future perspectives in anti-angiogenic therapy for advanced stage and adjuvant crc lee m. ellis, md...
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![Page 1: Future Perspectives in Anti-Angiogenic Therapy for Advanced Stage and Adjuvant CRC Lee M. Ellis, MD Departments of Cancer Biology and Surgical Oncology](https://reader035.vdocuments.us/reader035/viewer/2022070415/5697bff41a28abf838cbd2ae/html5/thumbnails/1.jpg)
Future Perspectives in Anti-Angiogenic Therapy for Advanced Stage and
Adjuvant CRC
Lee M. Ellis, MDDepartments of Cancer Biology and Surgical Oncology
UT MD Anderson Cancer CenterHouston, Texas, USA
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Overview
• Where are we now
• Where do we need to go
• A few comments on VEGF-targeted therapy in the adjuvant setting
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Anti-angiogenic Therapy:A Cure for Cancer or Hype????
1998
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The Scorecard: Phase III Trials Chemo +/- VEGF Targeted Rx in CRC
Trial Line of Therapy
1o Endpoint Met
RR Anti-VEGF Rx
PFS
mos
5FU/LCV +/- SU5416 First Line No ? ?
IFL +/- Bev First Line Yes 10% 4.4
FOLFOX +/- PTK/ZK First Line No -4% 0.2
XELOX/FOLFOX +/- Bev First Line Yes 0 1.4
FOLFOX +/- Bev Second Line Yes 14% 2.6
FOLFOX +/- PTK/ZK Second Line No ? 1.5
FOLFIRI +/- Sunitinib First Line No ? ?
FOLFOX +/- Bev (C-08) Adjuvant No NA DFS No
FOLFOX/XELOX +/- Bev (AVANT)
Adjuvant ? NA DFS ?
January 2010
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We Have All Seen These Patients, But We Do Not Have Any Predictive Biomarkers to Inform Us Who Will
Benefit from the Addition of Bev and Who Will Not
Chemo + Bevacizumab
Chun et al. JAMA 2009
PREDICTIVE biomarkers are essential to optimize current therapies, and future therapies, but so far they have remained elusive in the
field of angiogenesis.
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Overview of PFS in Front Line Phase III Trials: Chemo + ONE Targeted AgentWe do not seem to be making much
progress!Have we hit the ceiling?
More Must Be Better!
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More is Not Better!Addition of EGFR MoAB to an Oxali/5FU/Bev
Regimen Decreased PFS
PACCE CAIRO-2
Hecht et al. JCO 2009Tol et al. NEJM 2009
+ EGFR MoAB
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What Have We Learned So Far About VEGF Targeted Therapy in Patients with mCRC?
• All VEGF targeted agents are not created equal– As of today, no TKI has been shown to improve upon a
chemotherapy backbone
• There are real toxicities• Single agent therapy is not an option
– E3200
• We have not identified predictive biomarkers• More is not better
– 2 trials with FU/Ox/Bev + EGFR MoAB show negative interaction
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We Need to Do Better!But..how do we do this?
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Overview
• Where are we now
• Where do we need to go
• A few comments on VEGF-targeted therapy in the adjuvant setting
Defining our goal: To SIGNIFICANTLY improve overall survival
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VEGFR-1(Flt-1)
NRP-1/NRP-2 NRP-2
VEGF-D
VEGF-CVEGF-B VEGF-A
PlGF
VEGFR-2(Flk-1/KDR)
VEGFR-3(Flt-4)
VasculogenesisAngiogenesis
Lymphangiogenesis
BEVACIZUMAB
VEGF-TRAP
18F1 1121B
TG-403
Tyrosine Kinase InhibitorsSunitinibSorafenibPazopanib
AxitinibMotesanibCedirinibBrivinib
Many, many others
VEGF Targeted Agents in the Clinic or In Clinical Trials
Ellis, Hicklin Nat Rev Ca. 2008
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Current First Line Trials: Chemo +/- VEGF Targeted Therapy
Phase III• FOLFOX/CapOX +/- Cediranib (AZD2171) (HORIZON II)• FOLFOX + Bev vs FOLFOX + Cediranib (HORIZON III)• Chemo + Bev vs Chemo + Cetuximab (80405)Phase II• FOLFOX +/- Aflibercept (VEGF Trap)• Innumerable Phase II single arm studies
Although these strategies are necessary for companies to achieve their goals of approval/registration, these trials are not likely to lead to major advances in therapy for mCRC
• Although success is often times measured by “P<0.05”, obtaining a P value does not always translate into making progress in the field
- If you have a minimally active agent, but enroll enough pts on the study, you will obtain your desired P value, but you may
NOT advance the field
JCO Dec 2009
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We Must Be More Creative!!
