Transcript Bevacizumab in Recurrent Ovarian Cancer

Monday Night with Research To
Practice: An 8-Part Live CME
Webcast Series
Part II: Ovarian Cancer
Monday, September 27, 2010
7:30 PM - 8:30 PM ET
Copyright © 2010, Research To Practice, All rights reserved.
Deborah K Armstrong, MD
Associate Professor of Oncology, Gynecology and Obstetrics
The Sidney Kimmel Comprehensive Cancer Center
The Johns Hopkins University
Baltimore, Maryland
David R Spriggs, MD
Head, Division of Solid Tumor Oncology
Winthrop Rockefeller Chair of Medical Oncology
Memorial Sloan-Kettering Cancer Center
New York, New York
Neil Love, MD
Moderator
Research To Practice
Miami, 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
Advisory Committee
Abraxis BioScience, Amgen Inc,
Boehringer Ingelheim Pharmaceuticals Inc,
Genentech BioOncology
Paid Research
N/A
Speakers Bureau
N/A
N/A = Not Applicable
Disclosures for David R Spriggs, MD
Advisory Committee
AstraZeneca Pharmaceuticals LP,
Johnson & Johnson Pharmaceuticals
Paid Research
Genentech BioOncology
Speakers Bureau
N/A
N/A = Not Applicable
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.
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 Study
Burger 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 Cancer
Gelmon KA et al.
Proc ASCO 2010;Abstract 3002.
Copyright © 2010, Research To Practice, All rights reserved.
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?
72%
Yes
28%
No
0%
20%
40%
60%
80%
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.
Copyright © 2010, Research To Practice, All rights reserved.
Neoadjuvant Chemotherapy with Interval
Debulking Surgery versus Primary Debulking
Surgery in Stage IIIC/IV Ovarian Cancer (N=632)
Hazard Ratio for Death
(Intention-to-Treat)
NACT versus PDS
HR = 0.98, p = 0.01
Vergote I et al. NEJM 2010;363(10):943-53.
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
43%
IV carboplatin, IV paclitaxel
and bevacizumab
37%
IP carboplatin,
IV paclitaxel
Carboplatin, paclitaxel,
gemcitabine
0%
18%
2%
10%
20%
30%
40%
50%
During the past year, approximately how many
new patients with ovarian cancer have you
treated with intraperitoneal chemotherapy?
None
68%
1-2
17%
Number of
Patients
8%
3-5
7%
>5
0%
20%
40%
National Patterns of Care Survey, September 2010 (n = 81)
60%
80%
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?
Likely to be
quite
tolerable
23%
Likely to be
somewhat
difficult
69%
8%
Likely to be
very difficult
0%
20%
40%
National Patterns of Care Survey, September 2010 (n = 26)
60%
80%
Survival Outcomes with IP Chemotherapy in
Optimally Debulked Ovarian Cancer
Phase III
Study
1GOG-104
2GOG-114
3GOG-172
N
654
523
415
Regimen
IP cis + IV cyclophosphamide
IV cis + IV cyclophosphamide
IP cis + IV paclitaxel + IV carbo
IV cis + IV paclitaxel
IP cis + IV paclitaxel + IP paclitaxel
IV cis + IV paclitaxel
cis = cisplatin; carbo = carboplatin
1 Alberts
DS et al. NEJM 1996;335:1950-1955.
M et al. JCO 2001;19:1001-1007.
3 Armstrong DK et al. NEJM 2006;354:34-43.
2 Markman
Survival
Outcome
HR=0.76
RR=0.81
RR=0.75
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 Study
Burger RA et al.
Proc ASCO 2010;Abstract LBA1.
Copyright © 2010, Research To Practice, All rights reserved.
GOG-0218 Primary Endpoint: PFS
1.0
CP + Bev  Bev vs. CP
HR = 0.717, p < 0.0001
0.9
0.8
Proportion
surviving
progression free
0.7
0.6
0.5
0.4
0.3
0.2
CP (Arm I)
0.1
+ Bev (Arm II)
+ Bev  Bev maintenance (Arm III)
0
0
12
24
Months since randomization
With permission from Burger RA et al. Proc ASCO 2010;Abstract LBA1.
36
GOG-0218: Select Adverse Events
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%
0%
0%
0.3%
0.8%
1.3%
2.1%
Adverse Event
CNS bleeding
Non-CNS bleeding
*GI events include perforation, fistula, necrosis and leak.
