Transcript Slide 1

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Phase III Trial of Bevacizumab in the Primary
Treatment of Advanced Epithelial Ovarian,
Primary Peritoneal, or Fallopian Tube Cancer:
A Gynecologic Oncology Group (GOG) Study
R.A. Burger,1 M.F. Brady,2 M.A. Bookman,3
J.L. Walker,4 H.D. Homesley,5 J. Fowler,6
B.J. Monk,7 B.E. Greer,8 M. Boente,9 S.X. Liang10
1Fox
Chase Cancer Center, Philadelphia, PA; 2Gynecologic Oncology Group Statistical
and Data Center, Roswell Park Cancer Institute, Buffalo, NY; 3University of Arizona
Cancer Center, Tucson, AZ; 4University of Oklahoma Health Sciences Center,
Oklahoma City, OK; 5Brody School of Medicine, Greenville, NC; 6James Cancer
Hospital at the Ohio State University, Hilliard, OH; 7University of California, Irvine
Medical Center, Orange, CA; 8Seattle Cancer Care Alliance, Seattle, WA; 9Minnesota
Oncology and Hematology, Minneapolis, MN; 10State University of New York at Stony
Brook, Stony Brook, NY, USA
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GOG-0218: Background and Rationale
• Ovarian cancer (epithelial ovarian [OV], primary peritoneal [PP], and
fallopian tube [FT] cancers) remains a major public health problem1
• Vascular endothelial growth factor (VEGF)-associated tumor
angiogenesis in ovarian cancer is associated with malignant
behavior2,3
• Bevacizumab (BEV), monoclonal antibody to VEGF, inhibits tumor
angiogenesis
– Promising single-agent activity in phase II recurrent ovarian cancer
studies4,5
– BEV combined with chemotherapy had been approved for the treatment
of patients with metastatic colorectal and lung cancers
• GOG-0218 designed to study addition of BEV to standard
chemotherapy in front-line treatment of ovarian cancer
1. Jemal et al. CA Cancer J Clin 2009;59:225–49
2. Hollingsworth et al. Am J Pathol 1995;147:33–41
3. Burger et al. J Clin Oncol 2007;25:2902–8
4. Burger et al. J Clin Oncol 2007;25:5165–71
5. Cannistra et al. J Clin Oncol 2007;25:5180–6
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GOG-0218: Schema
Arm
Carboplatin (C) AUC 6
Front-line:
Epithelial OV, PP
or FT cancer
• Stage III optimal
(macroscopic)
• Stage III
suboptimal
• Stage IV
n=1800 (planned)
Paclitaxel (P) 175 mg/m2
R
A
N
D
O
M
I
Z
E
I
(CP)
Placebo
Carboplatin (C) AUC 6
1:1:1
Paclitaxel (P) 175 mg/m2
BEV 15 mg/kg
II
(CP + BEV)
Placebo
Carboplatin (C) AUC 6
Stratification variables:
• GOG performance status
(PS)
• Stage/debulking status
Paclitaxel (P) 175 mg/m2
BEV 15 mg/kg
Cytotoxic
(6 cycles)
Maintenance
(16 cycles)
III
(CP + BEV
 BEV)
15 months
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GOG-0218: Analysis Plan
• Primary analysis
– Compare investigator-determined progression-free survival
(PFS) for each BEV arm vs control
• If both results positive, compare Arm III (CP + BEV  BEV)
vs Arm II (CP + BEV)
– Disease progression based on: RECIST, global clinical
deterioration, or CA-1251
– Planned sample size of 1800 based on:
• 90% power to detect PFS hazard ratio (HR) 0.77
– Median PFS shift: 14.0 months  18.2 months
• Secondary analyses: Overall survival (OS), safety, quality of life;
correlative laboratory studies
1. Gynecologic Cancer Intergroup Criteria - Rustin et al. J Natl Cancer Inst 2004
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GOG-0218: Key Eligibility Criteria
• Histologic diagnosis of epithelial OV, PP, or FT cancer
• Following maximal debulking surgery: stage III optimal
(macroscopic residual disease 1 cm) or suboptimal (>1 cm),
or stage IV
• No prior chemotherapy
• 1–12 weeks after initial surgery
• GOG PS 0–2
