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Presentation on theme: "Welcome! Please take a moment to complete the short in your packet. Your participation will help us assess the effectiveness of this program and shape."— Presentation transcript:

1 Welcome! Please take a moment to complete the short in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities.

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3 Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

4 Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board : Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee : Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member : Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrongs spouses institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant : Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher : Amgen, Genentech, Merck, Novartis; Speaker : Johnson & Johnson, Roche/Genentech

5 Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose

6 Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum- sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly

7 Basis for Basic 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: Piccart MJ et al. J Natl Cancer Inst. 2000;92: DuBois A et al. J Natl Cancer Inst. 2003;95: Ozols RF et al. J Clin Oncol. 2003;21:

8 First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission

9 First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission

10 Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking (not obligatory) Interval debulking if no PD 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:

11 NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:

12 First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission

13 Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer GOG Improved outcome in CP-treated patients when cisplatin administered IP (relative risk, 0.76) GOG Improved outcome in TP-treated patients when cisplatin administered IP (relative risk, 0.78) GOG 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: Markman M, et al. J Clin Oncol. 2001;19: Armstrong DK et al. N Engl J Med. 2006;354: Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: cfm. Accessed March 9, 2006.

14 GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354: 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 Rx GroupLost to AliveDeadTotal Follow-up IV IP

15 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):

16 Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months Landrum L et.al. GOG Symposium, July 2012.

17 GOG 252 Stage II/III Disease: Small Volume Residual 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 III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m 2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days

18 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission

19 JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m 2 Carbolatin AUC = 6 Paclitaxel 80 mg/m 2 /w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary 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 therapy Improved PFS with dose-dense weekly paclitaxel

20 JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:

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 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: NCT

22 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission

23 GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage 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) Stage/debulking status RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE 1:1:1 15 months Paclitaxel (P) 175 mg/m 2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:

24 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, months Stratified analysis HR (95% CI) (0.759–1.040) One-sided P-value (log rank)0.080* + BEV (Arm II) CP (Arm I) * P- value boundary = BEV BEV maintenance (Arm III) Proportion surviving progression free Months since randomization Arm III CP + BEV BEV (n=623) 360 (57.8) (0.625–0.824) <0.0001* Burger RA et al. N Engl J Med. 2011;365:

25 GOG-0218 CA-125 to Determine Progression Protocol-defined PFS analysis CA-125-censored PFS analysis Median PFS CP (Arm I)10.3 months12.0 months CP + BEV BEV (Arm III) 14.1 months18.0 months Absolute diff. median PFS3.8 months6.0 months Hazard ratio Censored for CA125, % CP (Arm I)020 CP + BEV BEV (Arm III) 029 Burger RA et al. N Engl J Med. 2011;365:

26 GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization a Stratified analysis 625/625/623442/432/437173/162/171 46/39/40 No. at risk Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV BEV (n=623) Patients with events, n (%) 156 (25.0) 150 (24.0) 138 (22.2) Median, months HR a (95% CI) (0.827–1.297) (0.727–1.152) One-sided P value Burger RA et al. N Engl J Med. 2011;365:

27 ICON7: Study Design Stratification variables: Stage/surgery Time since surgery 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 IIB/C Stage III Stage IV n=1528 Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365: Perren et al. ESMO 2010.

28 ICON 7 Summary of Updated Results Parameter Protocol-defined Analysis Bulk Disease Analysis PFSHR = 0.87, P = CP17.4 months CP + BEV BEV 19.8 months OSHR = 0.84, P = 0.099HR = 0.64, P = CP28.8 months CP + BEV BEV 36.6 months Kristensen G et al. J Clin Oncol ; 29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:

29 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission

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

31 Progression-free survival Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed Median, months P = Percentage Markman M et al. J Clin Oncol. 2003;21: GOG 178

32 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL 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 = ) Paclitaxel Every 28 days for up to 12 courses Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Paclitaxel poliglumex Every 28 days for up to 12 courses

33 Summary: Initial Treatment of Advanced Ovarian Cancer Surgery –Attempt at maximal surgical cytoreduction –Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy –6-8 cycles taxane-platinum combination is standard –IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years –Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed –Bevacizumab during and after chemotherapy improves PFS but not OS

34 Case Discussions

35 Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? 1.Neoadjuvant chemotherapy 2.Primary radical debulking surgery

36 What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery

37 Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) –81 cohorts (Stage III/IV) –n = 6885 patients Results –Expert centers have high optimal rates –Optimal vs not: 11 mos (50% increase) – Each 10% in cytoreduction = 5.5% in survival – Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248.