Burger RA et al. Proc ASCO 2010;Abstract LBA1.
Phase III Study of Adding Bevacizumab to
Standard Chemotherapy
Carbo
+
Paclitaxel
Eligibility
• High-risk Stage I or IIA
• Any Stage IIB-IV
• Ovarian epithelial,
fallopian tube and
peritoneal cancer
R
Carbo
+
Paclitaxel
+
Bev 7.5 mg/kg
Protocol ID: MREC-ICON7
Target Accrual: 1,520
www.clinicaltrials.gov, September 2010.
Bev 7.5 mg/kg
q21 d x 12 mo
Phase III Study of Bevacizumab and Intravenous or
Intraperitoneal Chemotherapy in Stage II-IV Ovarian
Epithelial, Fallopian Tube or Primary Peritoneal Cancer
Protocol ID: GOG-0252
R
Target Accrual: 1,250
Cycles 1-6
Paclitaxel IV
Carbo IV
Bev 15 mg/kg IV
Paclitaxel IV
Carbo IP
Bev 15 mg/kg IV
Bev 15 mg/kg IV
to 22 cycles
www.clinicaltrials.gov, September 2010.
Paclitaxel IV
Cis IP
Paclitaxel IP
Bev 15 mg/kg IV
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?
None
1
64%
11%
Number of
Patients
2
12%
>2
13%
0%
20%
40%
National Patterns of Care Survey, September 2010 (n = 81)
60%
80%
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?
≤2%
22%
3-5%
46%
Percent
excess risk
14%
6-10%
18%
>10%
0%
10%
20%
National Patterns of Care Survey, September 2010 (n = 81)
Median = 5%
30%
40%
50%
Dr Armstrong, why hasn’t there been more
uniformity in the field of gyn oncology for the
use of IP therapy?
Copyright © 2010, Research To Practice, All rights reserved.
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 PlatinumResistant, 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
7%
Oral etoposide 0%
15%
Gemcitabine
41%
PLD
Weekly paclitaxel
9%
Pemetrexed 0%
Topotecan
7%
21%
Bevacizumab
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
25000
Bevacizumab
20000
15000
CA-125
10000
5000
0
Bevacizumab Trials in Relapsed EOC
GOG 170-D1
(N = 62)
NCI 57892
(N = 90)
Cannistra3
(N = 44)
Study Treatment
Single 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
21%
40%
24%
56%
16%
28%
0
2 (3%)
5 (11%)
Efficacy Results
ORR
6-mo PFS
GI perforation
1Burger
RA et al. J Clin Oncol 2007;25(33):5165-71.
A et al. J Clin Oncol 2008;26(1):76-82.
3Cannistra SA et al. J Clin Oncol 2007;25(33):5180-86.
2Garcia
A Randomized, Phase III Study of
Carboplatin and Pegylated Liposomal
Doxorubicin Versus Carboplatin and
Paclitaxel in Relapsed Platinumsensitive Ovarian Cancer (OC):
CALYPSO Study of the Gynecologic
Cancer Intergroup (GCIG)
Pujade-Lauraine E et al.
Proc ASCO 2009;Abstract LBA5509.
Copyright © 2010, Research To Practice, All rights reserved.
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.
Can We Define Tumors That Will
Respond to PARP Inhibitors? A
Phase II Correlative Study of
Olaparib in Advanced Serous
Ovarian Cancer and TripleNegative Breast Cancer
Gelmon KA et al.
Proc ASCO 2010;Abstract 3002.
Copyright © 2010, Research To Practice, All rights reserved.
Objective Response Rates to Olaparib in Patients
with Advanced OC or TNBC According to BRCA
Mutation Status
Ovarian
Breast
BRCA Mutation-Positive
BRCA Mutation-Negative*
7/17 (41.2%)
11/46 (23.9%)
0/8 (0)
0/15 (0)
*BRCA mutation-negative patients in study were 46 patients with high-grade serous
ovarian carcinoma and 15 patients with triple-negative breast cancer.
Gelmon KA et al. Proc ASCO 2010;Abstract 3002.
Change in Target Lesion Size by OC Tumor Type
and BRCA Mutation Status
Best % change from baseline
100
80
Serous OC/BRCA-positive
Non-serous OC/BRCA-positive
60
Serous OC/BRCA-negative
Non-serous OC/BRCA-negative
40
20
0
-20
-40
-60
-80
-100
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.
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