+ BRCA2 +/- Increased sensitivity of BRCA1 -/- and BRCA2 -/- cells to PARP inhibition BRCA1 -/- BRCA1 +/+ BRCA1 +/- No difference in sensitivity between heterozygous and wild-type BRCA cells Farmer et al. Nature 2005; 434:917-21 Targeted inhibition  selective and less toxic therapy

27. From targeted therapy to the AZD2281 Phase I study Oral, small molecule PARP inhibitor Oral, small molecule PARP inhibitor IC 50 for PARP1 enzyme in the low nM range IC 50 for PARP1 enzyme in the low nM range Phase I trial began at RMH then NKI; later expanded to other centres Phase I trial began at RMH then NKI; later expanded to other centres Escalation phase: All tumour types Escalation phase: All tumour types Primary objectives of safety and tolerability Primary objectives of safety and tolerability Expansion phase: BRCA mutation carriers (HR deficient) especially ovarian cancer Expansion phase: BRCA mutation carriers (HR deficient) especially ovarian cancer Further assessment of efficacy Further assessment of efficacy

28. Overall recruitment Escalation Phase (n=46) 1,2 Escalation Phase (n=46) 1,2 Various tumour types; BRCA carrier status not mandatory Various tumour types; BRCA carrier status not mandatory 10 dose level cohorts: 10 dose level cohorts: 10mg daily given for 2 out of 3 weeks 10mg daily given for 2 out of 3 weeks 600mg bid continuous dosing 600mg bid continuous dosing 11 BRCA carrier ovarian cancer 11 BRCA carrier ovarian cancer Expansion phase (n=52) at 200mg bid continuous 2 Expansion phase (n=52) at 200mg bid continuous 2 Confirmed BRCA mutation carriers Confirmed BRCA mutation carriers 39 ovarian cancer 39 ovarian cancer 1 Fong et al. Proceedings of ASCO 2006 2 Yap et al. Proceedings of ASCO 2007

29. Toxicities (first 60 patients, all tumour types) Most toxicities were Grade 1-2 (≥95%) Most toxicities were Grade 1-2 (≥95%) Most common toxicities were: Most common toxicities were: nausea 28%, vomiting 18%, dysgeusia 13%, anorexia 12% nausea 28%, vomiting 18%, dysgeusia 13%, anorexia 12% fatigue 28% fatigue 28% Grade 3-4 toxicities were rare: Grade 3-4 toxicities were rare: myelosuppression (≤5%) myelosuppression (≤5%) nausea and vomiting (2-3%) nausea and vomiting (2-3%) CNS: dizziness or mood changes (2-3%) CNS: dizziness or mood changes (2-3%) Pattern of toxicity similar in BRCA mutation carriers Pattern of toxicity similar in BRCA mutation carriers

30. Dose limiting toxicities (DLT) Dose (mg)/ Schedule Tumour type DLTOutcome 400 bid continuous Ovarian Ca G3 low mood and G3 fatigue Resolved within 24 hours of drug discontinuation Recurred with re-challenge 600 bid continuous Mesothelioma G4 thrombocytopenia Resolved 2 weeks after drug discontinuation 600 bid continuous Breast Ca G3 somnolence Resolved within 24 hours of drug discontinuation G1 on lower dose Maximum Tolerated Dose (MTD) = 400mg bid

31. Demographics BRCA-mutated ovarian cancer subpopulation Patients Dose (mg bid) ≤ 100 200400600 Total = 50 43961 No. evaluable for efficacy = 46 43741 Includes primary peritoneal cancer (2 pts), fallopian tube carcinoma (1 pt) and 1 ovarian cancer pt with compelling family history for BRCA mutation Excluded pts: 1 pt died from disease-related non-neutropenic sepsis after 1 cycle 1 pt had DLT on day 1 and again on day 8 with re-challenge of drug 2 pts had PD within 2-3 weeks after commencement

