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eastern cooperativeeastern cooperative oncology grouponcology group
High-dose BevacizumabHigh-dose Bevacizumab in Combination with FOLFOX4 in Combination with FOLFOX4
Improves Survival in Patients with Previously Improves Survival in Patients with PreviouslyTreated Advanced Colorectal Cancer: Treated Advanced Colorectal Cancer:
Results from the Eastern Cooperative Oncology Results from the Eastern Cooperative Oncology Group (ECOG) Study E3200.Group (ECOG) Study E3200.
High-dose BevacizumabHigh-dose Bevacizumab in Combination with FOLFOX4 in Combination with FOLFOX4
Improves Survival in Patients with Previously Improves Survival in Patients with PreviouslyTreated Advanced Colorectal Cancer: Treated Advanced Colorectal Cancer:
Results from the Eastern Cooperative Oncology Results from the Eastern Cooperative Oncology Group (ECOG) Study E3200.Group (ECOG) Study E3200.
Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol, Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol,
Peter J. O’Dwyer, Edith P. Mitchell, Steven R. Alberts, Peter J. O’Dwyer, Edith P. Mitchell, Steven R. Alberts,
Michael A. Schwartz, and Al B. Benson III. Michael A. Schwartz, and Al B. Benson III.
eastern cooperative oncology groupeastern cooperative oncology group
BackgroundBackground
Bevacizumab (rhuMAb-VEGF, Avastin)Bevacizumab (rhuMAb-VEGF, Avastin)
Binds VEGFA and its isoformsBinds VEGFA and its isoforms
T1/2 = 17-21 daysT1/2 = 17-21 days
VEGFVEGF
potent mediator of angiogenesispotent mediator of angiogenesis
expressed in 40-60% colorectal tumors expressed in 40-60% colorectal tumors
• associated with recurrence and prognosisassociated with recurrence and prognosis
Bevacizumab (rhuMAb-VEGF, Avastin)Bevacizumab (rhuMAb-VEGF, Avastin)
Binds VEGFA and its isoformsBinds VEGFA and its isoforms
T1/2 = 17-21 daysT1/2 = 17-21 days
VEGFVEGF
potent mediator of angiogenesispotent mediator of angiogenesis
expressed in 40-60% colorectal tumors expressed in 40-60% colorectal tumors
• associated with recurrence and prognosisassociated with recurrence and prognosis
eastern cooperative oncology groupeastern cooperative oncology group
BackgroundBackground
First-line Metastatic Colorectal Cancer:First-line Metastatic Colorectal Cancer: Improved TTP/PFS, RRImproved TTP/PFS, RR
• Kabbinavar et al. JCO, 2003Kabbinavar et al. JCO, 2003
• Kabbinavar et al. JCO, 2005Kabbinavar et al. JCO, 2005
Improved OSImproved OS
• Hurwitz, et al. NEJM, 2004Hurwitz, et al. NEJM, 2004 FDA approval: 2004FDA approval: 2004
First-line Metastatic Colorectal Cancer:First-line Metastatic Colorectal Cancer: Improved TTP/PFS, RRImproved TTP/PFS, RR
• Kabbinavar et al. JCO, 2003Kabbinavar et al. JCO, 2003
• Kabbinavar et al. JCO, 2005Kabbinavar et al. JCO, 2005
Improved OSImproved OS
• Hurwitz, et al. NEJM, 2004Hurwitz, et al. NEJM, 2004 FDA approval: 2004FDA approval: 2004
eastern cooperative oncology groupeastern cooperative oncology group
E3200: Study DesignE3200: Study Design
FOLFOX4 +Bevacizumab
(10 mg/kg, q 2 weeks)
FOLFOX4
Bevacizumab (10mg/kg, q 2 wks)
Previously treated metastatic CRC
PD
PD
PD
