1
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
2
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 standardchemotherapy in front-line treatment of ovarian cancer
1. Jemal et al. CA Cancer J Clin 2009;59:225–492. Hollingsworth et al. Am J Pathol 1995;147:33–41
3. Burger et al. J Clin Oncol 2007;25:2902–84. Burger et al. J Clin Oncol 2007;25:5165–71
5. Cannistra et al. J Clin Oncol 2007;25:5180–6
3
GOG-0218: Schema
Front-line: Epithelial OV, PP or FT cancer
• Stage III optimal (macroscopic)
• Stage III suboptimal• Stage IV
n=1800 (planned)
Stratification variables:• GOG performance status
(PS)• Stage/debulking status
1:1:1
15 months
Paclitaxel (P) 175 mg/m2
Carboplatin (C) AUC 6
Placebo
I
Arm
Cytotoxic (6 cycles)
Maintenance(16 cycles)
(CP)
Carboplatin (C) AUC 6
Paclitaxel (P) 175 mg/m2
PlaceboBEV 15 mg/kg
II(CP + BEV)
BEV 15 mg/kg
Carboplatin (C) AUC 6
Paclitaxel (P) 175 mg/m2III
(CP + BEV BEV)
4
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
5
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
6
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)
7
GOG-0218: Baseline Clinical Characteristics
Characteristic
Arm ICP
(n=625)
Arm IICP + BEV
(n=625)
Arm IIICP + BEV BEV
(n=623)
Median age, years (range) 60 (25–86) 60 (24–88) 60 (22–89)
Race, n (%)
Non-Hispanic white 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)
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
8
GOG-0218: Baseline Surgical–PathologicCharacteristics
Characteristic, n (%)
Arm ICP
(n=625)
Arm IICP + BEV(n=625)
Arm IIICP + BEV BEV
(n=623)
Stage/residual size
III optimal (macroscopic) 218 (35) 205 (33) 216 (35)
III suboptimal 254 (41) 256 (41) 242 (39)
IV 153 (25) 164 (26) 165 (27)
Histology
Serous 543 (87) 523 (84) 525 (84)
Endometrioid 20 (3) 15 (2) 25 (4)
Clear cell 11 (2) 23 (4) 18 (3)
Mucinous 8 (1) 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 categorizationaGrade 3 includes all clear cell tumors
9
GOG-0218: Patient Disposition
Characteristic
Arm ICP
(n=625)
Arm IICP + BEV(n=625)
Arm IIICP + BEV BEV
(n=623)
Median (range) number BEV/placebo cycles 11 (0–22a) 12 (0–22a) 14 (0–21)
On treatment at time of analysis, n (%) 86 (14) 82 (13) 117 (19)
Completed regimen, n (%) 100 (16) 104 (17) 148 (24)
Discontinued study treatment, n (%)
Disease progression 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)
Deaths 8 (1) 7 (1) 13 (2)
Patient refusal 44 (7) 55 (9) 50 (8)
Other 19 (3) 27 (4) 37 (6)
aOne patient in each group received BEV/placebo in cycle 1Percentages may not total 100% due to rounding or categorization
10
Adverse event (grade when limited), n (%)
Arm ICP
(n=601)
Arm IICP + BEV(n=607)
Arm IIICP + BEV BEV
(n=608)
GI eventsa (grade ≥2) 7 (1.2) 17 (2.8) 16 (2.6)
Hypertension (grade ≥2) 43 (7.2)b 100 (16.5)b 139 (22.9)b
Proteinuria (grade ≥3) 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)
GOG-0218: Select Adverse EventsOnset between cycle 2 and 30 days after date of last treatment
RPLS = reversible posterior leukoencephalopathy syndromeaPerforation/fistula/necrosis/leak
bp<0.05
GOG-0218: Disease Assessment
Months
CP + placebo/BEV(6 cycles)
Maintenance placebo/BEV(16 cycles)
Imaginga
CA-125
Exam
11
aConventional CT or MRI
0 3 6 9 12 15
Same intervals for all modalities:
Every 3 months for 2 years, then
every 6 months for 3 years, then
annually
Post-treatment follow-up
CP (Arm I)
Arm I CP
(n=625)
Patients with event, n (%)423
(67.7)
Median PFS, months 10.3
Stratified analysis HR (95% CI)
One-sided p-value (log rank)
GOG-0218: Investigator-Assessed PFS
+ BEV (Arm II)
ap-value boundary = 0.0116
+ BEV → BEV maintenance (Arm III)Pro
po
rtio
n s
urv
ivin
g p
rog
ress
ion
fre
e
Months since randomization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 12 24 36
Arm IIICP + BEV BEV
(n=623)
360 (57.8)
14.1
0.717 (0.625–0.824)
<0.0001a
12
Arm IICP + BEV(n=625)
418 (66.9)
11.2
0.908(0.759–1.040)
0.080a
13
GOG-0218: Subgroup Analyses of PFSCP + BEV BEV (Arm III) vs CP (Arm I)
Hazard ratio
Experimental arm (CP + BEV BEV;
Arm III) betterControl arm
(CP; Arm I) better
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
Treatment hazard ratio
0.33 0.5 0.67 1.0 1.5 2.0 3.0
14
GOG-0218: Ramification of Using CA-125 as Determinant of Progression
