Copyright © 2010, Research To Practice, All rights reserved.

Part II: Ovarian CancerMonday, September 27, 20107:30 PM - 8:30 PM ET

Monday Night with Research To Practice: An 8-Part Live CME Webcast Series

Deborah K Armstrong, MDAssociate Professor of Oncology, Gynecology and ObstetricsThe Sidney Kimmel Comprehensive Cancer CenterThe Johns Hopkins UniversityBaltimore, Maryland

David R Spriggs, MDHead, Division of Solid Tumor OncologyWinthrop Rockefeller Chair of Medical OncologyMemorial Sloan-Kettering Cancer CenterNew York, New York

Neil Love, MDModeratorResearch To PracticeMiami, Florida

Disclosures for Moderator Neil Love, MD

Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abraxis BioScience, Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, Genzyme Corporation, Lilly USA LLC, Millennium Pharmaceuticals Inc, Monogram BioSciences Inc, Myriad Genetics, Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi-Aventis and Spectrum Pharmaceuticals Inc.

Disclosures for Deborah K Armstrong, MD

N/A = Not Applicable

Advisory CommitteeAbraxis BioScience, Amgen Inc, Boehringer Ingelheim Pharmaceuticals Inc, Genentech BioOncology

Paid Research N/A

Speakers Bureau N/A

Disclosures for David R Spriggs, MD

Advisory CommitteeAstraZeneca Pharmaceuticals LP, Johnson & Johnson Pharmaceuticals

Paid Research Genentech BioOncology

Speakers Bureau N/A

N/A = Not Applicable

Copyright © 2010, Research To Practice, All rights reserved.

Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian CancerVergote I et al.N Engl J Med 2010;363(10):943-53.

Phase III Trial of Bevacizumab (BEV) in the Primary Treatment of Advanced Epithelial Ovarian Cancer (EOC), Primary Peritoneal Cancer (PPC), or Fallopian Tube Cancer (FTC): A Gynecologic Oncology Group StudyBurger RA et al.Proc ASCO 2010;Abstract LBA1.

Can We Define Tumors That Will Respond to PARP Inhibitors? A Phase II Correlative Study of Olaparib in Advanced Serous Ovarian Cancer and Triple-Negative Breast CancerGelmon KA et al.Proc ASCO 2010;Abstract 3002.

Case History: Dr Spriggs

• A 53-year-old woman with symptomatic ascites and clinically suspected bulky Stage III ovarian cancer

– Gyn exam and Pap smear 8 months ago were normal

• A gynecologic oncologist consultant estimates a 50/50 probability of an optimal debulking surgery

1) Would you generally recommend neoadjuvant chemotherapy?

28%

72%

0% 20% 40% 60% 80%

Yes

No

Copyright © 2010, Research To Practice, All rights reserved.

Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer

Vergote I et al.N Engl J Med 2010;363(10):943-53.

Neoadjuvant Chemotherapy with Interval Debulking Surgery versus Primary Debulking Surgery in Stage IIIC/IV Ovarian Cancer (N=632)

Vergote I et al. NEJM 2010;363(10):943-53.

Hazard Ratio for Death(Intention-to-Treat)NACT versus PDSHR = 0.98, p = 0.01

Case History: Dr Spriggs (continued)

• Patient elects primary surgery

– Visible residual disease (0.5 cm with miliary pattern) on bowel surface

• Surgeon leaves an intraperitoneal port

2) The patient returns to your office three weeks after surgery. What is your recommendation for chemotherapy?

IV paclitaxel, IP cisplatin and IP paclitaxel

IV carboplatin, IV paclitaxel and bevacizumab

IP carboplatin,IV paclitaxel

Carboplatin, paclitaxel, gemcitabine

2%

18%

37%

43%

0% 10% 20% 30% 40% 50%

During the past year, approximately how many new patients with ovarian cancer have you treated with intraperitoneal chemotherapy?

7%

8%

17%

68%

0% 20% 40% 60% 80%

None

1-2

3-5

>5

Number of Patients

National Patterns of Care Survey, September 2010 (n = 81)

How would you advise a younger (eg, age 55), healthy woman inquiring about the side effects and risks of intraperitoneal therapy compared to IV chemo?

8%

69%

23%

0% 20% 40% 60% 80%

Likely to be quite

tolerable

Likely to be somewhat

difficult

Likely to be very difficult

National Patterns of Care Survey, September 2010 (n = 26)

Survival Outcomes with IP Chemotherapy in Optimally Debulked Ovarian Cancer

Phase III

Study N RegimenSurvival Outcome

1GOG-104 654IP cis + IV cyclophosphamide

IV cis + IV cyclophosphamideHR=0.76

2GOG-114 523IP cis + IV paclitaxel + IV carbo

IV cis + IV paclitaxelRR=0.81

3GOG-172 415IP cis + IV paclitaxel + IP paclitaxel

IV cis + IV paclitaxelRR=0.75

1 Alberts DS et al. NEJM 1996;335:1950-1955.2 Markman M et al. JCO 2001;19:1001-1007.3 Armstrong DK et al. NEJM 2006;354:34-43.

cis = cisplatin; carbo = carboplatin

Copyright © 2010, Research To Practice, All rights reserved.