Stratification factors:Stratification factors:
ECOG PS: 0 vs 1, 2ECOG PS: 0 vs 1, 2
Prior XRTPrior XRT
Giantonio BJ, et al. ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: TreatmentE3200: Treatment
5-FU bolus400 mg/m2
5-FU bolus400 mg/m2
5-FU infusion600 mg/m2
LV 200 mg/m2
Oxaliplatin 85 mg/m2
5-FU infusion600 mg/m2
LV 200 mg/m2
2 h 22 h 2 h 22 h
Cycle length = 14 daysCycle length = 14 days
Giantonio BJ, et al. ASCO 2005
BEVACIZUMABBEVACIZUMAB: 10 mg/kg every 14 days: 10 mg/kg every 14 days
FOLFOX4FOLFOX4::
eastern cooperative oncology groupeastern cooperative oncology group
E3200: Eligibility CriteriaE3200: Eligibility Criteria
Advanced or metastatic colorectal adenocarcinomaAdvanced or metastatic colorectal adenocarcinoma
Measurable disease by RECIST criteriaMeasurable disease by RECIST criteria
Prior treatment with a fluoropyrimadine & irinotecanPrior treatment with a fluoropyrimadine & irinotecan
No prior oxaliplatin or bevacizumabNo prior oxaliplatin or bevacizumab
PS 0-2 & adequate end organ functionPS 0-2 & adequate end organ function
BP <150/100 mmhg on a stable anti-hypertensive regimenBP <150/100 mmhg on a stable anti-hypertensive regimen
24 hr urine protein <500 mg if dipstick 24 hr urine protein <500 mg if dipstick 1+1+
No history of thrombotic or hemorrhagic eventsNo history of thrombotic or hemorrhagic events
No therapeutic anticoagulation or anti-platelet agentsNo therapeutic anticoagulation or anti-platelet agents
aspirin <325/day allowedaspirin <325/day allowed
Advanced or metastatic colorectal adenocarcinomaAdvanced or metastatic colorectal adenocarcinoma
Measurable disease by RECIST criteriaMeasurable disease by RECIST criteria
Prior treatment with a fluoropyrimadine & irinotecanPrior treatment with a fluoropyrimadine & irinotecan
No prior oxaliplatin or bevacizumabNo prior oxaliplatin or bevacizumab
PS 0-2 & adequate end organ functionPS 0-2 & adequate end organ function
BP <150/100 mmhg on a stable anti-hypertensive regimenBP <150/100 mmhg on a stable anti-hypertensive regimen
24 hr urine protein <500 mg if dipstick 24 hr urine protein <500 mg if dipstick 1+1+
No history of thrombotic or hemorrhagic eventsNo history of thrombotic or hemorrhagic events
No therapeutic anticoagulation or anti-platelet agentsNo therapeutic anticoagulation or anti-platelet agents
aspirin <325/day allowedaspirin <325/day allowed
Giantonio BJ, et al. ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: Study ObjectivesE3200: Study Objectives
Primary Objective:Primary Objective:
overall survivaloverall survival
88% power to detect a 40% improvement in 88% power to detect a 40% improvement in overall survival (7 months → 9.8 months) when overall survival (7 months → 9.8 months) when bevacizumab is added to FOLFOX4 bevacizumab is added to FOLFOX4
Secondary Objectives:Secondary Objectives:
response rate response rate
progression free survivalprogression free survival
toxicitytoxicity
Primary Objective:Primary Objective:
overall survivaloverall survival
88% power to detect a 40% improvement in 88% power to detect a 40% improvement in overall survival (7 months → 9.8 months) when overall survival (7 months → 9.8 months) when bevacizumab is added to FOLFOX4 bevacizumab is added to FOLFOX4
