Transcript Challenges in translating anti-angiogenic therapy from the

ASCO 2005
“Advancing the science of clinical oncology”
Anti-VEGF Therapy Goes
Mainstream
Lee M. Ellis, MD
UT MD Anderson Cancer Center
Houston, TX
Lee Ellis, MD,
UT MDACC
What Have We Learned Today
About Anti-VEGF Therapy?
• Bevacizumab (BV) improves effects of chemo in
– NSCLC (first line)
– mCRC (second line)
• Dosing of BV (10 vs 5 mg/kg) is probably not an issue
in mCRC
• BV, as monotherapy, remains unproven in mCRC
– Although OS was comparable to FOLFOX, we do not
have data on therapy after progression (PFS of BV <
FOLFOX)
• PTK/ZK does not improve the effects of FOLFOX in
mCRC front line
• MD,No drug is without toxicity
Lee Ellis,
UT MDACC
Points for Discussion
•
•
•
•
•
Lee Ellis, MD,
UT MDACC
Biology
Brief review of trials
Mechanisms of Action
PTK/ZK: Why different results than BV
Toxicities
PlGF
VEGF-B
VEGF-A
VEGF-C, D
VEGF Family
and Receptors
Cell membrane
VEGF-R1
(Flt-1)
Functions Migration
Invasion
Lee Ellis, MD,
UT MDACC
VEGF-R2
VEGF-R3
(KDR/Flk-1)
(Flt-4)
Proliferation LymphangioSurvival
genesis
Permeability
VEGF-R
Neuropilin
Survival
Migration
Anti-VEGF Therapy is Not Synonymous
With Anti-Angiogenic Therapy
Anti-VEGF
Anti-angiogenic
Endothelial and
tumors cells
Endothelial cells
Inhibits permeability
Yes
??
Inhibits further
blood vessel growth
(hard to prove)
Effects blood flow
and function
Yes
TBD
Yes
TBD
Target
(Nitric oxide?)
Lee Ellis, MD,
UT MDACC
Phase III Trials: Chemo +/- Anti-VEGF Therapy
Trial
Year
Malignancy
Setting
Primary
Endpoint Met?
Capecitabine +/BV
2002
mBreast
Ca
Refractory
NO
Paclitaxel +/- BV
2005
mBreast
Ca
Front Line
YES
5-FU/LV +/2002
mCRC
Front Line
NO
WeSU5416
owe it to our patients to publish the results…good or bad!
IFL +/- BV
2003
(AV2107)
mCRC
First Line
YES
FOLFOX +/- BV
2005
(ECOG 3200)
mCRC
Refractory
YES
FOLFOX +/PTK/ZK
2005
(CONFIRM-1)
mCRC
First Line
NO
2005
Carbo/Paclitaxel
Lee Ellis, MD,
(ECOG 4599)
UT MDACC +/- BV
NSCLC
First Line
YES
Progression Free Survival
8
*
PFS (months)
7
*
6
5
4
3
2
1
0
C+P
C+P+
BV
ECOG 4599
NSCLC
Lee Ellis, MD,
* PMDACC
< 0.05
UT
FOLFOX FOLFOX
+ BV
ECOG 3200
mCRC 2nd
FOLFOX FOLFOX
+ PTK/ZK
CONFIRM-1
mCRC 1st
(Central Rad Review)
Response Rates (CR + PR) (%)
Response Rates
50
45
40
35
30
25
20
15
10
5
0
*
*
C+P+
BV
FOLFOX FOLFOX
+ BV
ECOG 4599
NSCLC
ECOG 3200
mCRC 2nd
C+P
Lee Ellis, MD,
* PMDACC
< 0.05
UT
FOLFOX FOLFOX
+ PTK/ZK
CONFIRM-1
mCRC 1st
(Central Rad Review)
Phase III Trials: Chemo +/- BV
Trial
Disease Site
Front Line or
Refractory
D RR + BV
Capecitabine +/BV
mBreast Ca
Refractory
10%
Paclitaxel +/- BV
mBreast Ca
Front Line
Monday
IFL +/- BV
mCRC
First Line
10%
FOLFOX +/- BV
mCRC
ECOG 3200
Refractory
13%*
Carbo/Paclitaxel
+/- BV
NSCLC
ECOG 4599
First Line
15
Lee Ellis, MD,
UT MDACC
* Single agent BV RR in ECOG 3200 = 3%
Points for Discussion
•
•
•
•
•
Lee Ellis, MD,
UT MDACC
Biology
Brief review of trials
Mechanisms of Action
PTK/ZK: Why different results than BV
Toxicities
Proposed Mechanisms of
Action of Anti-VEGF Rx
• Anti-angiogenic
– Difficult to demonstrate in patients
• How does one explain the increase in RR
with chemo when, as a single agent,
responses are rare?