Protocol-definedPFS analysis
CA-125-censoredPFS 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
One-sided p-value (log rank) <0.0001 <0.0001
Censored for CA-125, %
CP (Arm I) 0 20
CP + BEV BEV (Arm III) 0 29
GOG-0218: Overall Survival Analysis At time of final PFS analysis
Arm ICP
(n=625)
Arm IICP + BEV(n=625)
Arm IIICP + BEV BEV
(n=623)
Patients with events, n (%)
156 (25.0)
150 (24.0)
138 (22.2)
Median, months 39.3 38.7 39.7
HRa
(95% CI)1.036
(0.827–1.297)0.915
(0.727–1.152)
One-sided p-value 0.361 0.252
Pro
po
rtio
n a
live
Months since randomization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 12 24 36 48
15
aStratified analysis
625/625/623 442/432/437 173/162/171 46/39/40No. at risk
16
GOG-0218: Overall Survival (OS)
• 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
OutcomeArm I
CP(n=625)
Arm IICP + BEV(n=625)
Arm IIICP + BEV BEV
(n=623)
Deaths, n (%)156
(25.0)150
(24.0)138
(22.2)
1-year survival, % 90.6 90.4 91.3
17
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
18
Acknowledgments
Patients who participated in the study
and significant others
AcknowledgmentsAbington Memorial Hospital
Abramson Cancer Center at the University of Pennsylvania
Aurora Women's Pavilion of West Allis Memorial Hospital
Cleveland Clinic Foundation
Community Clinical Oncology Program
Cooper Hospital University Medical Center
CTSU
Duke University Medical Center
Fox Chase Cancer Center
Fred Hutchinson Cancer Research Center
Georgia Core
Gynecologic Oncology Network
Gynecologic Oncology of West Michigan, PLLC
Indiana University Medical Center
M.D. Anderson Cancer Center
Magee Women's Hospital – University of Pittsburgh Medical Center
Mayo Clinic Rochester
Memorial Sloan-Kettering Cancer Center
Moffitt Cancer Center and Research Institute
Mount Sinai Medical Center
University of Iowa Hospitals and Clinics
University of Kentucky
University of Massachusetts Medical School
University of Minnesota Medical Center –Fairview
University of Mississippi Medical Center
University of New Mexico
University of North Carolina
University of Oklahoma Health Sciences Center
University of Texas Medical Branch University of Texas Southwestern Medical Center
University of Virginia
University of Wisconsin Hospitals and Clinics
Wake Forest University Health Sciences
Walter Reed Army Medical Center
Washington University School of Medicine
Wayne State University
Women and Infants’ Hospital
Women's Cancer Center of Nevada
Yale University
Other Investigators
19
New York University Medical Center
Northwestern University
Ohio State University Medical Center
Penn State Milton S. Hershey Medical Center
Roswell Park Cancer Institute
Rush University Medical Center
Saitama Medical University International/GOG Japan
Seoul National University Hospital/KGOG
State University of New York Downstate Medical Center
Stony Brook University Medical Center
The Hospital of Central Connecticut
University Hospitals – Ireland Cancer Center
University of Alabama at Birmingham
University of California at Los Angeles
University of California Medical Center at Irvine – Orange Campus
University of Chicago
University of Cincinnati
University of Colorado Cancer Center – Anschutz Cancer Pavilion
20
Acknowledgments
GOG, NCI, and Genentech
Back-Up Slides
GOG-0218: Select Adverse Events by Treatment PhaseSelect adverse events, n(grade when limited)
Arm ICP
Arm IICP + BEV
Arm IIICP + BEV BEV
Patients, n (n=601) (n=483) (n=607) (n=457) (n=608) (n=464)
Cycles, n 2906 4059 2911 4204 2891 4677
Treatment phasea Cytotoxic (cycles 2–6)
Maintenance(cycles ≥7)
Cytotoxic(cycles 2–6)
Maintenance (cycles ≥7)
Cytotoxic (cycles 2–6)
Maintenance (cycles ≥7)
GI eventsb (grade ≥2) 6 1 16 1 15 1
Hypertension (grade ≥2) 21 22 64 36 60 79
Proteinuria (grade ≥3) 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 0Venous thromboembolic
event26 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
22
aOnset within 30 days of last treatment
bPerforation/fistula/necrosis/leak
GOG-0218: Mean Patient-Reported TOI Score During Chemotherapy
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)
112
100
90
80
70
60
50
40
30
20
10
0
Mea
n T
OI
sco
re
Randomization Pre-cycle 4 Pre-cycle 7
CP (Arm I) CP + BEV BEV (Arm III)
23
112
100
90
80
70
60
50
40
30
20
10
0