1. 2012 ALGORITHM FOR MANAGEMENT OF ADVANCED OVARIAN CANCER Bradley J. Monk, MD, FACS, FACOG Professor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, a Member of Catholic Healthcare West Phoenix, Arizona USA bradley.monk@chw.edu

2. Newly Diagnosed Advanced Ovarian Cancer

3. Ovarian Carcinoma: Incidence and Mortality Incidence in US women –21,880 cases in 2010 –Eighth most common cancer –Second most common gynecologic cancer –1.5% lifetime risk of getting ovarian cancer Mortality in US women –14,850 deaths in 2010 –Fifth most common cause of cancer death –Most common cause of death due to gynecologic cancer –1.0% lifetime risk of dying of ovarian cancer ACS. Available at: http://www.cancer.org/

4. Cancer in the United Sates of America ACS. Available at: http://www.cancer.org/

5. First-line Therapy Global Standard Treatment IV Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) x 6 2004 Consensus Statements on the Management of Ovarian Cancer: Final Document of the 3rd International GCIG Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Annals Of Oncology 16 (Supplement 8) Viii7–viii12, 2005 Surgery with maximum cytoreduction effort

6. Basis for Current Standard: Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin –GOG Protocol 111 [1] –EORTC-NCIC OV 10 [2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy –AGO Trial [3] –GOG Protocol 158 [4] 1. McGuire WP, et al. N Eng J Med.1996;334:1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A, et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF, et al. J Clin Oncol. 2003;21:3194-3200.

7. 1.Docetaxel instead of paclitaxel 2.Neoadjuvant chemotherapy 3.Intraperitoneal Chemotherapy 4.Weekly dosing 5.Adding a targeted agent (e.g. bevacizumab) 6.Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable but Uncommon

8. 1.Docetaxel instead of paclitaxel 2.Neoadjuvant chemotherapy 3.Intraperitoneal Chemotherapy 4.Weekly dosing 5.Adding a targeted agent (e.g. bevacizumab) 6.Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable but Uncommon

9. IGCS Meeting October 25th 2009 Bangkok N Engl J Med. 2010 Sep 2;363(10):943-53

10. Randomization Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) Primary Debulking Surgery Neoadjuvant chemotherapy 3 x Platinum based CT Interval debulking (not obligatory) Interval debulking if no PD 3 x Platinum based CT > 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications

11. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14)

12. 1.Docetaxel instead of paclitaxel 2.Neoadjuvant chemotherapy 3.Intraperitoneal Chemotherapy 4.Weekly dosing 5.Adding a targeted agent (e.g. bevacizumab) 6.Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable but Uncommon

13. Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer GOG 104 1 Improved outcome in CP-treated patients when cisplatin administered IP (relative risk, 0.76) GOG 114 2 Improved outcome in TP-treated patients when cisplatin administered IP (relative risk, 0.78) GOG 172 3 Improved outcome in TP-treated patients when paclitaxel and cisplatin administered IP (relative risk, 0.73) CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006.

14. GOG172: Ovarian (optimal III) Cisplatin 75 mg/m 2 Paclitaxel 135 mg/m 2 (24 h) Cisplatin 100 mg/m 2 IP d1 Paclitaxel 135 mg/m 2 (24 h) IV d1 Paclitaxel 60 mg/m 2 IP d8 Epithelial Ovarian Cancer Epithelial Ovarian Cancer Optimal Stage III Optimal Stage III No prior therapy No prior therapy Elective Second-Look Elective Second-Look Open:23-Mar-98 Closed:29-Jan-01 Accrual:416 pts (evaluable) I II Armstrong, et al. NEJM 354:34-43, 2006

15. GOG Protocol 172 IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P =.03 IV = Intravenous; IP = Intraperitoneal. Adapted with permission from Armstrong DK, et al. N Engl J Med. 2006;354:34-43. Rx GroupLost to AliveDeadTotal Follow-up IV578127210 IP1193101205