• No history of significant vascular events
• No evidence of intestinal obstruction requiring parenteral support
• Written informed consent
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GOG-0218: Study Conduct
• 1873 patients from 336 sites (US, Canada, South Korea, Japan),
October 2005–June 2009
• Key protocol amendments
– Inclusion of optimally debulked (macroscopic residual disease)
patients
– Primary endpoint changed to PFS
• Final data analysis triggered by number of events in control arm
• Analyses
– Efficacy population: n=1873 (intent to treat)
– Safety population: n=1816 (intent to treat, as of cycle 2)
• Median follow-up: 17.4 months (range 0.0–50.7 months)
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GOG-0218: Baseline Clinical
Characteristics
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
60 (25–86)
60 (24–88)
60 (22–89)
526 (84)
519 (83)
521 (84)
Asian
41 (7)
37 (6)
39 (6)
Non-Hispanic black
25 (4)
28 (5)
27 (4)
Hispanic
21 (3)
28 (5)
25 (4)
Characteristic
Median age, years (range)
Race, n (%)
Non-Hispanic white
Other, specified
8 (1)
5 (<1)
4 (<1)
GOG PS, n (%)
0
311 (50)
315 (50)
305 (49)
1
272 (44)
270 (43)
267 (43)
2
42 (7)
40 (6)
51 (8)
Percentages may not total 100% due to rounding or categorization
GOG-0218: Baseline Surgical–Pathologic
Characteristics
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Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
III optimal (macroscopic)
218 (35)
205 (33)
216 (35)
III suboptimal
254 (41)
256 (41)
242 (39)
IV
153 (25)
164 (26)
165 (27)
543 (87)
523 (84)
525 (84)
Endometrioid
20 (3)
15 (2)
25 (4)
Clear cell
11 (2)
23 (4)
18 (3)
Mucinous
8 (1)
Characteristic, n (%)
Stage/residual size
Histology
Serous
5 (<1)
8 (1)
Tumor grade
3a
412 (66)
435 (70)
430 (69)
2
94 (15)
77 (12)
92 (15)
1
33 (5)
28 (4)
16 (3)
Not specified/pending
86 (14)
85 (14)
85 (14)
Percentages may not total 100% due to rounding or categorization
aGrade 3 includes all clear cell tumors
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GOG-0218: Patient Disposition
Characteristic
Median (range) number BEV/placebo cycles
On treatment at time of analysis, n (%)
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
11 (0–22a)
12 (0–22a)
14 (0–21)
86 (14)
82 (13)
117 (19)
100 (16)
104 (17)
148 (24)
299 (48)
264 (42)
164 (26)
Adverse events
69 (11)
86 (14)
94 (15)
Cycles 1–6
57 (9)
73 (12)
59 (9)
Cycle ≥7
12 (2)
13 (2)
35 (6)
8 (1)
7 (1)
13 (2)
Patient refusal
44 (7)
55 (9)
50 (8)
Other
19 (3)
27 (4)
37 (6)
Completed regimen, n (%)
Discontinued study treatment, n (%)
Disease progression
Deaths
aOne
patient in each group received BEV/placebo in cycle 1
Percentages may not total 100% due to rounding or categorization
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GOG-0218: Select Adverse Events
Onset between cycle 2 and 30 days after date of last treatment
GI eventsa (grade ≥2)
Arm I
CP
(n=601)
7 (1.2)
Arm II
CP + BEV
(n=607)
17 (2.8)
Arm III
CP + BEV  BEV
(n=608)
16 (2.6)
Hypertension (grade ≥2)
43 (7.2)b
100 (16.5)b
139 (22.9)b
4 (0.7)
4 (0.7)
10 (1.6)
Pain (grade ≥2)
250 (41.7)
252 (41.5)
286 (47.1)
Neutropenia (grade ≥4)
347 (57.7)
384 (63.3)
385 (63.3)
Febrile neutropenia
21 (3.5)
30 (4.9)
26 (4.3)
Venous thromboembolic event
35 (5.8)
32 (5.3)
41 (6.7)
Arterial thromboembolic event
5 (0.8)
4 (0.7)
4 (0.7)
CNS bleeding
0
0
2 (0.3)
Non-CNS bleeding (grade ≥3)
5 (0.8)
8 (1.3)
13 (2.1)
RPLS
0
1 (0.2)
1 (0.2)
Adverse event (grade when limited), n (%)
Proteinuria (grade ≥3)
RPLS = reversible posterior leukoencephalopathy syndrome
aPerforation/fistula/necrosis/leak
bp<0.05