38 The Impact of Residual Tumor: What Is Optimal Debulking? % Progression- Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P< % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P< Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234.

39 Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? 1.IP chemotherapy 2.IV chemotherapy 3.Adding bevacizumab to either IV or IP

40 Case 1 Question 2 What would you recommend for this patient at this point? 1.IP chemotherapy 2.IV chemotherapy 3.Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)?

41 Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 –Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 –at presentation 5800 –nadir post therapy 7 –In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: months Genetic testing: BRCA1/2 negative

42 Case 2 Question 1 What treatment would you recommend for this patient? 1.Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin 2.PLD, carboplatin and bevacizumab 3.Gemcitabine and carboplatin 4.Gemcitabine, carboplatin and bevacizumab 5.Paclitaxel and carboplatin 6.Weekly paclitaxel and carboplatin 7.Paclitaxel, carboplatin and PARP inhibitor

43 Case 2, Question 1 What treatment would you recommend for this patient? 1.Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) 2.PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) 3.Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) 4.Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) 5.Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) 6.Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease 7.Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved, so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012)

44 She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? 1.It is not considered for patients like her who relapse months after completing initial chemotherapy 2.The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery 3.Survival is improved for secondary debulking even if all disease cant be removed at surgery 4.Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 5.1 and and 4 7.All of the above

45 Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026.

46 Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64.

47 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: 0.5 cm > cm PLD 30 mg/m 2 Carboplatin AUC = 5 q 28 days x 6 PLD 30 mg/m 2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m 2 Carboplatin AUC = 5 q 21 days x 6 Paclitaxel 175 mg/m 2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:

48 GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:

49 Selected Non-hematologic Toxicities During Treatment CD (n=466)CP (n=501) Alopecia grade 2*7%84% Alopecia * P< Pujade-Lauraine E et al. J Clin Oncol. 2010;28:

50 Targeted Agents in Ovarian Cancer Signaling/Angiogenesis –Bevacizumab/Aflibercept –RTKIs: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib –Trebananib, MEDI-3617 –PI3K/Akt/mTOR –MEKi Folate: -Vintafolide (EC-145) -Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3

51 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OC a Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo a Epithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m 2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m 2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:

52 CG + 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 (0.388–0.605) < Months No. at risk CG + BV Proportion progression free Aghajanian C et al. J Clin Oncol. 2012;30:

53 OCEANS: Third Interim OS Analysis a GC + PL (n=242) GC + BV (n=242) Events, n (%) 142 (58.7)144 (59.5) Median OS, months (95% CI) 33.7 ( ) 33.4 ( ) HR (95% CI) Log-rank P value (0.760–1.214) P= Number at risk: GC + PL GC + BV a Data cutoff date: March 30, Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012.

54 Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001.

55 MorAb : Study Conclusions Overall response rate 70% –Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 PFI1 Phase III studies –Platinum-sensitive: fully enrolled –Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001.

56 n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m 2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease 3 previous platinum-containing regimens Progression free for 6 months following completion of last platinum-containing regimen Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease 3 previous platinum-containing regimens Progression free for 6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m 2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001.

57 Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) O/P/C P/C Oza A. ASCO 2012; Abstract O/P/CP/C Events: Total patients (%)47:81 (58.0) 55:81 (67.9) Median (months) Hazard ratio = % CI (0.34, 0.77) P =0.0012

58 GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1 st or 2 nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m 2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles Dose Level ABT-888 Dose (mg, oral, BID) Level -120 mg Level 130 mg Level 250 mg Level 380 mg Level 4100 mg Level 5150 mg Level 6200 mg Level 7250 mg Level 8300 mg Level 9350 mg Level mg

59 Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: –Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) –Gemcitabine Carboplatin +/- Bevacizumab –PLD Carboplatin

60 Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend?

61 Case 3 Question 1 What treatment would you recommend for this patient? 1.Pegylated liposomal doxorubicin (PLD, doxil, lipodox) 2.Weekly paclitaxel 3.Gemcitabine 4.Bevacizumab 5.Weekly paclitaxel and bevacizumab 6.Gemcitabine, carboplatin and bevacizumab

62 Case 3 Question 1 What treatment would you recommend for this patient? 1.Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population) 2.Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen) 3.Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%) 4.Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population) 5.Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable) 6.Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.)

