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

www.billingsclinic.com

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

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

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

Cisplatin 

Carboplatin 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)

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

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): 2654-2666

Alternate Taxanes » 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

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

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: 91-100%

CA125: Does Early Treatment Matter?

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

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

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

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

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

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

» Weekly dosing (D1,8,15 of q28d) » Overall response rate: 67% » Median PFS: not reported

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

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):2039-2045.

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

Docetaxel » Platinum resistant » Dosed 100mg/m2 » Significant hematologic toxicities

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

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

Gemcitabine » Platinum resistant » Overall response rate: 29% » PFS: 20 weeks Ferrandina G et al. (2008) JCO. 26(6):890-896.

Liposomal Doxorubicin » Platinum resistant » Overall response rate: 16% » PFS: 16 weeks Ferrandina G et al. (2008) JCO. 26(6):890-896.

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):242-248.

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):1302-8.

Bevacizumab (alone) » Platinum resistant (83.7% primary) » Topotecan and/or Liposomal Doxorubicin

» Partial response: 15.9% » Median PFS: 4.4 months Cannistra SA et al (2007) JCO. 25(33):5180-5186.

» Recurrent disease (58% platinum res) » Response rate: 21% » Median PFS: 4.7 months 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

Thank You!

Health Care, Education and Research

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