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GOG-0218: Disease Assessment
CP + placebo/BEV
(6 cycles)
Months
Imaginga
CA-125
Exam
0
3
Maintenance placebo/BEV
(16 cycles)
6
9
12
Post-treatment
follow-up
15
Same intervals for
all modalities:
Every 3 months
for 2 years, then
every 6 months
for 3 years, then
annually
aConventional
CT or MRI
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GOG-0218: Investigator-Assessed PFS
Proportion surviving progression free
1.0
0.9
Patients with event, n (%)
0.8
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
423
(67.7)
418
(66.9)
360
(57.8)
10.3
11.2
14.1
Median PFS, months
0.7
Stratified analysis HR
(95% CI)
0.6
One-sided p-value (log rank)
0.908
0.717
(0.759–1.040) (0.625–0.824)
0.080a
<0.0001a
0.5
0.4
0.3
0.2
CP (Arm I)
+ BEV (Arm II)
0.1
+ BEV → BEV maintenance (Arm III)
0
0
12
24
Months since randomization
36
ap-value
boundary = 0.0116
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GOG-0218: Subgroup Analyses of PFS
CP + BEV  BEV (Arm III) vs CP (Arm I)
Hazard ratio
Stage 3 optimal (n=434)
0.618
Stage 3 suboptimal (n=496)
0.763
Stage 4 (n=318)
0.698
PS 0 (n=616)
0.710
PS 1/2 (n=632)
0.690
Age <60 years (n=629)
0.680
Age 60–69 years (n=409)
0.763
Age 70 years (n=210)
0.678
Experimental arm
(CP + BEV  BEV;
Arm III) better
0.33
0.5 0.67
Control arm
(CP; Arm I) better
1.0
1.5
Treatment hazard ratio
2.0
3.0
GOG-0218: Ramification of Using
CA-125 as Determinant of Progression
Protocol-defined
PFS analysis
CA-125-censored
PFS analysis
Median PFS, months
CP (Arm I)
10.3
12.0
CP + BEV  BEV (Arm III)
14.1
18.0
Absolute difference in median
PFS (months)
3.8
6.0
Hazard ratio
0.717
0.645
<0.0001
<0.0001
One-sided p-value (log rank)
Censored for CA-125, %
CP (Arm I)
0
20
CP + BEV  BEV (Arm III)
0
29
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GOG-0218: Overall Survival Analysis
At time of final PFS analysis
1.0
0.9
Proportion alive
0.8
0.7
0.6
0.5
0.4
Patients with
events, n (%)
0.3
Median, months
0.2
HRa
0.1
One-sided p-value
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
156
(25.0)
150
(24.0)
138
(22.2)
39.3
38.7
39.7
1.036
0.915
(0.827–1.297)
(0.727–1.152)
0.361
0.252
(95% CI)
0
No. at
risk
0
12
24
36
Months since randomization
625/625/623
442/432/437
173/162/171
48
46/39/40
aStratified
analysis
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GOG-0218: Overall Survival (OS)
Outcome
Deaths, n (%)
1-year survival, %
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
156
(25.0)
150
(24.0)
138
(22.2)
90.6
90.4
91.3
• Events observed in 24% of patients at time of data lock
• After primary endpoint changed from OS to PFS
– Unblinding to treatment assignment allowed at time of disease
progression
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GOG-0218: Conclusions
• GOG-0218 met the primary objective in the front-line treatment of
advanced ovarian (epithelial OV, PP and FT) cancer; PFS with
CP + BEV  BEV maintenance (Arm III) statistically superior to CP
alone (Arm I)
– PFS with CP + BEV (Arm II) not statistically superior to CP (Arm I)
• Interpretation of survival analysis limited
• Treatment regimen generally well tolerated; adverse events
(including GI perforation) similar to previous BEV studies
• BEV – first molecular targeted and first anti-angiogenic agent to
demonstrate benefit in this population
• CP + BEV  BEV maintenance should be considered one standard
option
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Acknowledgments
Patients who participated in the study
and significant others
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Acknowledgments