Phase III Trial of Bevacizumab (BEV) in the Primary Treatment of Advanced Epithelial Ovarian Cancer (EOC), Primary Peritoneal Cancer (PPC), or Fallopian Tube Cancer (FTC): A Gynecologic Oncology Group StudyBurger RA et al.Proc ASCO 2010;Abstract LBA1.

GOG-0218 Primary Endpoint: PFS

With permission from Burger RA et al. Proc ASCO 2010;Abstract LBA1.

1.0

0

Proportion surviving

progression free

Months since randomization

CP (Arm I)

12 3624

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

+ Bev (Arm II)+ Bev Bev maintenance (Arm III)

CP + Bev Bev vs. CPHR = 0.717, p < 0.0001

GOG-0218: Select Adverse Events

Adverse Event

Arm I

CP

(n = 601)

Arm II

CP + Bev

(n = 607)

Arm III

CP + Bev Bev

(n = 608)

GI events (grade ≥2)* 1.2% 2.8% 2.6%

HTN (grade ≥2) 7.2% 16.5% 22.9%

Proteinuria 0.7% 0.7% 1.6%

Venous thromboembolic events 5.8% 5.3% 6.7%

Arterial thrombotic events 0.8% 0.7% 0.7%

CNS bleeding 0% 0% 0.3%

Non-CNS bleeding 0.8% 1.3% 2.1%

Burger RA et al. Proc ASCO 2010;Abstract LBA1.

*GI events include perforation, fistula, necrosis and leak.

Eligibility

• High-risk Stage I or IIA• Any Stage IIB-IV • Ovarian epithelial,

fallopian tube and peritoneal cancer

Protocol ID: MREC-ICON7

Target Accrual: 1,520

Phase III Study of Adding Bevacizumab to Standard Chemotherapy

www.clinicaltrials.gov, September 2010.

Carbo+ Paclitaxel

Carbo+ Paclitaxel+Bev 7.5 mg/kg

Bev 7.5 mg/kg q21 d x 12 mo

R

Bev 15 mg/kg IVto 22 cycles

Protocol ID: GOG-0252 Target Accrual: 1,250

Phase III Study of Bevacizumab and Intravenous or Intraperitoneal Chemotherapy in Stage II-IV Ovarian Epithelial, Fallopian Tube or Primary Peritoneal Cancer

www.clinicaltrials.gov, September 2010.

Cycles 1-6

Paclitaxel IVCarbo IV

Bev 15 mg/kg IV

Paclitaxel IVCarbo IP

Bev 15 mg/kg IV

Paclitaxel IVCis IP

Paclitaxel IPBev 15 mg/kg IV

R

Case History: Dr Spriggs (continued)

• Patient treated with a regimen containing IV paclitaxel, IP cisplatin and IP paclitaxel

• Clinical remission after three cycles of therapy

– Normal CA125

– Negative CT

• Course complicated by nausea and grade 2 painful neuropathy

Treatment options for this patient

1. Single-agent liposomal doxorubicin

2. IV docetaxel / IV carboplatin

3. Single-agent IP carboplatin

4. Continue IV paclitaxel, IP cisplatin and IP paclitaxel — this is curative intent therapy

5. No further treatment

2010 Survey of 100 US-based Oncologists Estimated Number of New Cases Per Year (median)

Cancer Type New Cases per Year

Ovarian 5

Breast 40

Non-small cell lung 28

Colorectal 25

Renal 5

Follicular lymphoma 15

Multiple myeloma 10

Hepatocellular carcinoma 5*

*2009 survey data

During the past year, approximately how many new patients with ovarian cancer have you treated with bevacizumab + chemotherapy for surgically resected Stage III or IV disease?

13%

12%

11%

64%

0% 20% 40% 60% 80%

None

1

2

>2

Number of Patients

National Patterns of Care Survey, September 2010 (n = 81)

What would you tell a woman who has previously undergone uncomplicated debulking surgery without bowel resection is the excess risk for bowel perforation for receiving bevacizumab 1 year after completing chemotherapy?

18%

14%

46%

22%

0% 10% 20% 30% 40% 50%

≤2%

3-5%

6-10%

>10%

Percent excess risk

National Patterns of Care Survey, September 2010 (n = 81)

Median = 5%

Copyright © 2010, Research To Practice, All rights reserved.

Dr Armstrong, why hasn’t there been more uniformity in the field of gyn oncology for the use of IP therapy?