“Me too” drugs and trials are unlikely to significantly advance the field
It is time to move new approaches forward!!
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There Are Only a Few Ways to Improve Outcomes With VEGF Targeted Therapies
• Better drugs?– Unlikely to advance the field with different VEGF-targeted agents
• No clear hints in Phase II/III trials in CRC or other solid malignancies• Although kinase inhibition profiles may be slightly different, I doubt that they
are different enough to distance themselves from the pack• There may be an advantage with a “me too” drug if toxicity was significantly
less than other drugs in the class, but so far, this is not the case
• Better patient selection?– No predictive biomarkers, despite extensive search
• Better drug combinations? Different drugs/drug targets?
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Thoughts on Improving VEGF Targeted Based Therapies
Disclaimers– For the sake of discussion, I will focus on front line therapy, but my comments may apply to subsequent lines of therapy. – All drugs do not have to be used at once to achieve an improvement in OS.
Since this is an anti-angiogenic lecture, I will focus on endothelial cell targets, but please recognize that there are other targeted approaches that
focus on tumor cell biology that should be pursued.
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Targeting Resistance Pathways Before It Occurs
Caveats: – Resistance in mCRC is not for a single drug, but rather for a regimen
containing Bev. – Preclinical modeling is not likely to reflect the complexities of the cytokine
response to multi-agent therapy– We probably have not paid enough attention to induction of hypoxia in tumors
Ellis, Hicklin CCR 2008
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Until We Fully Understand the Mechanisms of Action of VEGF Targeted Therapies, We Will Not Be Able to Extract Maximal Benefit From Therapy
• Anti-angiogenic• “Normalization” of the vasculature • Direct effect on tumor cells• Vascular “constriction” • Offset effects of stress• Reverse immuno-suppression due to VEGF• Disruption of the cancer stem cell niche
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O'Connor et al. Clin Cancer Res 2009©2009 by American Association for Cancer Research
Acute Effects of Single Agent Bevacizumab Therapy in mCRC:The Rapid Decrease (4 hrs) in Enhancing Fraction and Plasma
Volume Suggests Vasoconstriction and Hypoxia (Gordon Jayson, FRCP, PhD)
This rapid induction of hypoxia leads to induction/stabilization of hypoxia inducible factor (HIF)
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VEGF Targeted Therapy Hypoxia and Gene Induction
• HIF Regulated Angiogenic Genes– Angiopoeitin-1– Angiopoeitin-2– VEGFR-1– VEGFR-2– MMP-2,9– PDGF-B– Tie-2– VEGF-A
Melillo and colleagues, Cell Cycle 2009
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Targeting HIF The “Response” to VEGF Targeted Therapies
• Intentional HIF inhibitors
• Topotecan• Anthracycline• HSP90 inhibitors• Proteosome inhibitors
Onnis, Rapisarda, Melillo: J Cell Mol Med 2009
Just because some agents historically have not shown activity in CRC, does not mean they will not have value when combined with the right drugs.
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Rapisarda A et al. Melillo. Mol Cancer Ther 2009
Daily Administration of Topotecan In Combination With Bevacizumab, Inhibits Tumor Growth And HIF Induction
Regression!
Topotecan blocks the hypoxia response element
- luciferase promoter construct
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Other Vascular Targets
• DLL4/Notch
• Angiopoietins/Tie-2
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Inhibition of Notch Leads to Non-Functional Vessels
Yan, Plowman CCR 2007
Hicklin Nat Biotech 2007
Ridgway et al. Nature 2006
Notch inhibitors in clinical trials– MK0752
– PF-03084014
– REGN421 (Dll4 Ab)
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Dual Inhibition of VEGF and Ang/Tie-2 Pathways
Hong, MDACC
Ang-1/2/Tie-2 Inhibitors− AMG-386 peptibody− Arry-614 TKI− MGCD 265 TKI− CovX 60- Peptide-Ab− CEP-11981 TKI− BAY 73-4506
AMG 386
Bevacizumab
Motesanib
Sorafenib
Sunitinib
or
or
or
and
VEGF TKI
MoAB Ang-2
Combo
MCT 2010
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We Must Develop Rationale Combination Therapy Targeting the Vasculature:
Chemo + VEGF-targeted Agent + Rationale Drug
• Signaling inhibitors to– mTOR– PI3K– Src– MAPK/Mek– HIF
• Cell surface/GFR inhibitors to– C-Met– FGF-R– Ephs– Tie-2 (Ang-1/2)– Notch (DLL4)– EGFL7– SDF-1– “Vertical” VEGF/R inhibition
• Beware toxicity
– Other VEGFRs • VEGFR-3, NRP-1, NRP-2
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We Cannot Ignore the Complex Interactions of Chemotherapy and VEGF Biology