16. GOG Protocol 172 Toxicity No difference in QOL at 12 months IV = Intravenous; IP = Intraperitoneal; GI = Gastrointestinal; QOL = Quality of life. Armstrong DK, et al. N Engl J Med. 2006;354:34-43. IV, % (N = 210) IP, % (N = 201) G3/4Leukopenia*6476 G3/4Platelet412 G3/4GI*2446 G3/4Renal*27 G3/4Neurologic Event*919 G3/4Fatigue*418 G3/4Infection*616 G3/4Metabolic*727 G3/4Pain*111 *P ≤ 0.05

17. GOG 252: Stage II/III Disease: Small Volume Residual Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m 2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days Cisplatin 75 mg/m 2 (IP d2) Paclitaxel 135 mg/m 2 (d1, 3h) Paclitaxel 60 mg/m 2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed:30 Nov 2011 Accrual:1100 Study Chair: J Walker I III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496

18. 1.Docetaxel instead of paclitaxel 2.Neoadjuvant chemotherapy 3.Intraperitoneal Chemotherapy 4.Weekly dosing 5.Docetaxel instead of paclitaxel 6.Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable but Uncommon

19. JGOG: Dose-Dense Weekly Paclitaxel Paclitaxel 180 mg/m 2 Carbolatin AUC = 6 Paclitaxel 80 mg/m 2 /w x3 Epithelial Ovarian or PeritonealEpithelial Ovarian or Peritoneal Stage II - IVStage II - IV No prior therapyNo prior therapy Stratfied: residual disease, stage, and histologyStratfied: residual disease, stage, and histology Primary endpoint: PFSPrimary endpoint: PFS Secondary endpoint: OSSecondary endpoint: OS Epithelial Ovarian or PeritonealEpithelial Ovarian or Peritoneal Stage II - IVStage II - IV No prior therapyNo prior therapy Stratfied: residual disease, stage, and histologyStratfied: residual disease, stage, and histology Primary endpoint: PFSPrimary endpoint: PFS Secondary endpoint: OSSecondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S, et al. J Clin Oncol. 2008; 26:A5506. x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapyDose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxelImproved PFS with dose-dense weekly paclitaxel Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapyDose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxelImproved PFS with dose-dense weekly paclitaxel

20. JGOG: Dose-Dense Weekly Paclitaxel Katsumata N et al Lancet. 2009 Oct 17;374(9698):1331-8.

21. GOG 262: Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression RANDOMIZERANDOMIZE N = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712

22. 1.Docetaxel instead of paclitaxel 2.Neoadjuvant chemotherapy 3.Intraperitoneal Chemotherapy 4.Weekly dosing 5.Adding a targeted agent (e.g. bevacizumab) 6.Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable but Uncommon

23. 23 Phase III Trial of Bevacizumab in the Primary Treatment of Advanced Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer: A Gynecologic Oncology Group (GOG) Study R.A. Burger, 1 M.F. Brady, 2 M.A. Bookman, 3 J.L. Walker, 4 H.D. Homesley, 5 J. Fowler, 6 B.J. Monk, 7 B.E. Greer, 8 M. Boente, 9 S.X. Liang 10 1 Fox Chase Cancer Center, Philadelphia, PA; 2 Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; 3 University of Arizona Cancer Center, Tucson, AZ; 4 University of Oklahoma Health Sciences Center, Oklahoma City, OK; 5 Brody School of Medicine, Greenville, NC; 6 James Cancer Hospital at the Ohio State University, Hilliard, OH; 7 University of California, Irvine Medical Center, Orange, CA; 8 Seattle Cancer Care Alliance, Seattle, WA; 9 Minnesota Oncology and Hematology, Minneapolis, MN; 10 State University of New York at Stony Brook, Stony Brook, NY, USA J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1) N Engl J Med. 2011 Dec 29;365(26):2473-83.

24. GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic)Stage III optimal (macroscopic) Stage IIIStage III suboptimal suboptimal Stage IVStage IV n=1800 (planned) Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic)Stage III optimal (macroscopic) Stage IIIStage III suboptimal suboptimal Stage IVStage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS)GOG performance status (PS) Stage/debulking statusStage/debulking status RANDOMRANDOMIIZEZERANDOMRANDOMIIZEZEI RANDOMRANDOMIIZEZERANDOMRANDOMIIZEZEI 1:1:1 15 months Paclitaxel (P) 175 mg/m 2 Carboplatin (C) AUC 6 Placebo IArm Cytotoxic (6 cycles) BEV 15 mg/kg Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 III Maintenance (16 cycles)

25. GOG-0218: Investigator-Assessed PFS Arm I CP (n=625) Arm II CP + BEV (n=625) Patients with event, n (%) 423 (67.7) 418 (66.9) Median PFS, months10.311.2 Stratified analysis HR (95% CI) 0.908 (0.759–1.040) One-sided p-value (log rank)0.080* + BEV (Arm II) CP (Arm I) *p-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.00.90.80.70.60.50.40.30.20.10 0122436 Arm III CP + BEV  BEV (n=623) 360 (57.8) 14.1 0.717 (0.625–0.824) <0.0001*

26. Hazard ratio Experimental arm (CP + BEV  BEV; Arm III) better Control arm (CP; Arm I) better Stage 3 optimal (n=434)0.618 Stage 3 suboptimal (n=496)0.763 Stage 4 (n=318)0.698 PS 0 (n=616)0.710 PS 1/2 (n=632)0.690 Age <60 years (n=629)0.680 Age 60–69 years (n=409)0.763 Age  70 years (n=210) 0.678 GOG-0218: Subgroup Analyses of PFS CP + BEV  BEV (Arm III) vs CP (Arm I) Treatment hazard ratio

27. 27 ICON7: a phase III Gynaecologic Cancer InterGroup (GCIG) trial of adding bevacizumab to standard chemotherapy in women with newly diagnosed epithelial ovarian, primary peritoneal or fallopian tube cancer Tim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Philip Beale, Andreas Cervantes, Amit Oza on behalf of GCIG ICON7 collaborators (MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG, GEICO, NCIC-CTG) ESMO 2010N Engl J Med. 2011 Dec 29;365(26):2484-96.

28. ICON7: Study Design Stratification variables: Stage/surgery Stage/surgery Time since surgery Time since surgery GCIG group GCIG group *Might vary based on GCIG group ** Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m 2 Carboplatin AUC 6* AVASTIN Paclitaxel 175 mg/m 2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC)Stage I-IIA (Gr 3 or CC) Stage IIB/CStage IIB/C Stage IIIStage III Stage IVStage IVn=1528 Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC)Stage I-IIA (Gr 3 or CC) Stage IIB/CStage IIB/C Stage IIIStage III Stage IVStage IVn=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness,translational No IRC present Perren, et al. ESMO 2010

29. Number at risk CP764723693556464307216143915025 CPB7.5+764748715647585399263144733619 1.00 0.75 0.50 0.25 0 Proportion alive without progression Time (months) 036912151821242730 CPCPB7.5+ Events, n (%) 392 (51)367 (48) Median, months 17.319.0 Log-rank test p=0.0041 HR (95% CI)0.81 (0.70–0.94) 17.3 19.0 CP CPB7.5+ ICON 7 PFS Benefit: Academic Analysis Perren, et al. ESMO 2010

30. ICON 7 Subgroups No. of events/no. of patients Origin of cancerResearchControlHR Age<60202/449210/4500.84 60–69134/242142/2370.76 ≥7031/7340/770.82 ECOG PS0154/334145/3581.01 1175/366210/3540.66 227/4531/430.78 HistologySerous274/525278/5290.85 Mucinous12/1910/150.77 Endometroid26/6025/570.81 Clear cell22/6722/600.90 FIGOI6/549/650.73 II14/8319/800.72 III277/523290/5220.79 IV70/10474/970.69 Residual disease Optimal (≤1 cm)226/559233/5520.87 Suboptimal (>1cm)131/192145/1950.68 GradeGrade 110/4116/560.76 Grade 286/17577/1420.77 Grade 3267/538294/5560.81 Hazard ratio (fixed) 0120.51.5 CP better Age: Trend p=0.69, interaction p=0.83; ECOG: Trend p=0.027, interaction p=0.022 Histology: Interaction test p=0.085; FIGO: Trend p=0.71, interaction p=0.91 Residual disease: Trend p=0.10; Grade: Trend p=0.76, interaction p=0.95 CPB7.5+ better Perren, et al. ESMO 2010

