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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 Trial Line of Therapy 1o Endpoint Met RR AntiVEGF 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. We do not seemintoFront be making muchIII Overview of PFS Line Phase Trials: Chemoprogress! + ONE Targeted Agent 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 CAIRO-2 PACCE + EGFR MoAB Hecht et al. JCO 2009 Tol et al. NEJM 2009 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 VEGF Targeted Agents in the Clinic or In Clinical Trials VEGF-TRAP TG-403 PlGF VEGF-A VEGF-B BEVACIZUMAB VEGF-C VEGF-D 1121B 18F1 VEGFR-1 (Flt-1) NRP-1/ NRP-2 VEGFR-2 (Flk-1/KDR) VEGFR-3 (Flt-4) NRP-2 Tyrosine Kinase Inhibitors Sunitinib Sorafenib Pazopanib Axitinib Motesanib Cedirinib Brivinib Many, many others Vasculogenesis Angiogenesis Lymphangiogenesis Ellis, Hicklin Nat Rev Ca. 2008 Current First Line Trials: Chemo +/- VEGF Targeted Therapy Although these strategies are necessary for companies to Phase III achieve their goals of+/-approval/registration, these trials • FOLFOX/CapOX Cediranib (AZD2171) (HORIZON II) are not •likely to lead to vs major advances in therapy for mCRC FOLFOX + Bev FOLFOX + Cediranib (HORIZON III) • Chemo + Bev vs Chemo + Cetuximab (80405) • Although success is often times measured by “P<0.05”, obtaining a PPhase valueIIdoes not always translate into making progress in the field • FOLFOX +/- Aflibercept (VEGF Trap) - If you have Phase a minimally active but enroll enough pts on • Innumerable II single armagent, studies 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: Ellis, Hicklin CCR 2008 – 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 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 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) ©2009 by American Association for Cancer Research O'Connor et al. Clin Cancer Res 2009 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 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. Onnis, Rapisarda, Melillo: J Cell Mol Med 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 Rapisarda A et al. Melillo. Mol Cancer Ther 2009 Other Vascular Targets • DLL4/Notch • Angiopoietins/Tie-2 Inhibition of Notch Leads to NonFunctional Vessels Hicklin Nat Biotech 2007 Yan, Plowman CCR 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 AMG 386 and MoAB Ang-2 VEGF TKI Combo Bevacizumab or Motesanib MCT 2010 or Sorafenib or 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 Sunitinib Hong, MDACC 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 C08 - 1 yr of Bevacizumab 100 FOLFOX + Bev 80 60 BEV 40 The current question: Would a longer duration of bevacizumab lead to more cures? 20 0 0.0 0.5 1.0 1.5 2.0 DFS 2.5 3.0 Why Would Longer Bev Exposure Lead to Tumor Cell Eradication After Already Receiving 12 Months of Bev? FOLFOX + Bev Bev After 12 months of therapy, I think we can declare these tumor cells (and endothelial cells) resistant! Unique Toxicities Observed in C-08 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 • These toxicities are important when benefit of prolonged therapy may be marginal AVANT Adjuvant Colon Cancer Study 24 Weeks 48 Weeks FOLFOX4 q2wk n=3451 Stage III or high-risk stage II colon cancer 1:1:1 FOLFOX4 q2wk Stratified by stage and region Bev 5 mg/kg, q2wk Bev 7.5 mg/kg q3wk XELOX q3wk Bevacizumab 7.5 mg/kg 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 Toxicities Observed In AVANT Trial Focus on FOLFOX vs FOLFOX/Bev Arms Grade 3/4/5 Toxicities FOLFOX + Bleeding 0.6 FOLFOX/ Bev 1.2 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 0.6 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!