• Acute administration of oxaliplatin in vitro induced VEGF, VEGF-C, PlGF, VEGFR-1, NRP-1 (Fan et al MCT, 2008)
• We need better preclinical models– Including combination chemotherapy– At the minimum, orthotopic models that replicate the
complexities of the tumor microenvironment
> We need to develop transgenic models of metastasis
• Clinical trials should evaluate biomarkers for sensitivity/resistance to a regimen, and not just single agent therapy
– Kopetz et al. JCO 2009
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Moving Therapies Forward
• There are some interesting combination studies in later lines of therapy, and in Phase I studies, but we need to be brave enough to move these approaches forward– Examples
• Sirolimus + Bev, FU, Irinotecan: Ghiringhelli, WJG 2009• Dasatinib + FOLFOX, Cetuximab: Kopetz, 2010 GI Cancers
Symposium
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Overview
• Where are we now
• Where do we need to go
• A few comments on VEGF-targeted therapy in the adjuvant setting
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These Comments (and Those That I Made At ASCO) Are Predicated On The Idea That
AVANT Is Negative Or The Same As CO-8
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Adjuvant Therapy in CRC and Cure
• The goal of adjuvant therapy in CRC is CURE (OS)– DFS is not really meaningful without an improvement in
overall survival in asymptomatic patients– DFS is used a surrogate for OS for chemotherapy
based regimens - BUT C-08 taught us that early DFS cannot be used
as a surrogate for OS for regimens where Bev is administered for a finite period of time
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0.0 0.5 1.0 1.5 2.0 2.5 3.0
0
20
40
60
80
100
DFS
FOLFOX
BEV
C08 - 1 yr of Bevacizumab
The current question: Would a longer duration of bevacizumab lead to more cures?
+ Bev
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Why Would Longer Bev Exposure Lead to Tumor Cell Eradication After Already Receiving 12 Months of Bev?
After 12 months of therapy, I think we can declare these tumor cells (and endothelial cells) resistant!
FOLFOX+ Bev
Bev
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Unique Toxicities Observed in C-08
• These toxicities are important when benefit of prolonged therapy may be marginal
Grade 3/4 Toxicities Seen With Bev After Chemo (Allegra et al. JCO 2009)
FOLFOX FOLFOX + Bev Definition of Grade 3 Toxicity
Any pain 2.1 4.8* Severe pain; pain or analgesics severely interfering with activities of daily living (ADL)
Depression 1.3 2.9* Severe mood alteration interfering with ADL
Dizziness 0.7 1.8*Interfering with ADL
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AVANT Adjuvant Colon Cancer Study
n=3451 Stage III or
high-risk stage II colon cancer
FOLFOX4 q2wk
Bev 7.5 mg/kg q3wk
24 Weeks 48 Weeks
Stratified bystage and
region
1:1:1
Bev 5 mg/kg, q2wk
XELOX q3wk
• 3451 patients were enrolled between November 2004 and June 2007
• Primary analysis: compare DFS between control and each treatment arm in stage III patients
• Projected final analysis time: Q3, 2010
FOLFOX4 q2wk
Bevacizumab 7.5 mg/kg q3wk
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Toxicities Observed In AVANT TrialFocus on FOLFOX vs FOLFOX/Bev Arms Grade 3/4/5 Toxicities FOLFOX FOLFOX/
Bev
Bleeding 0.6 1.2 0.6
Fistula/abscess 0.3 1.4 1.1
GI Perforation 0.1 0.7 0.6
VTEs 5.5 8.3 2.8
ATEs 1.0 1.6 0.6
SAE 19.7 25.9 6.2
Discontinuation due to AE 28.4 40.2 11.8
Hoff et al. ESMO 2009
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Although Preclinical Modeling Can Support Nearly Any Hypothesis
(including a benefit of prolonged administration of VEGF targeted therapy),
We Cannot Ignore Clinical Data
• We now know that the benefit of adjuvant Bev lasts only as long a Bev is administered – Or maybe even a little longer
• We either need to administer Bev: – Forever (not feasible, nor would patients comply)– Or not at all
• I would not expect any other VEGF targeted agent to be effective either, as toxicity and compliance are likely to be more of an issue
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Conclusions/Recommendations
• We must be more aggressive for patients with mCRCSuggestion:– Phase II trials: Chemo + VEGF Targeted Rx + ? (rationale selection)
Future Suggestion:– Consider “dropping” a chemotherapeutic agent if efficacy is good
• 5FU + VEGF Inhibitor + New Agent?• Defer irinotecan and oxaliplatin for second line therapy limiting the
duration of long term toxicity of front line therapy
• If AVANT is the same as C-08, then we should not consider long term VEGF blockade as a therapeutic option in the adjuvant setting– Likewise…lets be more creative in adjuvant therapy
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Thank You for Your Attention!
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