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
Func
tions
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 (p
g/m
L)
Baseli
ne
Post Bev
Post FOLFIR
I
First R
estag
ing
Second R
estag
ing
Prior t
o Progressio
n
Progres
sion
0
500
1000
1500
2000
2500VE
GF-
C (p
g/m
L)
ULN
**
* p<0.05 by Mann Whitney U test
Prospective Cohort: VEGF-C Increased Prior to Progression
Baseli
ne
Post Bev
Post FOLFIR
I
First R
estag
ing
Second R
estag
ing
Prior t
o Progres
sion
Progres
sion
0
100
200
300
400VE
GF-
D (p
g/m
L)
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
Con
cent
ratio
n, p
g/m
L
ULN
p < 0.0001
p < 0.0001
No Chemo Chemo Only Chemo+Bev0
500
1000
1500
Group
Con
cent
ratio
n, p
g/m
L
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
Con
cent
ratio
n, p
g/m
L
ULN
p < 0.0001
Minimal VEGF-D Elevation Confirmed
Summary
PlGF
VEGF-C
VEGF-D
Prospective Retrospective Conclusions
Baseli
ne
After B
evac
izumab
After F
OLFIRI+B
Prior t
o Progres
sion
Progres
sion
0
20
30
40
ULN
p<0.001*
p<0.001*
p<0.01*
PlG
F (p
g/m
L)
No Treatment Chemo Only Chemo+Bev0
20
40
60
80
Group
Con
cent
ratio
n, p
g/m
L
ULN
Baseli
ne
Post Bev
Post FOLFIR
I
First R
estag
ing
Second Res
taging
Prior to
Progres
sion
PD 0
500
1000
1500
2000
2500
VEG
F-C
(pg/
mL)
ULN
No Chemo Chemo Only Chemo+Bev0
500
1000
1500
Group
Con
cent
ratio
n, p
g/m
L
ULN
Baseli
ne
Post Bev
Post FOLFIRI
First R
estag
ing
Second R
estag
ing
Prior to
Progressio
n PD
0
100
200
300
400
VEG
F-D
(pg/
mL)
ULN
No Chemo Chemo Only Chemo+Bev0
100
200
300
400
500
Group
Con
cent
ratio
n, p
g/m
L
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)
VEG
F-D
(pg/
mL)
0 1 2 3 4 5 60
100
200
300
400
500
600
700 VEGF-D T1/2 = 1.5 months(95% CI: 1.2 - 2.0)
Time from last bevacizumab dose (mo)
PlG
F (p
g/m
L)
0 1 2 3 4 5 60
20
40
60
80
100
120 PlGF 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” Study Primary 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 (p
g/m
L)
Lieu et al. ASCO 2011 Abstract #3533
Lieu et al. ASCO 2011 Abstract #3533