Secondary Objectives:Secondary Objectives:
response rate response rate
progression free survivalprogression free survival
toxicitytoxicity
Giantonio BJ, et al. ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: Accrual HistoryE3200: Accrual History
Accrual PeriodAccrual Period
Arms A & B:Arms A & B:
• November 2001 - April 2003November 2001 - April 2003
Arm C (bevacizumab alone)Arm C (bevacizumab alone)
• November 2001- February 2003November 2001- February 2003
• Closed to accrual by ECOG DMCClosed to accrual by ECOG DMC
Accrual PeriodAccrual Period
Arms A & B:Arms A & B:
• November 2001 - April 2003November 2001 - April 2003
Arm C (bevacizumab alone)Arm C (bevacizumab alone)
• November 2001- February 2003November 2001- February 2003
• Closed to accrual by ECOG DMCClosed to accrual by ECOG DMC
Giantonio BJ, et al. ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: DemographicsE3200: Demographics
FOLFOX4 + FOLFOX4 + bevacizumabbevacizumab
FOLFOX4FOLFOX4 bevacizumabbevacizumab
289289 290290 243243
MaleMale 60.1%60.1% 60.7%60.7% 59.1%59.1%
Median age (range)Median age (range) 62.0 62.0 (21-85)(21-85)
61.3 61.3 (25-84)(25-84)
59.6 59.6 (23-82)(23-82)
ECOG PSECOG PS
0 0 48.6%48.6% 51.0%51.0% 49.4%49.4%
11 46.5%46.5% 43.5%43.5% 44.6%44.6%
22 4.9%4.9% 5.5%5.5% 6.0%6.0%
Prior XRTPrior XRT 26%26% 25.5%25.5% 26.8%26.8%
Giantonio BJ, et al. ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: Prior Treatment HistoryE3200: Prior Treatment History
FOLFOX4 + FOLFOX4 + bevacizumabbevacizumab
FOLFOX4FOLFOX4 bevacizumabbevacizumab
CTx for advanced CTx for advanced disease onlydisease only
229229 221221 188188
Adjuvant FU Adjuvant FU CPT-11 for adv CPT-11 for adv diseasedisease
33 88 77
Adjuvant FU Adjuvant FU & CPT-11& CPT-11
22 44 00
UnknownUnknown 5656 5656 4848
Giantonio BJ, et al. ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: Treatment StatisticsE3200: Treatment Statistics
FOLFOX4 + FOLFOX4 + bevacizumabbevacizumab
FOLFOX4FOLFOX4 BevacizumabBevacizumab
282282 279279 228228
MeanMean 11.211.2 7.77.7 7.17.1
MedianMedian 1010 77 44
RangeRange 1-421-42 1-401-40 1-481-48
Giantonio BJ, et al. ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: Overall SurvivalE3200: Overall SurvivalP
r o
b a
b i
l i
t y
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS (months)
0 3 6 9 12 15 18 21 24 27 30 33 36
ALIVEALIVEDEADDEAD MEDIANMEDIANTOTALTOTAL
A:FOLFOX4 + bevacizumabA:FOLFOX4 + bevacizumab 289289 246246 4343 12.912.9B:FOLFOX4B:FOLFOX4 290290 257257 3333 10.810.8C:bevacizumabC:bevacizumab 243243 216216 2727 10.210.2
HR = 0.76
A vs B: p = 0.0018
B vs C: p = 0.95
Giantonio BJ, et al. ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: Progression-Free SurvivalE3200: Progression-Free SurvivalP
r o
b a
b i
l i
t y
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
PFS (months)
0 2 4 6 8 10 12 14 16 18 20
CENSCENSFAILFAIL MEDIANMEDIANTOTALTOTAL
A:FOLFOX4 + bevacizumabA:FOLFOX4 + bevacizumab 273273 228228 4545 7.27.2B:FOLFOX4B:FOLFOX4 273273 241241 3232 4.84.8C:bevacizumabC:bevacizumab 229229 215215 1414 2.72.7
HR = 0.64HR = 0.64
