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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)