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CJ Allegra, GA Yothers, MJ O'Connell, S Sharif, NJ Petrelli, LH Colangelo, N Wolmark

Overall Survival and Updated Disease-Free Survival Results of the NSABP C-08 Trial Assessing Bevacizumab in Stage II & III Colon Cancer. CJ Allegra, GA Yothers, MJ O'Connell, S Sharif, NJ Petrelli, LH Colangelo, N Wolmark. Traditional Therapeutic Development Paradigm. Safety

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CJ Allegra, GA Yothers, MJ O'Connell, S Sharif, NJ Petrelli, LH Colangelo, N Wolmark

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  1. Overall Survival and Updated Disease-Free Survival Results of the NSABP C-08 Trial Assessing Bevacizumab in Stage II & III Colon Cancer CJ Allegra, GA Yothers, MJ O'Connell, S Sharif, NJ Petrelli, LH Colangelo, N Wolmark

  2. Traditional Therapeutic Development Paradigm Safety Activity in advanced disease Efficacy in advanced disease Test in adjuvant setting

  3. Recent Data Suggests this Paradigm for Adjuvant CRC Development May be Flawed • Oxaliplatin success • Irinotecan fail • Cetuximab fail • Bevacizumab fail • Batting .250!!

  4. Oxaliplatin + Bev in Advanced CRC • E3200 – FOLFOX +/- bev in previously treated CRC 1 • 577 patients randomized • ORR 22.7% v 8.6% (p<0.0001) • PFS 7.3 v 4.7 months (p<0.0001) • OS 12.9 v 10.8 months (p=0.001) • NO16966 – XELOX/FOLFOX +/- bev in untreated CRC 2 • 1401 patients randomized • ORR 38% v 38% (p=0.99) • PFS 9.4 v 8.0 months (p=0.0023) • OS 21.3 v 19.9 months (p=0.077 1 Giantonio et al JCO April, 2007 2 Saltz et al JCO April, 2008

  5. NSABP C-08 Stage ll + lll Strat: # Pos. N Randomize mFF6 mFF6 + B

  6. mFOLFOX 6 + B Ox 85 q2w 6 mo 5FU 2400 (46 hrs) 400 400 LV B:5 mg/kg IVq2 wks x 1yr

  7. C-08Accrual mFF6 mFF6+B Randomized Lost / Ineval Analysis 1356 18 1338 1354 16 1338

  8. C-08 Patient Characteristics (%)

  9. mFF6 mFF6+B P Hypertension 1.8 12 <0.0001 Pain 6.3 11.1 <0.0001 Proteinuria 0.8 2.7 <0.001 Wound Comp 0.3 1.7 <0.001 Grade 3+ Toxicities Increased with Bevacizumab (%)

  10. Grade 3+ Toxicities During the 9 mo Period Beginning 3 mo post Therapy Completion (%)

  11. C-08 DFS – Median FU 56 mos. Borderline significant detriment post landmark. Time-Treatment Interaction Remains Significant P < 0.0001.

  12. Possible Explanations for the Apparent Decrease in Survival After Relapse • Bev changes the biology of the disease to a more aggressive phenotype • do not see expected change in OS • Bev is less effective and/or less frequently used in patients previously exposed to bev • do not see expected change in OS • Bev alters our ability to detect an existing recurrence until later since CT relies on differences in vascularity & permeability • wouldnot expect a change in OS

  13. Conclusions • Time varying effect of Bev on recurrence is still evident with 56 mos F/U • Bev delays recurrence and may interfere with relapse detection during treatment, but does not prevent recurrence • No evidence in C-08 for a negative impact of Bev exposure on DFS, time to recurrence, OS, or CC specific survival • Our data further call into question our traditional paradigm of adjuvant colon drug development & support the need for new testing platforms in patients with minimal disease e.g. Stage 4 NED

  14. Special Thank You • NSABP investigators • Our patients • NSABP Ops office • Clinical trials nurses and coordinators • NSABP leadership and colleagues • Drs. Wolmark, O’Connell, Yothers & Sharif • Industry & NCI Colleagues • Dr. Meg Mooney

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