Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol,

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


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


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



Improved OSImproved OS

• Hurwitz, et al. NEJM, 2004Hurwitz, et al. NEJM, 2004 FDA approval: 2004FDA approval: 2004


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


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


BEVACIZUMABBEVACIZUMAB: 10 mg/kg every 14 days: 10 mg/kg every 14 days

FOLFOX4FOLFOX4::


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



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



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



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%



E3200: Prior Treatment HistoryE3200: Prior Treatment History


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



E3200: Treatment StatisticsE3200: Treatment Statistics


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



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



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



E3200: Response RatesE3200: Response Rates



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%


*FOLFOX+B vs FOLFOX: P < 0.0001*FOLFOX+B vs FOLFOX: P < 0.0001


E3200: E3200: Grade 3/4 ToxicityGrade 3/4 Toxicity



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


E3200: E3200: Grade 3/4 Hemorrhagic ToxicityGrade 3/4 Hemorrhagic Toxicity



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



E3200: E3200: Grade 3/4 Arterial & Venous ThrombosesGrade 3/4 Arterial & Venous Thromboses



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


* Cardiac ischemia and cerebrovascular ischemia combined* Cardiac ischemia and cerebrovascular ischemia combined


E3200: E3200: Bowel PerforationBowel Perforation



287287 284284 234234

Bowel Bowel PerforationPerforation 3 (1%)3 (1%) 00 3 (1.3%)3 (1.3%)



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%



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.



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


E3200: AcknowledgementsE3200: Acknowledgements

The ParticipantsThe ParticipantsThe ParticipantsThe Participants

Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol,

Documents

Transcript of Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol,