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....
![Page 1: 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,](https://reader035.fdocuments.us/reader035/viewer/2022062421/56649d1a5503460f949f02c7/html5/thumbnails/1.jpg)
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
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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
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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
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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
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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
![Page 6: 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,](https://reader035.fdocuments.us/reader035/viewer/2022062421/56649d1a5503460f949f02c7/html5/thumbnails/6.jpg)
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
)
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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
![Page 8: 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,](https://reader035.fdocuments.us/reader035/viewer/2022062421/56649d1a5503460f949f02c7/html5/thumbnails/8.jpg)
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
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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
![Page 10: 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,](https://reader035.fdocuments.us/reader035/viewer/2022062421/56649d1a5503460f949f02c7/html5/thumbnails/10.jpg)
· 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
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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
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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
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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
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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
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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
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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
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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
![Page 18: 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,](https://reader035.fdocuments.us/reader035/viewer/2022062421/56649d1a5503460f949f02c7/html5/thumbnails/18.jpg)
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
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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
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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
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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
![Page 22: 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,](https://reader035.fdocuments.us/reader035/viewer/2022062421/56649d1a5503460f949f02c7/html5/thumbnails/22.jpg)
Lieu et al. ASCO 2011 Abstract #3533