Abington Memorial Hospital
New York University Medical Center
University of Iowa Hospitals and Clinics
Abramson Cancer Center at the University
of Pennsylvania
Northwestern University
University of Kentucky
Ohio State University Medical Center
University of Massachusetts Medical School
Aurora Women's Pavilion of West Allis
Memorial Hospital
Penn State Milton S. Hershey Medical Center
Roswell Park Cancer Institute
University of Minnesota Medical Center –
Fairview
Rush University Medical Center
University of Mississippi Medical Center
Saitama Medical University International/GOG
Japan
University of New Mexico
Cooper Hospital University Medical Center
CTSU
Seoul National University Hospital/KGOG
Duke University Medical Center
Fox Chase Cancer Center
State University of New York Downstate
Medical Center
University of Oklahoma Health Sciences
Center
Fred Hutchinson Cancer Research Center
Stony Brook University Medical Center
University of Texas Medical Branch University
of Texas Southwestern Medical Center
Georgia Core
The Hospital of Central Connecticut
University of Virginia
Gynecologic Oncology Network
University Hospitals – Ireland Cancer Center
University of Wisconsin Hospitals and Clinics
Gynecologic Oncology of West Michigan,
PLLC
University of Alabama at Birmingham
Wake Forest University Health Sciences
University of California at Los Angeles
Walter Reed Army Medical Center
Indiana University Medical Center
University of California Medical Center at Irvine
– Orange Campus
Washington University School of Medicine
Magee Women's Hospital – University of
Pittsburgh Medical Center
University of Chicago
Women and Infants’ Hospital
University of Cincinnati
Women's Cancer Center of Nevada
Mayo Clinic Rochester
University of Colorado Cancer Center –
Anschutz Cancer Pavilion
Yale University
Cleveland Clinic Foundation
Community Clinical Oncology Program
M.D. Anderson Cancer Center
Memorial Sloan-Kettering Cancer Center
Moffitt Cancer Center and Research
Institute
Mount Sinai Medical Center
University of North Carolina
Wayne State University
Other Investigators
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Acknowledgments
GOG, NCI, and Genentech
Back-Up Slides
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GOG-0218: Select Adverse Events by
Treatment Phase
Select adverse events, n
(grade when limited)
Patients, n
Cycles, n
Treatment phasea
GI eventsb (grade ≥2)
Arm I
CP
(n=601)
2906
Arm II
CP + BEV
(n=483)
4059
(n=607)
2911
Arm III
CP + BEV  BEV
(n=457)
4204
(n=608)
2891
(n=464)
4677
Cytotoxic Maintenance Cytotoxic Maintenance Cytotoxic Maintenance
(cycles 2–6) (cycles ≥7) (cycles 2–6) (cycles ≥7) (cycles 2–6) (cycles ≥7)
6
1
16
1
15
1
21
22
64
36
60
79
2
2
4
0
0
10
Pain (grade ≥2)
127
123
117
135
112
174
Neutropenia (grade ≥4)
345
2
382
2
385
0
Febrile neutropenia
21
0
30
0
26
0
Venous thromboembolic event
26
9
27
5
27
14
Arterial thromboembolic event
4
1
1
3
3
1
CNS bleeding
0
0
0
0
0
2
Non-CNS bleeding (grade ≥3)
3
2
8
0
10
3
RPLS
0
0
1
0
0
1
Hypertension (grade ≥2)
Proteinuria (grade ≥3)
aOnset
within 30 days of last treatment
bPerforation/fistula/necrosis/leak
GOG-0218: Mean Patient-Reported TOI
Score During Chemotherapy
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Mean TOI score
112
100
90
80
70
60
50
40
30
20
10
0
Randomization
CP (Arm I)
CP + BEV  BEV (Arm III)
Pre-cycle 4
Pre-cycle 7
TOI = Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary
(FACT-O TOI): FACT-G [Physical Well-Being (7 items), Functional Well-Being
(7 items)] and the Ovarian Cancer Subscale (12 item)