Landmark Trials in Ovarian Cancer

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1 Landmark Trials in Ovarian Cancer Where we ve been and where we re headed Erin E. Stevens, MD Gynecologic Oncology Billings Clinic Cancer Center February 28, 2015 Health Care, Education and Research

2 Objectives To understand the current standard of care for treatment of ovarian cancer. Primary treatment Surveillance Recurrence treatment To identify clinical trials in development and future directions for research.

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5 Incidence Rates by Race and Ethnicity in US ( )

6 Death Rates by Race and Ethnicity ( )

7 Incidence Rate by State (2011) Rates are per 100,000 and are age-adjusted to the 2000 U.S. standard population

8 Overview Primary Surgical Management & Staging Primary Chemotherapy Surveillance Recurrent Chemotherapy Regimens Platinum Sensitive Platinum Resistant Uncommon Ovarian Malignancies Next Directions

9 Barakat RR, et al. (2013) Principles and Practice of Gynecologic Oncology.

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12 Chemotherapy Historical Perspective How Did We Get to Carboplatin & Paclitaxel as Standard of Care?

13 Platinum Based Chemotherapy Cyclophophamide, Doxorubicin, +/- Cisplatin Omura, G et al. (1986) Cancer. 57: GOG 47

14 Cisplatin Carboplatin Single agent HR = 1.01 (95% CI ) Combination HR = 1.02 (95% CI ) Overall HR = 1.02 (95% CI ) Aabo, K et al. (1998) BriJ Cancer. 78(11):

15 Taxane Based Chemotherapy Cyclophosphamide/Cisplatin versus Paclitaxel/Cisplatin McGuire WP et al. (1996) NEJM, 334(1)1-6. GOG111

16 Taxane Based Chemotherapy Cisplatin versus Paclitaxel versus Combination Cisplatin better PFS but OS was not statistically different Toxicities and completion rates favored combination Muggia FM et al. (2000) J Clin Oncol. 18(1): GOG 132

17 Paclitaxel: 3 hour versus 24 hour» Recurrent disease 24 hour regimen was to avoid hypersensitivity 3 hour had less myelosuppression No difference in response rates Eisenhauer EA et al. (1994) JCO 12(12):

18 Alternate Taxanes» Docetaxel mg/m 2 Less neurotoxicity Greater myelotoxicity Equivalent PFS and OS Vasey PA et al. (2004) J Natl Cancer Inst; 96: » Albumin-bound nab-paclitaxel (Abraxane) Has not been directly compared» Microparticle bound paclitaxel (Xyotax) GOG 212: study for consolidation therapy

19 Ovarian Cancer: Present Day Landmark trials Standard Chemotherapy GOG 172, JGOG, NACT Advanced Disease MITO-7, 218, ICON7 Recurrent Disease Recent results: 262 Current NCCN standard of care Awaiting results: 212, 252

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21 Ovarian Cancer: Armstrong IP

22 Ovarian Cancer: JGOG Dose Dense Katsumata N et al (2013) Lancet 14(10):

23 Ovarian Cancer: Neoadjuvant Chemotherapy Vergote et al. (2010) NEJM 363:

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25 Ovarian Cancer: MITO - 7

26 Addition of Bevacizumab in Primary Treatment Regimens Barakat RR, et al. (2013) Principles and Practice of Gynecologic Oncology.

27 Ovarian Cancer: GOG 218

28 Ovarian Cancer: GOG 218

29 Ovarian Cancer: ICON7

30 Ovarian Cancer: ICON7 Suboptimally debulked patients

31 Ovarian Cancer: GOG 262

32 Ovarian Cancer: GOG 262 Dose dense is superior to q3 week CT Subanalysis **very underpowered** Addition of bevacizumab to q3 week regimen is near equivalent PFS to dose dense 10 months without vs 14 months with Addition of bevacizumab in dose dense regimen did not have an increased PFS 15 months both arms

33 Awaiting Results GOG 212 Maintenance chemotherapy (12 months) of taxol, CT-2103, or observation after complete clinical response to primary CT chemotherapy GOG 252 Phase III Clinical Trial of Bevacizumab with IV versus IP Chemotherapy in Ovarian, Fallopian Tube and Primary Peritoneal Carcinoma

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35 Epithelial Ovarian Cancer: Surveillance

