Future Perspectives in Anti-Angiogenic Therapy for Advanced Stage and Adjuvant CRC Lee M. Ellis, MD Departments of Cancer Biology and Surgical Oncology UT MD Anderson Cancer Center Houston, 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 TrialLine of Therapy 1 o Endpoint Met  RR Anti- VEGF Rx  PFS mos 5FU/LCV +/- SU5416First LineNo?? IFL +/- BevFirst LineYes10%4.4 FOLFOX +/- PTK/ZKFirst LineNo-4%0.2 XELOX/FOLFOX +/- BevFirst LineYes01.4 FOLFOX +/- BevSecond LineYes14%2.6 FOLFOX +/- PTK/ZKSecond LineNo?1.5 FOLFIRI +/- SunitinibFirst LineNo?? FOLFOX +/- Bev (C-08)AdjuvantNoNA DFS No  FOLFOX/XELOX +/- Bev (AVANT) Adjuvant?NADFS ? 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 Agent We 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 2009 Tol et al. NEJM 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 VEGF-DVEGF-C VEGF-B VEGF-A PlGF VEGFR-2 (Flk-1/KDR) VEGFR-3 (Flt-4) Vasculogenesis Angiogenesis Lymphangiogenesis BEVACIZUMAB VEGF-TRAP 18F1 1121B TG-403 Tyrosine Kinase Inhibitors Sunitinib Sorafenib Pazopanib Axitinib Motesanib Cedirinib Brivinib 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 –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 TKI − BAY AMG 386 Bevacizumab Motesanib Sorafenib Sunitinib 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

DFS FOLFOX BEV C 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) FOLFOXFOLFOX + BevDefinition of Grade 3 Toxicity Any pain2.14.8* Severe pain; pain or analgesics severely interfering with activities of daily living (ADL) Depression1.32.9* Severe mood alteration interfering with ADL Dizziness0.71.8* 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 by stage 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 Trial Focus on FOLFOX vs FOLFOX/Bev Arms Grade 3/4/5 ToxicitiesFOLFOXFOLFOX/ Bev  Bleeding Fistula/abscess GI Perforation VTEs ATEs SAE Discontinuation due to AE 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 mCRC Suggestion: –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!