63 Assume You Will Be Using Treatment With Bevacizumab: Which of the Following Are True Statements About Bevacizumab for Her 1.She will be at increased risk for bowel perforation 2.There is an increased risk of thrombo-embolic phenomena with bevacizumab 3.The response rate of ovarian cancer to single-agent bevacizumab is greater than for any other solid tumors tested to date 4.Hypertension and proteinuria are common side effects of bevacizumab 5.All of the above All the above are true statements in this case.

64 Annals of Oncology 22 (Supplement 8): viii61–viii64, 2011.

65 Active Agents in Ovarian Cancer

66 Platinum-resistant Ovarian Cancer Cytotoxic Therapy STUDY*AGENTNRESPONSE RATE 126-JDocetaxel58 22% 126-NWeekly Paclitaxel48 21% 126-MIxabepilone50 14% 126-QPemetrexed48 21% 126-Rnab-Paxlitaxel47 23% Thresholds: 10%, 25% Randomized phase II, NKTR-102* 145 mg/m 2 q14 d33 21% 145 mg/m 2 q21 d31 23% *Median of 3 prior lines *1 prior line Vergote IB et al. J Clin Oncol 2010;28:15s(suppl; abstr 5013).

67 Bevacizumab in Relapsed Ovarian Cancer GOG 170-D* (N = 62) NCI 5789** (N = 70) Phase II Study*** (N = 44) Study Treatment Single agent BV 15 mg/kg q 3 wk BV 10 mg/kg q 2 wks + low dose oral cyclophos. Single agent BV 15 mg/kg q 3 wk Prior Regimens 1 – 21/62 (34%) /62 (62%) Median = 2 Range /44 (52%) /44 (48%) Platinum Resistant 42%40%100% Efficacy ORR 6-mo PFS 21% 39% 24% 56% 16% 27% GIP or fistula 04 (6%)5 (11%) *Burger RA et al. J Clin Oncol 2007; 25: 5165–5171. **Garcia AA et al. J Clin Oncol 2008; 26: 76–82. ***Cannistra SA et al. J Clin Oncol 2007; 25: 5180–5186.

68 Ovarian Cancer: Targeted Therapy STUDYAGENTTargetn RESPONSE RATE Sanofi-Aventis Aflibercept (VEGF-TRAP) 1 VEGF 2 mg/kg % 4 mg/kg7.3% NCIC-CTEPSunitinib 2 VEGF/PDGF 303.3% DFCI-CTEPCediranib 3 VEGF/c-kit 4617% ExelixisCabozantinib 4 VEGFR2/c-met 7024% GlaxoSmith Kline Pazopanib 5 VEGFR/PDGFR/c -kit 3618% Boehringer Ingleheim Nintedanib 6 VEGFR/PDGFR/F GFR % at 36 weeks vs. placebo405% at 36 weeks 1 Tew et al. J Clin Oncol 2007;25:(suppl; abstr 5508). 2 Biagi et al. Ann Oncol. 2011;22: Matulonis UA et al. J Clin Oncol. 2009;27: Buckanovich et al. J Clin Oncol. 2011;29(suppl; abstr 5008). 5 Friedlander et.al. Gyn Oncol. 2010,. 6 Ledermann et al. J Clin Oncol. 2011;29:3798.

69 PD Recurrent Ovarian Cancer Randomized Phase II Studies Weekly Paclitaxel AMG mg/kg IV weekly n=53 Weekly Paclitaxel AMG mg/kg IV weekly n=53 Weekly Paclitaxel Placebon=55 Paclitaxel 80 mg/m2 IV weekly, 3 weeks on/1 week off AMG mg/kg IV weekly 10 mg/kg3 mg/kgPlacebo *Median PFS, months *HR (Arm A+B vs placebo) = 0.76 (80% CI, 0.59, 0.98), p=0.17, Trend test, p=0.037 ORR (CR+PR)37%19%27% RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE Ovarian, primary peritoneal, or fallopian tube cancer n= prior lines Karlan BY et al. J Clin Oncol. 2010;28:15s(suppl; abstr 5000).