31. 1.Docetaxel instead of paclitaxel 2.Neoadjuvant chemotherapy 3.Intraperitoneal Chemotherapy 4.Weekly dosing 5.Adding a targeted agent (e.g. bevacizumab) 6.Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable but Uncommon

32. GOG 178—Investigating Paclitaxel as Consolidation CR = Complete response. Markman M, et al. J Clin Oncol. 2003;21:2460-2465. RANDOMIZERANDOMIZE 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months

33. GOG 178 Progression-free survival 0 20 40 60 80 100 012243648 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P =.0023 Percentage Markman M, et al. J Clin Oncol. 2003;21:2460-2465.

34. GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned N = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses

35. Recurrent Disease CHEMOTHERPAY

36. PopulationStudyTreatmentPFS Optimal Stage 3GOG 114IV Carb & Pac, IP Cis28 mos GOG 172IV Pac, IP Cis & Pac24 mos GOG 158IV Pac & Carb21 mos GOG 114IV Pac & Cis22 mos GOG 158IV Pac & Cis19 mos GOG 172IV Pac & Cis18 mos Suboptimal 3 & 4GOG 111IV Pac & Cis18 mos GOG 162IV Pac Cis12 mos GOG 152IV Pac Cis11 mos All Stage 3 & 4GOG 182IV Pac/Carbo x 816 mos When Does Advanced Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel.

37. Treatment Considerations and Goals: Recurrent Ovarian Cancer Treatment considerations in the management of recurrent ovarian cancer –Disease-free interval –Existing toxicities remaining due to the 1st-line therapy –Volume of disease at the time of relapse –Serologic relapse (CA-125) Primary goals of therapy for the treatment of recurrent ovarian cancer –Progression-free survival (PFS) –Increased survival –Prevention of symptoms –Palliation of symptoms –Quality of life (QoL)

38. Ovarian Cancer Treatment Considerations First-Line Treatment Recurrent Disease CureGoalPalliation HighToxicity Acceptance Low Less ImportantConvenienceMore Important

39. Recurrence After First-line Chemotherapy Platinum Sensitive > 6 Months Chemotherapy Doublet Platinum Refractory/Resistant < 6 Months Non-Platinum Single Agent The Traditional Treatment Paradigm

40. FDA-Approved Drugs in Ovarian Cancer 1978 Cisplatin CarboplatinAltretaminePaclitaxelTopotecan Liposomal doxorubicin (PLD) (accelerated) Liposomal doxorubicin (full) Gemcitabine (with carboplatin) 20061989199019921996 19992005 2009 Trabectedin; EU only (with PLD) 1964 Melphalan Doxorubicin 1974

41. OCEANS Stratification variables: Time to recurrenceTime to recurrence Cytoreductive surgeryCytoreductive surgery Gemcitabine 1000 mg/m 2 d1/8 Carboplatin AUC 4 Gemcitabine 1000 mg/m 2 d1/8 Arm A Arm B Placebo to progression Bevacizumab 15 mg/kg to progression Platinum- sensitive, recurrent OC, PP, FTC No prior bevacizumab n=480 Platinum- sensitive, recurrent OC, PP, FTC No prior bevacizumab n=480 Primary endpoint: PFS Secondary endpoints: ORR, OS, DR, safety Exploratory endpoints: IRC, CA 125 response, ascites IRC present ClinicalTrials.gov Identifier: NCT00434642

42. 242177451130CG + PL OCEANS: Primary analysis of PFS CG + PL (n=242) CG + BV (n=242) Events, n (%) 187 (77)151 (62) Median PFS, months (95% CI) 8.4 (8.3–9.7) 12.4 (11.4–12.7) Stratified analysis HR (95% CI) Log-rank p-value 0.484 (0.388–0.605) <0.0001 Months No. at risk 2422039233110CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0612182430 ASCO 2011

