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GOG-0218: Background and Rationale

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.

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GOG-0218: Background and Rationale

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  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,3J.L. Walker,4 H.D. Homesley,5 J. Fowler,6B.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;59:225–49 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

  3. GOG-0218: Schema Arm Carboplatin (C) AUC 6 I • 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 (CP) Placebo Carboplatin (C) AUC 6 1:1:1 II RANDOM I Z E Paclitaxel (P) 175 mg/m2 (CP + BEV) BEV 15 mg/kg Placebo Carboplatin (C) AUC 6 III • Stratification variables: • GOG performance status (PS) • Stage/debulking status Paclitaxel (P) 175 mg/m2 (CP + BEV  BEV) BEV 15 mg/kg Cytotoxic (6 cycles) Maintenance (16 cycles) 15 months

  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 1cm) 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) 6

  7. GOG-0218: Baseline Clinical Characteristics Percentages may not total 100% due to rounding or categorization

  8. GOG-0218: Baseline Surgical–PathologicCharacteristics Percentages may not total 100% due to rounding or categorization aGrade 3 includes all clear cell tumors

  9. GOG-0218: Patient Disposition aOne patient in each group received BEV/placebo in cycle 1 Percentages may not total 100% due to rounding or categorization

  10. GOG-0218: Select Adverse EventsOnset between cycle 2 and 30 days after date of last treatment RPLS = reversible posterior leukoencephalopathy syndrome aPerforation/fistula/necrosis/leak bp<0.05

  11. 11 GOG-0218: Disease Assessment CP + placebo/BEV (6 cycles) Maintenance placebo/BEV (16 cycles) Post-treatment follow-up Months 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 Imaginga CA-125 Exam aConventional CT or MRI

  12. GOG-0218: Investigator-Assessed PFS + BEV → BEV maintenance (Arm III) ap-value boundary = 0.0116 12 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Proportion surviving progression free CP (Arm I) + BEV (Arm II) 0 12 24 36 Months since randomization

  13. GOG-0218: Subgroup Analyses of PFSCP + BEV  BEV (Arm III) vs CP (Arm I) 13 Treatment hazard ratio

  14. GOG-0218: Ramification of Using CA-125 as Determinant of Progression 14

  15. GOG-0218: Overall Survival Analysis At time of final PFS analysis 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Proportion alive 0 12 24 36 48 Months since randomization No. at risk 625/625/623 442/432/437 173/162/171 46/39/40 aStratified analysis

  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

  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

  19. Acknowledgments 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 Abington 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

  20. Acknowledgments GOG, NCI, and Genentech

  21. Back-Up Slides

  22. GOG-0218: Select Adverse Events by Treatment Phase 22 aOnset within 30 days of last treatment bPerforation/fistula/necrosis/leak

  23. 23 GOG-0218: Mean Patient-Reported TOI Score During Chemotherapy 112 100 90 80 70 60 50 40 30 20 10 0 112 100 90 80 70 60 50 40 30 20 10 0 Mean TOI score CP (Arm I) CP + BEV  BEV (Arm III) Randomization 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)

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