70 Recurrent Ovarian Cancer Randomized Phase II Studies STUDY*AGENTS 186-G Bevacizumab-Everolimus vs Bevacizumab-Placebo Completed accrual 186-I Bevacizumab-Fosbretabulin vs Bevacizumab Accrual in progress 186-J Weekly Paclitaxel-Pazopanib vs Weekly Paclitaxel-Placebo Accrual in progress Primary endpoint: PFS*1-3 prior lines

71 Olaparib: An Orally Active PARP Inhibitor in Ovarian Cancer Provides clinical evidence of activity in ovarian cancer patients with and without BRCA1/2 mutations 1. Fong PC et al. J Clin Oncol 2010;28:2512– Audeh MW et al. Lancet 2010;376:245– Gelmon KA et al. Lancet Oncol 2011;12:852–861. *Complete response (CR) + partial response (PR) + stable disease (SD)

72 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC) Recurrent EOC platinum resistant 2 prior therapies no clinical or radiologic evidence of bowel involvement Non-Platinum Chemotherapy Non-Platinum Chemotherapy + Bevacizumab 15 mg/kg Chemotherapy Options Paclitaxel 80 mg/m 2 d 1,8,15, 22 q28 Topotecan 4 mg/m 2 d 1, 8,15 q28 or Topotecan 1.25 mg/m 2 d 1-5 q21 PLD 40 mg/m 2 d 1 q28 Stratified chemotherapy PFI (< 3 vs 3-6 mo) prior anti-angiogenesis Treat to progression N = 361 Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002.

73 AURELIA Progression-free Survival Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002.

74 Response Rates For Chemotherapy Alone Weekly Paclitaxel, Pegylated Liposomal Doxorubicin or Topotecan) or With Bevacizumab (BEV + CT) a Two-sided chi-square test with Schouten correction P=0.001 a P<0.001 a Patients (%) Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002.

75 Questions about AURELIA Given known single agent response to bevacizumab, how would a bevacizumab alone arm compare? Is it better to use chemo with bevacizumab rather than sequentially? –This should be answered by the overall survival data due in 2013, since patients on the chemo alone arm could subsequently get bevacizumab Should we limit this therapy to patients at low risk of GI perforation? Will these same benefits be seen in patients who had bevacizumab with initial chemotherapy?

76 Randomized 1:1:1 Randomized 1:1:1 Olaparib 200 mg bid n=32 Olaparib 200 mg bid n=32 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) Phase II Trial of Olaparib vs PLD in BRCA-associated Recurrent Ovarian Cancer Olaparib 400 mg bid n=32 Olaparib 400 mg bid n=32 Patients: BRCA1/2 germline mutation Recurrent Ovarian Cancer Patients in PLD group were allowed to cross-over to olaparib 400 mg bid on confirmed PD One cycle=28 days Kaye SB et al. J Clin Oncol. 2012;30: PLD 50 mg/m 2 IV n=33 PLD 50 mg/m 2 IV n=33

77 RECIST and CA-125 Responses Patients, n (%) Olaparib 200 mg bid (n=32) Olaparib 400 mg bid (n=32) PLD (n=33) Confirmed RECIST response8 (25)10 (31)6 (18) CA-125 response by GCIG*11 (34)18 (56)11 (33) Confirmed RECIST response and/or CA-125 response 12 (38)19 (59)13 (39) *GCIG criteria is confirmed 50% reduction in CA-125 levels that had to be maintained for 28 days; CA-125 response in the absence of RECIST progression Kaye SB et al. J Clin Oncol. 2012;30:

78 PRECEDENT: Randomized phase II PLD +/- Vintafolide (EC145) in platinum-resistant ovarian cancer patients n= 149 patients 2:1 Randomization Vintafolide + PLD PLD only Optional etarfolatide (EC20) Scan Vintafolide = 2.5mg TIW wks 1, 3 PLD=50 mg/m 2 (IBW) q 28 d n= 94 patients PI: Naumann, RW Primary Endpoint: PFS (investigator-assessed) Secondary Endpoint: OS, RR, response duration Exploratory Endpoint: Scan result and outcome Naumann et al. J Clin Oncol. 2011(suppl; abstr 5045).

79 Primary Endpoint PFS Results PFS EC145+PLD n=100 PLD n=49 Median time to event5.0 months2.7 months HR (2-sided p-value)0.63 (P-value=0.031) PLD Alone Vintafolide + PLD Naumann et al. J Clin Oncol. 2011(suppl; abstr 5045).

80 Summary for Platinum-resistant Recurrent Ovarian Cancer No benefit for combination chemotherapy Sequential single-agent chemotherapy is standard Multiple targeted agents with some demonstrated activity Multiple trials of chemotherapy plus a targeted agent showing increased ORR or PFS (but none to date with OS advantage) –Chemotherapy plus bevacizumab (Aurelia) –Weekly paclitaxel plus trebananib (AMG-386) –PLD plus vintafolide

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