43. Duration of responseCG + PL (n=139) CG + BV (n=190) Median, months7.410.4 HR (95% CI)0.534 (0.408–0.698) p<0.0001 a OCEANS: Objective Response 100 80 60 40 20 0 % 78.5 57.4 PR = 61 PR = 48 CR = 17 CR = 9 Difference: 21.1% p<0.0001 a Compared for descriptive purposes only CG + PL (n=242) CG + BV (n=242) ASCO 2011

44. OCEANS: Interim OS 1.0 0.8 0.6 0.4 0.2 0 Proportion alive 0 Months 612303642 No. at risk: 1824 2422351952680CG + PL13177 2422382004280CG + BV14682 CG + PL (n=242) CG + BV (n=242) Events, n (%)78 (32)63 (26) Median OS, months (95% CI) 29.9 (26.4–NE) 35.5 (30.0–NE) Stratified analysis HR (95% CI) Log-rank p-value 0.751 (0.537–1.052) 0.094 a NE = not estimable a p-value does not cross pre-specified boundary of 0.001 ASCO 2011

45. Summary and Looking Towards the Future Unanswered Questions Regarding Bevacizumab in Ovarian Cancer 1.Best clinical setting (frontline vs recurrence) 2.Single agent or combination 3.Dose 4.Duration 5.Continuation beyond progression 6.Cost effectiveness 7.Impact on patient reported outcomes (PRO or QOL) Other agents that effect angiogenesis and the tumor vasculature active and in late stage development

46. NCCN “ Preferred” Agents in “Platinum Resistant” Ovarian Cancer Level IIA Docetaxel Etoposide, oral Gemcitabine PLD Weekly paclitaxel Topotecan Bevacizumab National Comprehensive Cancer Network (NCCN) www.nccn.org

47. Summary and Conclusions Advanced ovarian cancer is very lethal despite many active medicines IV carboplatin and paclitaxel standard adjuvant front-line therapy Little survival benefit in recurrent setting No approved targeted agent No agent approved since 2006

48. 2012:Phase III Registration Studies in Ovarian Cancer* Front-line added to chemotherapy then as Maintenance 1.BIBF 1120 (OVAR 12) 2.AMG 386 (with Carboplatin or Paclitaxel) Maintenance alone 1.Polyglutamate paclitaxel (GOG 212) 2.Pazopanib (OVAR 16) Platinum-resistant recurrent ovarian cancer 1.Karenitecin 2.Bevacizumab (with chemotherapy - AURELIA) 3.AMG 386 (with PLD or Paclitaxel) 4.EC-145 (with PLD) Platinum-sensitive recurrent ovarian cancer 1.Bevacizumab (with chemotherapy - OCEANS, GOG 213) 2.Trabectedin (with PLD) 3.Cediranib (with chemotherapy - ICON7) 4.Farletuzumab (with Carboplatin or Paclitaxel) 5.Water soluble formulation of Paclitaxel *Phase II studies of PARP inhibitors, NKTR-102 and XL-184 may lead to FDA approval PLD = Pegylated Liposomal Doxorubicin

49. Histologically or cytologically confirmed non-mucinous epithelial ovarian cancer including primary peritoneal or fallopian tube malignancies Measurable disease by CT or MRI scan Relapse within < 6 months after first-line platinum/taxane chemotherapy Up to 4 prior lines of therapy Neurologic function: neuropathy (sensory and motor) ≤CTCAE Grade 1 ClinicalTrials.gov Identifier: NCT00738699 (FAR122) Co-Primary Endpoints = Progression-free survival and Overall survival N = 550 Weekly paclitaxel (80mg/m2) x 12 then 3 out of 4 weeks with placebo MORAb-003 2.5 mg/kg (N=367) Weekly paclitaxel (80mg/m2) x 12 then 3 out of 4 weeks with placebo (N=183) RANDOMIZE Farletuzumab (MORAb-003): Phase II Platinum Resistant Patients