A vs B: p < 0.0001A vs B: p < 0.0001
B vs C: p < 0.0001B vs C: p < 0.0001
Giantonio BJ, et al. ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: Response RatesE3200: Response Rates
FOLFOX4 + FOLFOX4 + bevacizumabbevacizumab
FOLFOX4FOLFOX4 BevacizumabBevacizumab
271271 271271 230230
OR*OR* 21.8%21.8% 9.2%9.2% 3.0%3.0%
CRCR 1.9%1.9% 0.7%0.7% 00
PRPR 19.9%19.9% 8.5%8.5% 3.0%3.0%
SDSD 51.7%51.7% 45.0%45.0% 29.1%29.1%
Giantonio BJ, et al. ASCO 2005
*FOLFOX+B vs FOLFOX: P < 0.0001*FOLFOX+B vs FOLFOX: P < 0.0001
eastern cooperative oncology groupeastern cooperative oncology group
E3200: E3200: Grade 3/4 ToxicityGrade 3/4 Toxicity
FOLFOX4 + FOLFOX4 + bevacizumabbevacizumab
FOLFOX4FOLFOX4 BevacizumabBevacizumab
287287 284284 234234 PP
G3G3 G4G4 G3G3 G4G4 G3G3 G4G4 A vs BA vs B
HypertensionHypertension 5%5% 1%1% 2%2% <1%<1% 7%7% 00 0.0180.018
BleedingBleeding 3%3% <1%<1% <1%<1% 00 2%2% 00 0.0110.011
NeuropathyNeuropathy 16%16% <1%<1% 9%9% <1%<1% <1%<1% <1%<1% 0.0160.016
VomitingVomiting 9%9% 1%1% 3%3% <1%<1% 5%5% 00 0.0100.010
ProteinuriaProteinuria 1%1% 00 00 00 <1%<1% 00 0.250.25
Giantonio BJ, ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: E3200: Grade 3/4 Hemorrhagic ToxicityGrade 3/4 Hemorrhagic Toxicity
FOLFOX4 + FOLFOX4 + bevacizumabbevacizumab
FOLFOX4FOLFOX4 BevacizumabBevacizumab
287287 284284 234234
G3G3 G4G4 G3G3 G4G4 G3G3 G4G4
HematemesisHematemesis 22 00 00 00 22 00
Melena/GI bleedMelena/GI bleed 55 11 11 00 11 00
OtherOther 22 00 00 00 22 00
Worst GradeWorst Grade 9 9 (3.1%)(3.1%)
1 1 (<1%)(<1%)
1 1 (<1%)(<1%) 00
5 5 (2.1%)(2.1%) 00
Giantonio BJ, ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: E3200: Grade 3/4 Arterial & Venous ThrombosesGrade 3/4 Arterial & Venous Thromboses
FOLFOX4 + FOLFOX4 + bevacizumabbevacizumab
FOLFOX4FOLFOX4 BevacizumabBevacizumab
287287 284284 234234 pp
G3G3 G4G4 G3G3 G4G4 G3G3 G4G4 A vs BA vs B
Venous Venous ThrombosisThrombosis 99 11 33 44 00 11 0.460.46
Cardiac Cardiac IschemiaIschemia 11 22 00 11 11 00
0.62*0.62*Cerebrovascular Cerebrovascular IschemiaIschemia 11 00 00 00 00 00
Giantonio BJ, ASCO 2005
* Cardiac ischemia and cerebrovascular ischemia combined* Cardiac ischemia and cerebrovascular ischemia combined
eastern cooperative oncology groupeastern cooperative oncology group
E3200: E3200: Bowel PerforationBowel Perforation
FOLFOX4 + FOLFOX4 + bevacizumabbevacizumab
FOLFOX4FOLFOX4 BevacizumabBevacizumab
287287 284284 234234
Bowel Bowel PerforationPerforation 3 (1%)3 (1%) 00 3 (1.3%)3 (1.3%)
Giantonio BJ, ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: 60 Day All-Cause MortalityE3200: 60 Day All-Cause Mortality
FOLFOX4 + Bevacizumab:FOLFOX4 + Bevacizumab: 6%6%
FOLFOX4FOLFOX4 4%4%
BevacizumabBevacizumab 6%6%
FOLFOX4 + Bevacizumab:FOLFOX4 + Bevacizumab: 6%6%
FOLFOX4FOLFOX4 4%4%
BevacizumabBevacizumab 6%6%
Giantonio BJ, et al. ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: ConclusionsE3200: Conclusions
Bevacizumab (10 mg/kg) + FOLFOX4 improves OS, Bevacizumab (10 mg/kg) + FOLFOX4 improves OS, PFS, and response for previously treated patients with PFS, and response for previously treated patients with advanced colorectal cancer. advanced colorectal cancer.
