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

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 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

Study Designs of AVF2107 and N9741 N=795 Irinotecan + 5-FU/LV(IFL) oxaliplatin(IROX) Oxaliplatin + 5-FU/LV (FOLFOX) R Goldberg et al: J Clin Oncol 2004 N=923 Irinotecan + 5-FU/LV(IFL) 5-FU/LV + BV Irinotecan + 5-FU/LV (IFL) + BV R Hurwitz et al: N Engl J Med 2004 AVF2107N9741 ** * Arms included in analysis

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 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

Criteria for Tumor Response in AVF2107 and N9741

PFS - Responders AVF2107 N9741

PFS - Non-Responders AVF2107 N9741

OS - Responders/Non-Responders AVF2107 N9741 IFL vs IFL+ BVHR R0.60 (P =.014) NR0.76 (P =.019) Survival (months) Percent Surviving IFL (R) n=143 IFL/BV (R) n=180 IFL (NR) n=268 IFL/BV (NR) n= Percent Surviving Survival (months) IFL (R) n=133 FOLFOX (R) n=193 IFL (NR) n=252 FOLFOX (NR) n=190 IFL vs FOLFOXHR R0.71 (P =.005) NR0.74 (P =.003)

Treatment Benefit and Response Median (months) HRP-value IFL+BVIFL IFL+BV vs IFL AVF2107 Responders N=323 PFS OS Non- responders N=490 PFS OS FOLFOXIFL FOLFOX vs IFL N9741 Responders N=326 PFS OS Non- responders N=442 PFS OS

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 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