50. November 28, 2011 –Study stopped by IDMC for futility –40% of OS events = 161 deaths –HR boundaries PFS > 0.9 and OS > 1.00 –Corresponding conditional power 0.1985 for PFS and > 0.5000 for OS –No new safety issues identified Farletuzumab (MORAb-003): Phase II Platinum Resistant Patients

51. Imaging Agent EC20 imaging agent EC145 therapeutic Folate Linked Imaging Agent and Drugs Desacetylvinblastine Folate Spacer Cleavable Bond

52. PRECEDENT – A Randomized Phase II Trial of PLD ± EC145 in Platinum-Resistant Ovarian Cancer (EC-FV-04) PLD 50 mg/m 2 q 28 days EC145 2.5 mg/m 2 q MWF every other wk PLD 50 mg/m 2 RANDOMIZE Recurrent EOC 1st or 2nd Relapse < 6 mo platinum based therapy N = 149 2:1 Randomization 1° Endpoint PFS HR 0.68 at 95 events 2° Endpoint ORR and OS Correlate EC 20 scan and response Optional EC20 Scan n = 94 Naumann RW, et al. ASCO 2011. Abstract 5045. PLD= Pegylated liposomal doxorubicin

53. + Censored Progression-Free Survival EC145/PLD n = 100 PLD n = 49 Median PFS21.7 weeks11.7 weeks Hazard Ratio (2-sided P value)0.626 (P = 0.031) EC145 + PLD PLD Alone Probability of Progression-Free Survival Weeks From Randomization Date PRECEDENT Trial Final PFS Results Naumann RW, et al. ASCO 2011. Abstract 5045. PLD= Pegylated liposomal doxorubicin

54. EC145 + PLD PLD Alone Note: OS data are expected to mature late 2011. Current median follow-up: 25.6 wks Censoring rate: > 60% Overall Survival EC145+PLD n = 100 PLD Alone n = 49 Hazard Ratio (2-sided P value)0.879 (P = 0.680) 6-month survival rate80.8%71.8% PRECEDENT Trial Preliminary Survival Results Median Follow-up Naumann RW, et al. ASCO 2011. Abstract 5045. PLD= Pegylated liposomal doxorubicin

55. Disappointing Mature Overall Survival (OS) Press Release - Dec 13, 2011 The median OS in the EC145 study arm = 14.1 months The median OS in the PLD control = 16.9 months HR = 1.099 intent-to-treat http://www.endocyte.com/wp-content/uploads/2011/04/2011.12.13_EU-Supplemental-Analysis.pdf

56. Study for Women With Platinum Resistant Ovarian Cancer Evaluating EC145 in Combination With Doxil® (PROCEED) Placebo IV days 1,3,5 and 15,17,19 of a 4-week cycle PLD 50 mg/m2 (IBW) every 4 weeks. EC145 IV days 1,3,5 and 15,17,19 of a 4-week cycle PLD 50 mg/m2 (IBW) every 4 weeks. RANDOMIZERANDOMIZE ClinicalTrials.gov Identifier: NCT01170650 Estimated Enrollment:500 Study Start Date: September 2010 Estimated Study Completion Date: July 2014 Estimated Primary Completion Date: August 2012 Primary Endpoint: PFS Secondary Endpoints: OS, toxicity Primary or secondary platinum-resistant ovarian cancer. Measurable disease (RECIST v1.1-defined) Prior platinum-based chemotherapy for management of primary regimens PLD= Pegylated liposomal doxorubicin

57. Phase II study of the oral PARP inhibitor olaparib (AZD2281) versus liposomal doxorubicin in ovarian cancer patients with BRCA1 and/or BRCA2 mutations Stan Kaye, 1 Bella Kaufman, 2 Jan Lubinski, 3 Ursula Matulonis, 4 Charlie Gourley, 5 Beth Karlan, 6 Dianna Taylor, 7 Mark Wickens, 7 James Carmichael 7 1. Royal Marsden Hospital, Sutton, Surrey, UK 2. Chaim Sheba Medical Center, Tel Hashomer, Israel 3. Pomeranian Medical University, Szczecin, Poland 4. Dana-Farber Cancer Institute, Boston, MA, USA 5. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK 6. Cedars-Sinai Medical Center, Los Angeles, CA, USA 7. AstraZeneca, Alderley Park, Macclesfield, UK Clinicaltrials.gov number, NCT00628251 ESMO 2010 Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710.

