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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

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.

http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015/index

http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015/index

Incidence Rates by Race and Ethnicity in US (1999-2011)

http://www.cdc.gov/cancer/ovarian/statistics/race.htm

Death Rates by Race and Ethnicity (1999-2011)

http://www.cdc.gov/cancer/ovarian/statistics/race.htm

Incidence Rate by State (2011)

http://www.cdc.gov/cancer/ovarian/statistics/state.htm

Rates are per 100,000 and are age-adjusted to the 2000 U.S. standard population

Overview

• Primary Surgical Management & Staging • Primary Chemotherapy • Surveillance • Recurrent Chemotherapy Regimens

• Platinum Sensitive • Platinum Resistant

• Uncommon Ovarian Malignancies • Next Directions

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

Chemotherapy

Historical Perspective

How Did We Get to Carboplatin & Paclitaxel as Standard of Care?

Platinum Based Chemotherapy • Cyclophophamide, Doxorubicin, +/- Cisplatin

Omura, G et al. (1986) Cancer. 57:1725-30. GOG 47

Single agent HR = 1.01 (95% CI 0.81-1.26) Combination HR = 1.02 (95% CI 0.92 – 1.13) Overall HR = 1.02 (95% CI 0.93-1.12)

Cisplatin Carboplatin

Aabo, K et al. (1998) BriJ Cancer. 78(11):1479-1487

Taxane Based Chemotherapy • Cyclophosphamide/Cisplatin versus Paclitaxel/Cisplatin

McGuire WP et al. (1996) NEJM, 334(1)1-6. GOG111

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): 106-115. GOG 132

» Recurrent disease – 24 hour regimen

was to avoid hypersensitivity

– 3 hour had less myelosuppression

– No difference in response rates

Paclitaxel: 3 hour versus 24 hour

Eisenhauer EA et al. (1994) JCO 12(12): 2654-2666

» Docetaxel 60-75 mg/m2

– Less neurotoxicity – Greater myelotoxicity – Equivalent PFS and OS Vasey PA et al. (2004) J Natl Cancer Inst; 96:1682-1691

» Albumin-bound nab-Paclitaxel (Abraxane) – Has not been directly compared

» Microparticle bound paclitaxel (Xyotax) – GOG 212: study for consolidation therapy

Alternate Taxanes

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

Ovarian Cancer: Armstrong IP

Ovarian Cancer: JGOG Dose Dense

Katsumata N et al (2013) Lancet 14(10):1020-6.

Ovarian Cancer: Neoadjuvant Chemotherapy

Vergote et al. (2010) NEJM 363:943-53.

Ovarian Cancer: MITO - 7

Addition of Bevacizumab in Primary Treatment Regimens

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

Ovarian Cancer: GOG 218

Ovarian Cancer: GOG 218

Ovarian Cancer: ICON7

Ovarian Cancer: ICON7

Suboptimally debulked patients

Ovarian Cancer: GOG 262

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

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

Epithelial Ovarian Cancer: Surveillance

» 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: 91-100%

Ovarian: CA125

CA125: Does Early Treatment Matter?

Rustin GJ (2010) Lancet. 326: 1155-1163.

» Bloating » Early satiety » Abdominal pain » Pelvic pain » Bowel habit changes » Urinary Urgency » Urinary Frequency

Ovarian: Symptoms

» Benefits of Routine Imaging – Diagnose asymptomatic recurrence – Higher rate of optimal secondary

cytoreductive surgery – May benefit overall survival

» Insufficient data to support routine use

Ovarian: Routine Imaging

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

» Carboplatin/Paclitaxel » Carboplatin alone » Carboplatin/Docetaxel » Carboplatin/Liposomal Doxorubicin » Carboplatin/Gemcitabine

Platinum Sensitive

» 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

Carboplatin/Docetaxel

Strauss HG et al. (2006) Gyn Oncol. 104:612-616.

Kushner DM et al. (2007) Gyn Oncol. 105:358-64.

Carboplatin/Liposomal Doxorubicin (CALYPSO)

Pujade-Lauraine E et al. (2010) JCO. 28(20)3323-29

» 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

Carboplatin/Gemcitabine (OCEANS)

Aghajanian C et al (2012) JCO. 30(17):2039-2045.

» Docetaxel » Oral Etoposide » Gemcitabine » Liposomal Doxorubicin* » Paclitaxel (weekly)* » Topotecan* » Bevacizumab

Platinum Resistant

* Addition of bevacizumab may be considered

» Platinum resistant » Dosed 100mg/m2

» Significant hematologic toxicities

» Response rate: 22.4% » Median PFS: 2.5 months

Docetaxel

Rose PG et al. (2003) Gyn Oncol. 88:130-135.

» Platinum resistant » Overall response rate: 29% » PFS: 20 weeks

Gemcitabine

Ferrandina G et al. (2008) JCO. 26(6):890-896.

» Platinum resistant » Overall response rate: 16% » PFS: 16 weeks

Liposomal Doxorubicin

Ferrandina G et al. (2008) JCO. 26(6):890-896.

» 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

Topotecan (TOWER)

Sehouli J et al. (2011) JCO. 29(2):242-248.

» 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

AURELIA (+Bevacizumab)

Pujade-Lauraine E et al (2014) JCO. 32(13):1302-8.

» 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

Bevacizumab (alone)

Cannistra SA et al (2007) JCO. 25(33):5180-5186.

Burger RA et al (2007) JCO. 25(33):5165-5171.

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

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Thank You!