response rate using conventional criteria is a poor surrogate for clinical benefit on...
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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
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
A. Grothey, E.E. Hedrick, R.D. Mass, S. Sarkar, R.K. Ramanathan, H. Hurwitz,
R.M. Goldberg, D.J. Sargent
Background and Specific AimsBackground 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 armB) 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 armB) RR, PFS or OS is the preferred endpoint for assessment of treatment benefits
Study Designs of AVF2107 and N9741Study Designs of AVF2107 and N9741
N=795
Irinotecan + Irinotecan + 5-FU/LV5-FU/LV
(IFL)(IFL)
Irinotecan + Irinotecan + oxaliplatinoxaliplatin
(IROX)(IROX)
Oxaliplatin + Oxaliplatin + 5-FU/LV 5-FU/LV(FOLFOX)(FOLFOX)
R
Goldberg et al: J Clin Oncol 2004
N=923
Irinotecan + Irinotecan + 5-FU/LV5-FU/LV
(IFL)(IFL)
5-FU/LV + BV5-FU/LV + BV
Irinotecan + Irinotecan + 5-FU/LV5-FU/LV
(IFL) + BV(IFL) + BV
R
Hurwitz et al: N Engl J Med 2004
AVF2107 N9741
* *
* Arms included in analysis
MethodsMethods• 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
Criteria for Tumor Response in AVF2107 and N9741
Best response to therapy
AVF2107 (RECIST)
N9741 (WHO)
Comp lete re s ponse
(CR)
Dis appearan ce wi thout new
les io ns; c onfirme d at >4 wks
Dis appearan ce wi thout new le s ions ;
confirme d at >4 wks
Partia l res pons e
(PR)
>30% s hrinkag e witho ut n e w
les io ns; c onfirme d at ≥4 wks
>50% s hrinkag e witho ut n e w
les io ns; c onfirme d at >4 wks
Sta ble d ise ase
(SD)
Criteria for res pons e (CR, PR) or
PD n ot me t
Criteria for res pons e (CR, PR) or PD
not me t
Progre s s ive di s ease
(PD)
>20% gro wth or a ny new le si on >25% gro wth, >50% re gro wth from
PR, or any new le s ion
PFS - RespondersPFS - Responders
AVF2107
N9741
PFS - Non-RespondersPFS - Non-Responders
AVF2107
N9741
OS - Responders/Non-RespondersOS - Responders/Non-Responders
AVF2107
N9741
IFL vs IFL+ BV HR
R 0.60 (P = .014)
NR 0.76 (P = .019)
Survival (months)
1.0
0.8
0.6
0.4
0.2
0
Pe
rce
nt
Su
rviv
ing
0 10 20 30 40
IFL (R) n=143IFL/BV (R) n=180IFL (NR) n=268IFL/BV (NR) n=222
0 6 12 18 24 30 36
1.0
0.8
0.6
0.4
0.2
0
Pe
rce
nt
Su
rviv
ing
Survival (months)
IFL (R) n=133FOLFOX (R) n=193IFL (NR) n=252FOLFOX (NR) n=190
IFL vs FOLFOX HR
R 0.71 (P = .005)
NR 0.74 (P = .003)
Treatment Benefit and ResponseTreatment Benefit and ResponseMedian (months)
HR P-valueIFL+BV IFL
IFL+BV vs IFL
AVF2107
RespondersN=323
PFS 14.0 10.6 0.53 .0002
OS 27.7 21.8 0.60 .0136
Non-respondersN=490
PFS 7.0 4.4 0.63 .0001
OS 14.7 12.6 0.76 .0188
FOLFOX IFL
FOLFOX vs IFL
N9741
RespondersN=326
PFS 12.5 10.0 0.89 .317
OS 26.8 23.8 0.71 .0047
Non-respondersN=442
PFS 6.3 4.4 0.75 .0029
OS 15.1 12.4 0.74 .0030
ConclusionsConclusions
• 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