Background and Specific Aims - PowerPoint PPT Presentation

a grothey e e hedrick r d mass s sarkar r k ramanathan h hurwitz r m goldberg d j sargent n.
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Background and Specific Aims

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  1. Response rate using conventional criteria is a poor surrogate for clinical benefit on progression-free (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC): A comparative analysis of N9741 and AVF2107 A. Grothey, E.E. Hedrick, R.D. Mass, S. Sarkar, R.K. Ramanathan, H. Hurwitz, R.M. Goldberg, D.J. Sargent

  2. Background and Specific Aims • Background: • Mass et al (ASCO 2005) reported longer PFS and OS for patients treated with BV + IFL compared to IFL (AVF2107) regardless of response • Specific aims: • We compared data from two positive phase III trials in metastatic colorectal cancer patients, AVF2107 and N9741, to determine if: A) This observation is a consequence of addition of a biologic agent to chemotherapy or is common to trials in which a significant survival benefit is observed for one arm B) RR, PFS or OS is the preferred endpoint for assessment of treatment benefits

  3. Study Designs of AVF2107 and N9741 AVF2107 N9741 Irinotecan + 5-FU/LV (IFL) + BV Oxaliplatin + 5-FU/LV (FOLFOX) * * N=923 N=795 Irinotecan + 5-FU/LV (IFL) Irinotecan + 5-FU/LV (IFL) R R 5-FU/LV + BV Irinotecan + oxaliplatin (IROX) Hurwitz et al: N Engl J Med 2004 Goldberg et al: J Clin Oncol 2004 * Arms included in analysis

  4. Methods • Retrospective analysis • Definition of "responders" or "nonresponders” in • AVF2107g: RECIST • N9741: WHO criteria • PFS and OS were estimated from Kaplan-Meier curves • Hazard ratios (HR) for progression and death in each subgroup were estimated by Cox regression • A patient with SD at 6 weeks but PD at 12 weeks was classified as PD in AVF2107 and as SD in N9741 • An adjusted analysis was performed in which the definition of SD in AVF2107 was revised according to the criteria used in N9741

  5. Criteria for Tumor Response in AVF2107 and N9741

  6. PFS - Responders AVF2107 N9741

  7. PFS - Non-Responders AVF2107 N9741

  8. OS - Responders/Non-Responders IFL vs IFL+ BV HR R 0.60 (P = .014) NR 0.76 (P = .019) 1.0 0.8 0.6 0.4 0.2 0 AVF2107 Percent Surviving IFL (R) n=143 IFL/BV (R) n=180 IFL (NR) n=268 IFL/BV (NR) n=222 0 10 20 30 40 Survival (months) IFL vs FOLFOX HR R 0.71 (P = .005) NR 0.74 (P = .003) 1.0 0.8 0.6 0.4 0.2 0 IFL (R) n=133 FOLFOX (R) n=193 IFL (NR) n=252 FOLFOX (NR) n=190 N9741 Percent Surviving 0 6 1 2 1 8 2 4 3 0 3 6 Survival (months)

  9. Treatment Benefit and Response

  10. Conclusions • In AVF2107 and N9741 patients without response according RECIST or WHO still have significant benefit from the superior regimen in terms of • PFS and • OS • The magnitude of benefit is similar for responders and non-responders • This finding is true regardless of whether the regimen includes chemotherapy alone or the antiangiogenic biologic BV • PFS and the percentage of patients experiencing tumor control may more accurately reflect patient benefit than response rate in phase III trials in metastatic CRC