58. Randomized 1:1:1 Olaparib 200 mg bid in 28-day cycles PLD 50 mg/m 2 IV every 4 weeks PD or withdrawal from treatment for other reason As above or max lifetime cumulative dose reached Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib (200 mg and 400 mg bid) with pegylated liposomal doxorubicin (PLD) Study Design Olaparib 400 mg bid in 28-day cycles BRCA1/2 germline carriers with Ovarian Ca Progressive or recurrent disease < 12 months after previous platinum- based chemotherapy Patients in PLD group were allowed to cross over to olaparib 400 mg bid on confirmed PD Stats: HR 0.55 (median PFS of 4 to 7.3 mos) N planned: 90 (30/arm) Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710. J Clin Oncol. 2011 Dec 27. [Epub ahead of print]

59. Progression-Free Survival Olaparib 200 mg: 6.5 (5.6-8.0) months Median PFS (80% CI) Olaparib 400 mg: 8.8 (6.3-9.2) months PLD 50 mg/m 2 : 7.1 (5.5-7.8) months HR* vs PLD (80% CI) Olaparib 200 mg: 0.91 (0.60-1.39); P = 0.78 Olaparib 400 mg: 0.86 (0.56-1.30); P = 0.63 Olaparib 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66 Time From Randomization (months) Proportion of Patients Progression Free 0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 12 108 64 2 *HR < 1 favors olaparib. 32 0 38 1321 24 32 0 112 1721 28 33 0 38 1518 25 Number of patients at risk: Olaparib 200 mg Olaparib 400 mg PLD Stats: HR 0.55 (median PFS of 4 to 7.3 mos) N planned: 90 (30/arm) Olaparib 400 mg Olaparib 200 mg PLD Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710. J Clin Oncol. 2011 Dec 27. [Epub ahead of print]

60. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer Jonathan A. Ledermann J Clin Oncol 29: 2011 (suppl; abstr 5003)

61. Maintenance Olaparib: Study design Placebo (n=129) Olaparib 400mg bid, orally (n=136) Patients Platinum-sensitive high-grade serous ovarian cancer ≥2 previous platinum regimens Maintained PR or CR following last platinum regimen Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003) Primary endpoint PFS by RECIST Secondary endpoints TTP by CA-125 (GCIG criteria) or RECIST, OS, safety Randomized 1:1 82 sites in 16 countries Lederman J et al J Clin Oncol 29: 2011 (suppl; abstr 5003)

62. Progression-free survival 0 Time from randomization (months) 1361045123600 12972237100 At risk (n) Olaparib Placebo 0.6 0.8 0.9 0 0.1 0.2 0.3 0.4 0.5 0.7 1.0 369121518 No. of events: Total patients (%) Median PFS (months) Olaparib 60:136 (44.1) 8.4 Placebo 93:129 (72.1) 4.8 Hazard ratio 0.35 (95% CI, 0.25–0.49) P<0.00001 Olaparib 400 mg bid Placebo Randomized treatment Proportion of patients progression free Lederman J et al J Clin Oncol 29: 2011 (suppl; abstr 5003)

63. Olaparib: Another PARP Inhibitor Abandoned in Ovarian Cancer Press Release - Dec 20, 2011 The previously reported progression free survival benefit is unlikely to translate into an overall survival benefit, the definitive measure of patient benefit in ovarian cancer Attempts to identify a suitable tablet dose for use in Phase III studies have not been successful. http://www.astrazeneca.com/Media/Press-releases/Article/20111220-az-updates-olaparib-TC5214-development

64. Thank You Bradley.monk@chw.edu