Case History: Dr Armstrong

• 60 yo woman with extensive pelvic and peritoneal

implants, ascites and large volume disease at the root

of the mesentery

• Deemed unresectable by a gynecologic oncologist

• Neoadjuvant carbo/pac x 3 without response

• Topotecan x 3 without response

• Weekly paracentesis for palliation

• CA-125 = 6916

Commonly Utilized Regimens for Platinum- Resistant, Recurrent Ovarian Cancer

Platinum Resistant

(Relapse < 6 mo after chemo)

• Docetaxel

• Oral etoposide

• Gemcitabine

• PLD

• Weekly paclitaxel

• Pemetrexed

• Topotecan

Targeted therapy

• Bevacizumab

3) What would be your most likely treatment recommendation?

Docetaxel

Oral etoposide

Gemcitabine

PLD

Weekly paclitaxel

Pemetrexed

Topotecan

Bevacizumab 21%

7%

0%

9%

41%

15%

0%

7%

0% 10% 20% 30% 40% 50%

Case History: Dr Armstrong (continued)

• Patient enrolled on GOG 170D with bevacizumab 15 mg/kg IV q 3 weeks

• Resolution of ascites in 1 wk and all GI symptoms w/in 3 wks

• Marked response by imaging but unpredictable by CA-125

• Remained on therapy for 21 months before progression

Single Agent Bevacizumab in Refractory Ovarian Cancer: GOG 170D

Pre-Treatment Post-4 cycles

Bevacizumab in Recurrent Ovarian Cancer: GOG 170D

0

5000

10000

15000

20000

25000

Day 1

18 M

onths

CA-125

Bevacizumab

Bevacizumab Trials in Relapsed EOC

GOG 170-D1

(N = 62)NCI 57892

(N = 90)Cannistra3

(N = 44)

Study TreatmentSingle agent BV 15 mg/kg q 3 wk

BV 10 mg/kg q 2 wks + low dose oral cytoxan

Single agent BV 15 mg/kg

q 3 wk

Prior Treatment Setting

Relapsed, up to 2 prior regimens,

1 platinum-based

Relapsed, prior platinum therapy for primary w/

post-platinum maximum of 2 regimens

Platinum resistant, up to

3 regimens

Efficacy Results ORR 6-mo PFS

21%40%

24%56%

16%28%

GI perforation 0 2 (3%) 5 (11%)

1Burger RA et al. J Clin Oncol 2007;25(33):5165-71.2Garcia A et al. J Clin Oncol 2008;26(1):76-82.3Cannistra SA et al. J Clin Oncol 2007;25(33):5180-86.

Copyright © 2010, Research To Practice, All rights reserved.

A Randomized, Phase III Study of Carboplatin and Pegylated Liposomal Doxorubicin Versus Carboplatin and Paclitaxel in Relapsed Platinum-sensitive Ovarian Cancer (OC): CALYPSO Study of the Gynecologic Cancer Intergroup (GCIG)Pujade-Lauraine E et al. Proc ASCO 2009;Abstract LBA5509.

CALYPSO: Progression-Free Survival (PFS) with Carboplatin (C) and Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin and Paclitaxel (P) in Relapsed Platinum-Sensitive Ovarian Cancer

With permission from Pujade-Lauraine E et al. Proc ASCO 2009;Abstract LBA5509.

Copyright © 2010, Research To Practice, All rights reserved.

Can We Define Tumors That Will Respond to PARP Inhibitors? A Phase II Correlative Study of Olaparib in Advanced Serous Ovarian Cancer and Triple-Negative Breast CancerGelmon KA et al.Proc ASCO 2010;Abstract 3002.

BRCA Mutation-Positive BRCA Mutation-Negative*

Ovarian 7/17 (41.2%) 11/46 (23.9%)

Breast 0/8 (0) 0/15 (0)

Objective Response Rates to Olaparib in Patients with Advanced OC or TNBC According to BRCA Mutation Status

*BRCA mutation-negative patients in study were 46 patients with high-grade serousovarian carcinoma and 15 patients with triple-negative breast cancer.

Gelmon KA et al. Proc ASCO 2010;Abstract 3002.

Be

st %

ch

an

ge

fro

m b

ase

line

100

80

60

40

20

0

-20

-40

-60

-80

-100

Change in Target Lesion Size by OC Tumor Type and BRCA Mutation Status

The majority of patients with ovarian cancer had some tumor shrinking with olaparib irrespective of their BRCA mutation status.

With permission from Gelmon KA et al. Proc ASCO 2010;Abstract 3002.

Serous OC/BRCA-positiveNon-serous OC/BRCA-positive

Serous OC/BRCA-negativeNon-serous OC/BRCA-negative

What is the role of a second-look surgery in treatment plan

Would like to know about other late stage therapies in ovarian cancer targeting angiogenesis

Can we ever cure stage III or IV