C. Lieu, H. Tran, Z. Jiang, M. Mao, M. Overman, C. Eng, J. Morris, L. Ellis, J. Heymach, and S....
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Transcript of C. Lieu, H. Tran, Z. Jiang, M. Mao, M. Overman, C. Eng, J. Morris, L. Ellis, J. Heymach, and S....
C. Lieu, H. Tran, Z. Jiang, M. Mao, M. Overman, C. Eng, J. Morris, L. Ellis, J. Heymach, and S. Kopetz
Departments of Gastrointestinal Medical Oncology, Surgical Oncology, and Head and Neck/Thoracic Medical Oncology
The University of Texas MD Anderson Cancer Center
The Association of Alternate VEGF Ligands With Resistance to Anti-VEGF Therapy in Metastatic
Colorectal Cancer
Cell membrane
VEGF-A
VEGF-R1(Flt-1)
MigrationInvasionSurvival
VEGF-R3(Flt-4)
Lymphangio-genesis
VEGF-R2(KDR/Flk-1)Proliferation
SurvivalPermeability
PlGF VEGF-C, VEGF-D
Fun
ctio
ns
VEGF Biology
Y
Bevacizumab
Adapted from Bergers et al. Nat Rev Cancer. 2008;8:592-603.
VEGF-A VEGF-A
X
VEGF-
C
VEGF-D PlGF
Baseline Treatment with bevacizumab
AngiogenesisRestored
VEGF-A
X
Hypothesis: Alternate VEGF ligands are associated with the resistance to anti-VEGF therapy in patients with metastatic colorectal cancer
Study Design
Prospective Clinical Trial· Phase II trial of FOLFIRI +
bevacizumab in patients with metastatic colorectal cancer
· Forty-three patients enrolled· Intensive cytokine measurements
Retrospective Validation Cohort· The Texas Genetic Consortium
database (n = 710)· Heterogeneous treatment
histories· Single cytokine measurement
PD
PD
PD
Study Design
Prospective Clinical Trial· Phase II trial of FOLFIRI +
bevacizumab in patients with metastatic colorectal cancer
· Forty-three patients enrolled· Intensive cytokine measurements
Retrospective Validation Cohort· The Texas Genetic Consortium
database (n = 710)· Heterogeneous treatment
histories· Single cytokine measurement
PD
PD
PD
Prospective Cohort: PlGF Increased Prior to Progression
Kopetz et al. J Clin Oncol 28:453-459
0
20
30
40
ULN
p<0.001*
p<0.001*
p<0.01*
PlG
F (
pg
/mL
)
Bas
elin
e
Post
Bev
Post
FOLFIR
I
Firs
t Res
tagin
g
Sec
ond Res
tagin
g
Prior t
o Pro
gress
ion
Progre
ssio
n
0
500
1000
1500
2000
2500V
EG
F-C
(p
g/m
L)
ULN
*
*
* p<0.05 by Mann Whitney U test
Prospective Cohort: VEGF-C Increased Prior to Progression
Bas
elin
e
Post
Bev
Post
FOLFIR
I
Firs
t Res
tagin
g
Sec
ond Res
tagin
g
Prior t
o Pro
gress
ion
Progre
ssio
n
0
100
200
300
400
VE
GF
-D (
pg
/mL
)
ULN
Prospective Cohort: VEGF-D Minimally Increased at Progression
*
* p = 0.04
Study Design
Prospective Clinical Trial· Phase II trial of FOLFIRI +
bevacizumab in patients with metastatic colorectal cancer
· Forty-three patients enrolled· Intensive cytokine measurements
Retrospective Validation Cohort· The Texas Genetic Consortium
database (n = 710)· Heterogeneous treatment
histories· Single cytokine measurement
PD
PD
PD
· Separated patients into three groups:- Patients presenting prior to frontline therapy- Patients treated with chemotherapy without bevacizumab - Patients treated with chemotherapy and bevacizumab
· To minimize heterogeneity, samples were matched for:- Metastatic disease sites- Chemotherapy cycles- Time from last chemo to plasma collection
· 533 patients were included in the analysis
Retrospective Cohort
PlGF Elevated After Bevacizumab
No Treatment Chemo Only Chemo+Bev0
20
40
60
80
Group
Co
nce
ntr
atio
n,
pg
/mL
ULN
p < 0.0001
p < 0.0001
No Chemo Chemo Only Chemo+Bev0
500
1000
1500
Group
Co
nce
ntr
atio
n,
pg
/mL
ULN
VEGF-C Elevation Unable to be Confirmed
p < 0.0001
p = 0.64
No Chemo Chemo Only Chemo+Bev0
100
200
300
400
500
Group
Co
nce
ntr
atio
n,
pg
/mL
ULN
p < 0.0001
Minimal VEGF-D Elevation Confirmed
Summary
PlGF
VEGF-C
VEGF-D
Prospective Retrospective Conclusions
