Transcript Document 7177480

FOLFOX4 with or without Bevacizumab in
Previously Treated Advanced Colorectal
Cancer: Results from ECOG-E3200
Lee M Ellis, MD
Colorectal Cancer Update Think Tank Meeting
June 24, 2005
VEGF Family and Receptors
PlGF
VEGF-B
Bevacizumab
T1/2 ~20 days
VEGF-A
VEGF-C, D
X
X X
Cell membrane
Functions
VEGF-R1
(Flt-1)
Migration
Invasion
VEGF-R2
(KDR)
Proliferation
Survival
Permeability
VEGF-R3
(Flt-4)
Lymphangiogenesis
Neuropilin
Survival
Migration
Underlying 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
Metastatic 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.
ECOG 3200 Trial Design
n = 290
Eligibility
FOLFOX4 +
placebo
PD
n = 829
Previously treated
MCRC
n = 289
R
FOLFOX4 +
bevacizumab
10 mg/kg q2w
PD
Bevacizumab*
10 mg/kg q2w
PD
ECOG PS 0-1
n = 243


Primary end point: OS
Secondary end points: ORR, PFS, safety
* Third arm discontinued after predetermined interim analysis demonstrated the
inferiority of bevacizumab compared with FOLFOX4.
Source: Giantonio BJ et al. Presentation. ASCO 2005.
E3200: Overall Survival
1.0
Probability
0.9
0.8
HR = 0.76
0.7
A vs B: p = 0.0018
0.6
B vs C: p = 0.95
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
OS (months)
A: FOLFOX4 + bevacizumab
B: FOLFOX4
C: Bevacizumab
TOTAL
289
290
243
Source: Giantonio BJ et al. Presentation. ASCO 2005.
DEAD ALIVE
246
43
257
33
216
27
MEDIAN
12.9
10.8
10.2
E3200: Progression-Free Survival
1.0
0.9
Probability
0.8
0.7
HR = 0.64
0.6
A vs B: p < 0.0001
0.5
B vs C: p < 0.0001
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
FAIL
228
241
215
CENS
45
32
14
18
20
PFS (months)
A: FOLFOX4 + bevacizumab
B: FOLFOX4
C: Bevacizumab
TOTAL
273
273
229
Source: Giantonio BJ et al. Presentation. ASCO 2005.
MEDIAN
7.2
4.8
2.7
E3200: Response Rates
FOLFOX4 +
bevacizumab
n = 271
FOLFOX4
n = 271
Bevacizumab
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%
* FOLFOX + B versus FOLFOX: p < 0.0001
Source: Giantonio BJ et al. Presentation. ASCO 2005.
E3200: Grade III/IV Toxicity
FOLFOX4 +
bevacizumab
n = 287
GIII
GIV
FOLFOX4
n = 284
GIII
GIV
Bevacizumab
n = 234
GIII
GIV
p
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%
Source: Giantonio BJ et al. Presentation. ASCO 2005.
13%
ECOG 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)