gog-0218: background and rationale

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)


Paclitaxel (P) 175 mg/m2

PlaceboBEV 15 mg/kg

II(CP + BEV)

BEV 15 mg/kg


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

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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

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

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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

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GOG-0218: Patient Disposition

Characteristic

Arm ICP

(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

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Adverse event (grade when limited), n (%)

Arm ICP

(n=601)


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


418 (66.9)

11.2

0.908(0.759–1.040)

0.080a

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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

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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 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

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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 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

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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

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

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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

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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)

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Randomization Pre-cycle 4 Pre-cycle 7

CP (Arm I) CP + BEV BEV (Arm III)

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gog-0218: background and rationale

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