36 Ovarian: CA125» Double upper limit of normal on two occasions at least one week apart (GCIG Criteria)» Often elevated 2-5 months prior to clinical relapse Sensitivity: 62-94% Specificity: %

37 Rustin GJ (2010) Lancet. 326: CA125: Does Early Treatment Matter?

38 Ovarian: Symptoms» Bloating» Early satiety» Abdominal pain» Pelvic pain» Bowel habit changes» Urinary Urgency» Urinary Frequency

39 Ovarian: Routine Imaging» Benefits of Routine Imaging Diagnose asymptomatic recurrence Higher rate of optimal secondary cytoreductive surgery May benefit overall survival» Insufficient data to support routine use

40 Ovarian Cancer: Recurrent Disease All trials now focus on PFS Nothing we have done in ovarian cancer recurrent disease treatment has increased OS in the last 10 years Treating a patient at the time of biochemical or radiologic recurrence without presence of symptoms does not improve OS

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42 Platinum Sensitive» Carboplatin/Paclitaxel» Carboplatin alone» Carboplatin/Docetaxel» Carboplatin/Liposomal Doxorubicin» Carboplatin/Gemcitabine

43 Carboplatin/Docetaxel» Phase II Trial q3 week dose» Overall response rate: 72%» Median PFS: 19 months» Patients with platinum-free interval > 12 months showed better PFS/OS» Weekly dosing (D1,8,15 of q28d)» Overall response rate: 67%» Median PFS: not reported Strauss HG et al. (2006) Gyn Oncol. 104: Kushner DM et al. (2007) Gyn Oncol. 105:

44 Carboplatin/Liposomal Doxorubicin (CALYPSO) Pujade-Lauraine E et al. (2010) JCO. 28(20)

45 Carboplatin/Gemcitabine (OCEANS)» Randomization of Bevacizumab» 6-10 cycles of CG +/- bevacizumab followed by maintenance bevacizumab/placebo» Objective response rate: 57.4% vs 78.5%» PFS: 8.4 vs 12.4 months» Favors addition of bevacizumab Aghajanian C et al (2012) JCO. 30(17):

46 Platinum Resistant» Docetaxel» Oral Etoposide» Gemcitabine» Liposomal Doxorubicin*» Paclitaxel (weekly)*» Topotecan*» Bevacizumab * Addition of bevacizumab may be considered

47 » Platinum resistant» Dosed 100mg/m2 Docetaxel» Significant hematologic toxicities» Response rate: 22.4%» Median PFS: 2.5 months Rose PG et al. (2003) Gyn Oncol. 88:

48 Gemcitabine» Platinum resistant» Overall response rate: 29%» PFS: 20 weeks Ferrandina G et al. (2008) JCO. 26(6):

49 Liposomal Doxorubicin» Platinum resistant» Overall response rate: 16%» PFS: 16 weeks Ferrandina G et al. (2008) JCO. 26(6):

50 Topotecan (TOWER)» Weekly vs Conventional D1-5» Clinical benefit rates: 47% vs 58%» Benefit favors conventional regimen» Toxicity profile favors weekly» Less hematologic toxicities» Median PFS: 3.7 months» No difference between Tc or Tw Sehouli J et al. (2011) JCO. 29(2):

51 AURELIA (+Bevacizumab)» Platinum Resistant - Phase III» Randomization of Bevacizumab» Investigator Selected Regimen» Liposomal Doxorubicin» Weekly Paclitaxel» Topotecan» PFS 3.4 vs 6.7 months» Favors addition of bevacizumab Pujade-Lauraine E et al (2014) JCO. 32(13):

52 Bevacizumab (alone)» Platinum resistant (83.7% primary)» Topotecan and/or Liposomal Doxorubicin» Partial response: 15.9%» Median PFS: 4.4 months» Recurrent disease (58% platinum res)» Response rate: 21%» Median PFS: 4.7 months Cannistra SA et al (2007) JCO. 25(33): Burger RA et al (2007) JCO. 25(33):

53 Next Directions Primary Treatment Trials Dose-dense (or standard) CT with PARPi in primary and maintenance setting Placebo primary + maintenance PARPi primary + placebo maintenance PARPi primary + maintenance Neoadjuvant chemotherapy (NACT) CT vs CT+rituximab x 3 cycles, followed by CRS, followed by 3 cycles plus possible maintenance

54 Thank You! Health Care, Education and Research