32. Demographics BRCA-mutated ovarian cancer subpopulation CharacteristicsNumber BRCA1 / BRCA2 / Family history 41 / 8 / 1 Median age (range) 52 (37-80) yrs ECOG PS 0-1 47 Median duration from diagnosis to treatment (range) 4.7 (0.5–16) yrs Platinum status Sensitive (PD > 6 months after platinum) Resistant (PD ≤ 6 months after platinum) Refractory (PD on platinum or on completion of platinum) 102713 Median no. of prior systemic therapies (range) 3 (1-8)

33. 23 mm

34. 21mm 16mm

35. Total Platinum sensitive Platinum resistant Platinum refractory No. of evaluable patients 46102511 Responders by RECIST 13 (28%) 5 (50%) 8 (32%) 0 (0%) Responders by GCIG CA125 18 (39%) 8 (80%) 8 (32%) 2 (18%) Responders by either RECIST or GCIG criteria 21 (46%) 8 (80%) 11 (44%) 2 (18%) SD (> 4 cycles) 6 (13%) 1 (10%) 4 (16%) 1 (9%) Median duration of response in weeks (range) 24 (10-77) 23 (16-77) 24 (10-65) 26 (20-32) Response to AZD2281 by platinum-free interval

36. Total Platinum sensitive Platinum resistant Platinum refractory No. of evaluable patients 46102511 Responders by RECIST 13 (28%) 5 (50%) 8 (32%) 0 (0%) Responders by GCIG CA125 18 (39%) 8 (80%) 8 (32%) 2 (18%) Responders by either RECIST or GCIG criteria 21 (46%) 8 (80%) 11 (44%) 2 (18%) SD (> 4 cycles) 6 (13%) 1 (10%) 4 (16%) 1 (9%) Median duration of response in weeks (range) 24 (10-77) 23 (16-77) 24 (10-65) 26 (20-32) Response to AZD2281 by platinum-free interval

37. Total Platinum sensitive Platinum resistant Platinum refractory No. of evaluable patients 46102511 Responders by RECIST 13 (28%) 5 (50%) 8 (32%) 0 (0%) Responders by GCIG CA125 18 (39%) 8 (80%) 8 (32%) 2 (18%) Responders by either RECIST or GCIG criteria 21 (46%) 8 (80%) 11 (44%) 2 (18%) SD (> 4 cycles) 6 (13%) 1 (10%) 4 (16%) 1 (9%) Median duration of response in weeks (range) 24 (10-77) 23 (16-77) 24 (10-65) 26 (20-32) Response to AZD2281 by platinum-free interval

38. Total Platinum sensitive Platinum resistant Platinum refractory No. of evaluable patients 46102511 Responders by RECIST 13 (28%) 5 (50%) 8 (32%) 0 (0%) Responders by GCIG CA125 18 (39%) 8 (80%) 8 (32%) 2 (18%) Responders by either RECIST or GCIG criteria 21 (46%) 8 (80%) 11 (44%) 2 (18%) SD (> 4 cycles) 6 (13%) 1 (10%) 4 (16%) 1 (9%) Median duration of response in weeks (range) 24 (10-77) 23 (16-77) 24 (10-65) 26 (20-32) Response to AZD2281 by platinum-free interval

39. AZD2281 key messages Well tolerated oral therapy not associated with the typical toxicities of chemotherapy Well tolerated oral therapy not associated with the typical toxicities of chemotherapy Clear evidence of beneficial tumour response in BRCA mutated ovarian cancer patients Clear evidence of beneficial tumour response in BRCA mutated ovarian cancer patients 46% (21/46 pts) response rate (RECIST or GCIG CA125) 46% (21/46 pts) response rate (RECIST or GCIG CA125) 13% meaningful disease stabilisation 13% meaningful disease stabilisation Total clinical benefit rate of 59% Total clinical benefit rate of 59% A randomised phase II trial in BRCA ovarian cancer pts with platinum-free interval of 0-12 months A randomised phase II trial in BRCA ovarian cancer pts with platinum-free interval of 0-12 months AZD2281 vs pegylated liposomal doxorubicin AZD2281 vs pegylated liposomal doxorubicin