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

Overview

• Where are we now

• Where do we need to go

• A few comments on VEGF-targeted therapy in the adjuvant setting

Anti-angiogenic Therapy:A Cure for Cancer or Hype????

1998

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

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.

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!

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

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

We Need to Do Better!But..how do we do this?

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

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

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

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!!

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?

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.

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

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

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)

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

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.

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

Other Vascular Targets

• DLL4/Notch

• Angiopoietins/Tie-2

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)

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

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

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

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

Overview

• Where are we now

• Where do we need to go

• A few comments on VEGF-targeted therapy in the adjuvant setting

These Comments (and Those That I Made At ASCO) Are Predicated On The Idea That

AVANT Is Negative Or The Same As CO-8

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

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

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

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

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

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

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

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

Thank You for Your Attention!