– “Normalization” of the vasculature with improved
delivery of chemo and O2 (transient)
• Jain Science 2005, Yang Cancer 2005
– Vascular “constriction” (Sunday 11:15)
– Direct effect on tumor cells
Lee Ellis, MD,
UT MDACC
PlGF
VEGF-B
VEGF-A
VEGF-C, D
VEGF Family
and Receptors
Cell membrane
Functions
Lee Ellis, MD,
UT MDACC
VEGF-R1
(Flt-1)
Migration
Invasion
VEGF-R2
VEGF-R3
(KDR/Flk-1)
(Flt-4)
Proliferation LymphangioSurvival
genesis
Permeability
VEGF-R
Neuropilin
Survival
Migration
RKO
GEO
SW620
SW480
KM12L4
KM12SMLM2
VEGFR1
HT-29
VEGFR1 and NRP-1 on CRC Cells
VEGFR1
-Actin
Fan et al. Oncogene, 2005
NRP-1
Lee Ellis, MD,
UT MDACC
Parikh et al. Am J Path 2004
VEGFR and NRP-1 on Lung Cancer Cells
Expression of VEGFR-1,
VEGFR-2, and NP-1, in
Lung Cancer Cells In Vitro
Anti-VEGF Antibody
Decreases Number of Lung
Cancer Cells In Vitro
VEGFR-1
VEGFR-2
Neuropilin-1
Lee Ellis, MD,
Copyright
©2004 by the National Academy
UTSciences
MDACC
of
Castro-Rivera, Emely et al. (2004)
PNAS 101, 11432-11437
Dynamic Effect of Anti-VEGF
Therapy
Acute
Chronic
• Decreased flow due to
• Inhibition of blood vessel growth
vasoconstriction
• Direct effect on tumor cells
• Paradoxical transient increase
in chemo delivery
Lee Ellis, MD,
UT MDACC
Points for Discussion
•
•
•
•
•
Lee Ellis, MD,
UT MDACC
Biology
Brief review of trials
Mechanisms of Action
PTK/ZK: Why different results than BV
Toxicities
Addition of BV to Chemo Improves Efficacy
Addition of PTK/ZK Does Not
• PK?
• Antibody vs TKI?
• VEGF Receptor target profile
– TKIs do not target Neuropilin on tumor cells
Lee Ellis, MD,
UT MDACC
With Daily Dosing, We Do Not Know if the Target
Was Inhibited for the Entire Dosing Period?
CRC Liver Metastases: DCE-MRI Ki (perfusion/permeability)
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Pre PTK/ZK Rx
Post PTK/ZK Rx
(Day 2)
• Imaging done 2-9 hrs post dosing
• Half-life PTK/ZK = 3-6 hrs
• How long is the target affected?
Lee Ellis, MD,
UT MDACC
Morgan, B. et al. J Clin Oncol; 21:3955-3964 2003
Partial Inhibition of VEGFR is Ineffective!!
Stress Induction of VEGF
• VEGF-R inhibition (stress) leads to a
compensatory increase in VEGF levels
– PTK/ZK leads to an increase in plasma VEGF in
Phase I study in a dose dependent manner
• Drevs et al. Ann Onc 2005
– Increases in plasma VEGF with VEGFR-2 MoAB
• Bocci….Hicklin, Kerbel. Cancer Res 2004
Lee Ellis, MD,
UT MDACC
JCO June 20, 2005
Recent studies with TKIs: Longer half-lives or BID dosing
Lee Ellis, MD,
UT MDACC
Just because a trial does not meet
its primary endpoint does not mean
that the drug is not active!
• Capecitabine +/ BV in refractory breast cancer
• PTK/ZK has activity, but in this population with
daily dosing, it did not significantly improve the
effects of FOLFOX
– LDH as a predictive marker could be explored in
prospective trials, but it is not ready for prime time.
• Await OS data, and CONFIRM-2 data
• Consider alternative dosing schedules after
validation of PK
Lee Ellis, MD,
UT MDACC
Points for Discussion
•
•
•
•
•
Lee Ellis, MD,
UT MDACC
Biology
Brief review of trials
Mechanisms of Action
PTK/ZK: Why different results than BV
Toxicities
Adverse Events in Anti-VEGF
+ Chemo Trials
• NSCLC (ECOG 4599)
C/P +/-BV
– HTN 6%
– Hemoptysis and death (5 pts)
• mCRC 2nd line (ECOG 3200)
FOLFOX +/-BV vs BV
– HTN 6-7%
– Hemorrhage 2-3.5%
• mCRC 1st line (CONFIRM-1)
FOLFOX +/- PTK/ZK
– HTN 21%
– Dizziness 7-8%
Does HTN contribute to hemorrhage or dizziness, or are they
independent effects?
Lee Ellis, MD,
UT MDACC
VEGF Plays Important Roles in Physiology!!!
Although Progress Has Been Made, Our
Work Is Not Done!!
• Improvements in survival are good, but not good
enough (~2 mos) (our patients expect more)
• Identify predictive markers for
– efficacy
– adverse events
• Determine the role of combination therapy with
other biologics
– Will the addition of EGFR inhibitors improve efficacy
even further?
• BV + cetuximab in mCRC
• BV + erlotinib in NSCLC
Lee Ellis, MD,
UT MDACC
Take Home Messages
• The addition of BV to chemo improves efficacy
– First and second line mCRC
– First line NSCLC and Breast Cancer
– Be cognizant of HTN, bowel perforations and
hemorrhage (infrequent, but important)
• The role of tyrosine kinase inhibitors targeting
VEGFR (PTK/ZK) remains undefined in mCRC
– Await overall survival data in CONFIRM-1, and
outcomes of CONFIRM-2 Trials
• Ongoing studies in other malignancies with TKIs
– RCC and GIST
Lee Ellis, MD,
UT MDACC
Lee Ellis, MD,
UT MDACC