FOLFOX4 with or without Bevacizumab in Previously Treated Advanced Colorectal Cancer: Results from ECOG-E3200

1
FOLFOX4 with or without Bevacizumab in Previously
Treated Advanced Colorectal Cancer Results from
ECOG-E3200

• Lee M Ellis, MDColorectal Cancer Update Think
  Tank MeetingJune 24, 2005

2
VEGF Family and Receptors
VEGF-A
PlGF VEGF-B
VEGF-C, D
Bevacizumab T1/2 20 days
X
X
X
Cell membrane
VEGF-R1 (Flt-1) Migration Invasion
VEGF-R3 (Flt-4) Lymphangio- genesis
VEGF-R2 (KDR) Proliferation Survival Permeability
Neuropilin Survival Migration
Functions
3
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.

4
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.
5
ECOG 3200 Trial Design
FOLFOX4 placebo PD
n 290
Eligibility Previously treated MCRC ECOG PS 0-1
n 829
FOLFOX4 bevacizumab 10 mg/kg q2w PD
R
n 289
Bevacizumab10 mg/kg q2w PD
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.
6
E3200 Overall Survival
1.0
0.9
0.8
HR 0.76 A vs B p 0.0018 B vs C p 0.95
0.7
0.6
Probability
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)
ALIVE
DEAD
MEDIAN
TOTAL
A FOLFOX4 bevacizumab
289
246
43
12.9
B FOLFOX4
290
257
33
10.8
C Bevacizumab
243
216
27
10.2
Source Giantonio BJ et al. Presentation. ASCO
2005.
7
E3200 Progression-Free Survival
1.0
0.9
0.8
HR 0.64 A vs B p lt 0.0001 B vs C p lt 0.0001
0.7
0.6
Probability
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
PFS (months)
CENS
FAIL
MEDIAN
TOTAL
A FOLFOX4 bevacizumab
273
228
45
7.2
B FOLFOX4
273
241
32
4.8
C Bevacizumab
229
215
14
2.7
Source Giantonio BJ et al. Presentation. ASCO
2005.
8
E3200 Response Rates
FOLFOX4 bevacizumabn 271 FOLFOX4n 271 Bevacizumabn 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 lt 0.0001
Source Giantonio BJ et al. Presentation. ASCO
2005.
9
E3200 Grade III/IV Toxicity
FOLFOX4 bevacizumab n 287 FOLFOX4 bevacizumab n 287 FOLFOX4 n 284 FOLFOX4 n 284 Bevacizumab n 234 Bevacizumab n 234 p
GIII GIV GIII GIV GIII GIV A vs B
Hypertension 5 1 2 lt1 7 0 0.018
Bleeding 3 lt1 lt1 0 2 0 0.011
Neuropathy 16 lt1 9 lt1 lt1 lt1 0.016
Vomiting 9 1 3 lt1 5 0 0.010
Bowel perforation 1 1 0 0 13 13
Source Giantonio BJ et al. Presentation. ASCO
2005.
10
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)