Basel
ine
After B
evac
izum
ab
After F
OLFIRI+
B
Prior t
o Pro
gress
ion
Progre
ssio
n
0
20
30
40
ULN
p<0.001*
p<0.001*
p<0.01*
PlG
F (
pg
/mL
)
No Treatment Chemo Only Chemo+Bev0
20
40
60
80
Group
Co
nce
ntr
atio
n,
pg
/mL
ULN
Bas
elin
e
Post
Bev
Post
FOLFIR
I
Firs
t Res
tagin
g
Sec
ond Res
tagin
g
Prior t
o Pro
gress
ion
PD
0
500
1000
1500
2000
2500
VE
GF
-C (
pg
/mL
)
ULN
No Chemo Chemo Only Chemo+Bev0
500
1000
1500
Group
Co
nce
ntr
atio
n,
pg
/mL
ULN
Bas
elin
e
Post
Bev
Post
FOLFIR
I
Firs
t Res
tagin
g
Sec
ond Res
tagin
g
Prior t
o Pro
gress
ion
PD
0
100
200
300
400
VE
GF
-D (
pg
/mL
)
ULN
No Chemo Chemo Only Chemo+Bev0
100
200
300
400
500
Group
Co
nce
ntr
atio
n,
pg
/mL
ULN
1) PlGF is elevated after FOLFIRI+B
2) A similar elevation was seen after chemotherapy + bev but not after chemotherapy alone
1) VEGF-C is elevated after FOLFIRI+B
2) No difference was seen in the second cohort between the two “post-therapy” groups
3) Limitations include heterogeneity and high inter-patient variability
1) Modest elevations in VEGF-D were seen after FOLFIRI+B
2) Elevations were seen in the “post-therapy” groups but not impacted by bevacizumab therapy
How long do PlGF and VEGF-D stay elevated after bevacizumab?
Time from last bevacizumab dose (mo)
VE
GF
-D (
pg
/mL
)0 1 2 3 4 5 6
0
100
200
300
400
500
600
700VEGF-D T1/2 = 1.5 months
(95% CI: 1.2 - 2.0)
Time from last bevacizumab dose (mo)
PlG
F (
pg
/mL
)
0 1 2 3 4 5 60
20
40
60
80
100
120PlGF T1/2 = 1.6 months
(95% CI: 1.4 - 1.9)
No temporal change in PlGF and VEGF-D in patients treated with chemotherapy only
Limitations of Cytokine Analysis
· How well do circulating levels of VEGF ligands reflect the tumor microenvironment?- Or host response?
· Difficult to place magnitude of changes into context- What degree of elevation would be necessary to evoke a biologic
response
· Association vs. Causation- Are alternate VEGF ligands driving resistance to bevacizumab
· Return to preclinical models· Clinical trial
VEGF-APlGF VEGF-C, VEGF-D
Large molecule VEGF inhibitors
Y
Bevacizumab
YVGX-100
YRamucirumab(IMC-1121B) II
CT-322
Y
IMC-18F1
Aflibercept (VEGF Trap)Y
TB403
Phase III VEGF-Trap (Aflibercept) after Bevacizumab
2nd line CRC (after treatment with
oxaliplatin-based therapy)
N=1200 patients
Primary endpoint: OS
R
FOLFIRI + Placebo
FOLFIRI + Aflibercept 4mg/kg
“VELOUR” StudyPrimary endpoint OS met
Conclusions
· VEGF family ligands other than VEGF itself are associated with bevacizumab-containing chemotherapy resistance in mCRC
· Plasma levels of PlGF are increased prior to radiographic progression of disease
· Changes in VEGF-C were not able to be validated- Limited by technical concerns in the validation cohort
· VEGF-D is minimally increased at the time of progression- Unclear biologic significance
· Further study of agents targeting multiple VEGF-ligands are ongoing
Acknowledgments
· GI Medical Oncology- Scott Kopetz- Karen Mao- Camilla Ziang- James Abbruzzese
· Thoracic/H&N Medical Oncology- Hai Tran- John Heymach- Stef Fiorentino
· GU Medical Oncology- Gary Gallick
· Funding- ASCO Cancer Foundation
Young Investigators Award- Circadian Technologies- T32 Training Grant
Plasma PlGF in mCRC
· In a prospective cohort, plasma PlGF levels are elevated prior to progression and at the time of progression on a bevacizumab regimen
· In a validation cohort, compared with untreated patients and patients who have received chemotherapy only, patients who have received chemotherapy and bevacizumab had elevated levels of PlGF
· These changes appear specific to patients receiving bevacizumab
0
20
30
40
ULN
p<0.001*
p<0.001*
p<0.01*
PlG
F (
pg
/mL
)
Lieu et al. ASCO 2011 Abstract #3533
Lieu et al. ASCO 2011 Abstract #3533