Bevacizumab + FOLFOX4 is well tolerated.Bevacizumab + FOLFOX4 is well tolerated.
Hypertension, bleeding, and vomiting are associated Hypertension, bleeding, and vomiting are associated with FOLFOX4 + bevacizumab. with FOLFOX4 + bevacizumab.
Bowel perforation occurred infrequently but only in Bowel perforation occurred infrequently but only in bevacizumab treated patients.bevacizumab treated patients.
An increase in sensory neuropathy may be related to An increase in sensory neuropathy may be related to time on treatment.time on treatment.
Bevacizumab is inactive when used as a single agent in Bevacizumab is inactive when used as a single agent in this previously treated population.this previously treated population.
Bevacizumab (10 mg/kg) + FOLFOX4 improves OS, Bevacizumab (10 mg/kg) + FOLFOX4 improves OS, PFS, and response for previously treated patients with PFS, and response for previously treated patients with advanced colorectal cancer. advanced colorectal cancer.
Bevacizumab + FOLFOX4 is well tolerated.Bevacizumab + FOLFOX4 is well tolerated.
Hypertension, bleeding, and vomiting are associated Hypertension, bleeding, and vomiting are associated with FOLFOX4 + bevacizumab. with FOLFOX4 + bevacizumab.
Bowel perforation occurred infrequently but only in Bowel perforation occurred infrequently but only in bevacizumab treated patients.bevacizumab treated patients.
An increase in sensory neuropathy may be related to An increase in sensory neuropathy may be related to time on treatment.time on treatment.
Bevacizumab is inactive when used as a single agent in Bevacizumab is inactive when used as a single agent in this previously treated population.this previously treated population.
Giantonio BJ, et al. ASCO 2005
eastern cooperative oncology groupeastern cooperative oncology group
E3200: AcknowledgementsE3200: Acknowledgements
ECOGECOG
Jean MacdonaldJean Macdonald
Cindy JohnsonCindy Johnson
Robert ComisRobert Comis
NCINCI
Rick KaplanRick Kaplan
Helen ChenHelen Chen
Meg MooneyMeg Mooney
ECOGECOG
Jean MacdonaldJean Macdonald
Cindy JohnsonCindy Johnson
Robert ComisRobert Comis
NCINCI
Rick KaplanRick Kaplan
Helen ChenHelen Chen
Meg MooneyMeg Mooney
The Investigator TeamsThe Investigator Teams
PhysiciansPhysicians
NursesNurses
Research staffResearch staff
Study Chair LiaisonsStudy Chair Liaisons
Cecile Miller, RNCecile Miller, RN
Maryann Redlinger, RNMaryann Redlinger, RN
Kristi Kafel, RNKristi Kafel, RN
The Investigator TeamsThe Investigator Teams
PhysiciansPhysicians
NursesNurses
Research staffResearch staff
Study Chair LiaisonsStudy Chair Liaisons
Cecile Miller, RNCecile Miller, RN
Maryann Redlinger, RNMaryann Redlinger, RN
Kristi Kafel, RNKristi Kafel, RN