FOLFOX4 with or without Bevacizumab in FOLFOX4 with or without Bevacizumab in Previously Treated Advanced Colorectal Previously Treated Advanced Colorectal

Cancer: Results from ECOG-E3200Cancer: Results from ECOG-E3200

Lee M Ellis, MDColorectal Cancer Update Think Tank Meeting

June 24, 2005

VEGF-A

VEGF-R1(Flt-1)

MigrationInvasion

VEGF-R3(Flt-4)

Lymphangio-genesis

VEGF-R2(KDR)

ProliferationSurvival

Permeability

Cell membrane

PlGF VEGF-B

VEGF-C, D

Functions

NeuropilinSurvival

Migration

X X XBevacizumabT1/2 ~20 days

VEGF Family and ReceptorsVEGF Family and Receptors

Underlying HypothesisUnderlying Hypothesis

The addition of a neutralizing VEGF antibody (bevacizumab) improves the effects of FOLFOX in the second-line setting.

The addition of a tyrosine kinase inhibitor to VEGF receptors improves the effects of FOLFOX in the front-line setting.

Background: Advances in Therapy for Background: Advances in Therapy for Metastatic CRCMetastatic CRC

ASCO 2003 Hurwitz et al.

• The addition of bevacizumab to IFL chemotherapy achieved a median OS of ~20 months

Goldberg et al.

• FOLFOX led to a 20 month median survival Will the addition of anti-VEGF therapy to FOLFOX improve

results, or do we achieve maximal benefit with FOLFOX alone?

• Bevacizumab — MoAB to VEGF-A

• PTK/ZK (vatalanib) — tyrosine kinase inhibitor targeting VEGF receptors

Sources: Hurwitz et al. Proc ASCO 2003; Goldberg et al. Presentation. ASCO 2003.

Primary end point: OS Secondary end points: ORR, PFS, safety

n = 290

n = 289

n = 243Bevacizumab*10 mg/kg q2w PD

FOLFOX4 + bevacizumab 10 mg/kg q2w PD

Eligibility

Previously treated MCRC

ECOG PS 0-1

* Third arm discontinued after predetermined interim analysis demonstrated the inferiority of bevacizumab compared with FOLFOX4.

Source: Giantonio BJ et al. Presentation. ASCO 2005.

ECOG 3200 Trial DesignECOG 3200 Trial Design

FOLFOX4 + placebo PD

R

n = 829

E3200: Overall SurvivalE3200: Overall SurvivalP

rob

abil

ity

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

ALIVEDEAD MEDIANTOTALA: FOLFOX4 + bevacizumab 289 246 43 12.9B: FOLFOX4 290 257 33 10.8C: Bevacizumab 243 216 27 10.2

HR = 0.76

A vs B: p = 0.0018

B vs C: p = 0.95

Source: Giantonio BJ et al. Presentation. ASCO 2005.

Pro

bab

ilit

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

CENSFAIL MEDIANTOTALA: FOLFOX4 + bevacizumab 273 228 45 7.2B: FOLFOX4 273 241 32 4.8C: Bevacizumab 229 215 14 2.7

HR = 0.64

A vs B: p < 0.0001

B vs C: p < 0.0001

Source: Giantonio BJ et al. Presentation. ASCO 2005.

E3200: Progression-Free SurvivalE3200: Progression-Free Survival

E3200: Response RatesE3200: Response Rates

FOLFOX4 + bevacizumab

n = 271FOLFOX4

n = 271Bevacizumab

n = 230

OR* 21.8% 9.2% 3.0%

CR 1.9% 0.7% 0%

PR 19.9% 8.5% 3.0%

SD 51.7% 45.0% 29.1%

Source: Giantonio BJ et al. Presentation. ASCO 2005.

* FOLFOX + B versus FOLFOX: p < 0.0001

E3200: Grade III/IV ToxicityE3200: Grade III/IV Toxicity

FOLFOX4 + bevacizumab

n = 287FOLFOX4

n = 284Bevacizumab

n = 234 pGIII GIV GIII GIV GIII GIV A vs B

Hypertension 5% 1% 2% <1% 7% 0% 0.018

Bleeding 3% <1% <1% 0% 2% 0% 0.011

Neuropathy 16% <1% 9% <1% <1% <1% 0.016

Vomiting 9% 1% 3% <1% 5% 0% 0.010

Bowel perforation

1% 0% 13%

Source: Giantonio BJ et al. Presentation. ASCO 2005.

ECOG 3200ECOG 3200

The addition of BV to FOLFOX in second-line therapy improves efficacy (PFS, RR, OS)

Efficacy of FOLFOX can be improved with targeted therapy (BV, Cetuximab?)

Be cognizant of HTN, bowel perforations and hemorrhage (infrequent, but important)

Single-agent BV in second-line therapy was inferior to FOLFOX (currently, there is no role for use of BV as a single agent in mCRC)