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Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol,

High-dose Bevacizumab in Combination with FOLFOX4 Improves Survival in Patients with Previously Treated Advanced Colorectal Cancer: Results from the Eastern Cooperative Oncology Group (ECOG) Study E3200. Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol,

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Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol,

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  1. High-dose Bevacizumab in Combination with FOLFOX4 Improves Survival in Patients with PreviouslyTreated Advanced Colorectal Cancer: Results from the Eastern Cooperative Oncology Group (ECOG) Study E3200. Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol, Peter J. O’Dwyer, Edith P. Mitchell, Steven R. Alberts, Michael A. Schwartz, and Al B. Benson III.

  2. Background • Bevacizumab (rhuMAb-VEGF, Avastin) • Binds VEGFA and its isoforms • T1/2 = 17-21 days • VEGF • potent mediator of angiogenesis • expressed in 40-60% colorectal tumors • associated with recurrence and prognosis

  3. Background • First-line Metastatic Colorectal Cancer: • Improved TTP/PFS, RR • Kabbinavar et al. JCO, 2003 • Kabbinavar et al. JCO, 2005 • Improved OS • Hurwitz, et al. NEJM, 2004 • FDA approval: 2004

  4. E3200: Study Design • Stratification factors: • ECOG PS: 0 vs 1, 2 • Prior XRT FOLFOX4 + Bevacizumab (10 mg/kg, q 2 weeks) PD Previously treated metastatic CRC PD FOLFOX4 Bevacizumab (10mg/kg, q 2 wks) PD Giantonio BJ, et al. ASCO 2005

  5. 2 h 22 h 2 h 22 h E3200: Treatment BEVACIZUMAB: 10 mg/kg every 14 days FOLFOX4: 5-FU bolus 400 mg/m2 5-FU bolus 400 mg/m2 5-FU infusion 600 mg/m2 LV 200 mg/m2 5-FU infusion 600 mg/m2 LV 200 mg/m2 Oxaliplatin 85 mg/m2 Cycle length = 14 days Giantonio BJ, et al. ASCO 2005

  6. E3200: Eligibility Criteria • Advanced or metastatic colorectal adenocarcinoma • Measurable disease by RECIST criteria • Prior treatment with a fluoropyrimadine & irinotecan • No prior oxaliplatin or bevacizumab • PS 0-2 & adequate end organ function • BP <150/100 mmhg on a stable anti-hypertensive regimen • 24 hr urine protein <500 mg if dipstick 1+ • No history of thrombotic or hemorrhagic events • No therapeutic anticoagulation or anti-platelet agents • aspirin <325/day allowed Giantonio BJ, et al. ASCO 2005

  7. E3200: Study Objectives • Primary Objective: • overall survival 88% power to detect a 40% improvement in overall survival (7 months → 9.8 months) when bevacizumab is added to FOLFOX4 • Secondary Objectives: • response rate • progression free survival • toxicity Giantonio BJ, et al. ASCO 2005

  8. E3200: Accrual History • Accrual Period • Arms A & B: • November 2001 - April 2003 • Arm C (bevacizumab alone) • November 2001- February 2003 • Closed to accrual by ECOG DMC Giantonio BJ, et al. ASCO 2005

  9. E3200: Demographics Giantonio BJ, et al. ASCO 2005

  10. E3200: Prior Treatment History Giantonio BJ, et al. ASCO 2005

  11. E3200: Treatment Statistics Giantonio BJ, et al. ASCO 2005

  12. E3200: Overall Survival 1.0 0.9 HR = 0.76 A vs B: p = 0.0018 B vs C: p = 0.95 0.8 0.7 0.6 P r o b a b i l i t y 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 OS (months) TOTAL DEAD ALIVE MEDIAN A:FOLFOX4 + bevacizumab 289 246 43 12.9 B:FOLFOX4 290 257 33 10.8 C:bevacizumab 243 216 27 10.2 Giantonio BJ, et al. ASCO 2005

  13. E3200: Progression-Free Survival 1.0 HR = 0.64 A vs B: p < 0.0001 B vs C: p < 0.0001 0.9 0.8 0.7 0.6 P r o b a b i l i t y 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 PFS (months) TOTAL FAIL CENS MEDIAN A:FOLFOX4 + bevacizumab 273 228 45 7.2 B:FOLFOX4 273 241 32 4.8 C:bevacizumab 229 215 14 2.7 Giantonio BJ, et al. ASCO 2005

  14. E3200: Response Rates *FOLFOX+B vs FOLFOX: P < 0.0001 Giantonio BJ, et al. ASCO 2005

  15. E3200: Grade 3/4 Toxicity Giantonio BJ, ASCO 2005

  16. E3200: Grade 3/4 Hemorrhagic Toxicity Giantonio BJ, ASCO 2005

  17. E3200: Grade 3/4 Arterial & Venous Thromboses * Cardiac ischemia and cerebrovascular ischemia combined Giantonio BJ, ASCO 2005

  18. E3200: Bowel Perforation Giantonio BJ, ASCO 2005

  19. E3200: 60 Day All-Cause Mortality • FOLFOX4 + Bevacizumab: 6% • FOLFOX4 4% • Bevacizumab 6% Giantonio BJ, et al. ASCO 2005

  20. E3200: Conclusions • Bevacizumab (10 mg/kg) + FOLFOX4 improves OS, PFS, and response for previously treated patients with advanced colorectal cancer. • Bevacizumab + FOLFOX4 is well tolerated. • Hypertension, bleeding, and vomiting are associated with FOLFOX4 + bevacizumab. • Bowel perforation occurred infrequently but only in bevacizumab treated patients. • An increase in sensory neuropathy may be related to time on treatment. • Bevacizumab is inactive when used as a single agent in this previously treated population. Giantonio BJ, et al. ASCO 2005

  21. ECOG Jean Macdonald Cindy Johnson Robert Comis NCI Rick Kaplan Helen Chen Meg Mooney The Investigator Teams Physicians Nurses Research staff Study Chair Liaisons Cecile Miller, RN Maryann Redlinger, RN Kristi Kafel, RN E3200: Acknowledgements

  22. E3200: Acknowledgements The Participants

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