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Targeting Tumor Angiogenesis: What Have We Learned So Far?

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  1. Targeting Tumor Angiogenesis: What Have We Learned So Far? Lee M. Ellis, MD Departments of Cancer Biology and Surgical Oncology UT MD Anderson Cancer Center Houston, Texas, USA Tuesday June 8 Education Session Tumor Biology

  2. Overview: What Have We Learned So Far? • Current State in the Clinic • Where have we done well and where have we failed • Potential Mechanisms of Action of Anti-VEGF Therapy • Biomarkers

  3. VEGF-TRAP TG-403 PlGF VEGF-B VEGF-C BEVACIZUMAB* VEGF-A VEGF-D 1121B 18F1 Tyrosine Kinase Inhibitors Sunitinib* Sorafenib* Pazopanib* Axitinib Motesanib Cedirinib Brivinib Many, many others VEGF Targeted Agents in the Clinic or In Clinical Trials NRP-1/ NRP-2 NRP-2 VEGFR-1 (Flt-1) VEGFR-3 (Flt-4) VEGFR-2 (Flk-1/KDR) Vasculogenesis Angiogenesis Lymphangiogenesis * FDA approved agents Ellis, Hicklin Nat Rev Ca. 2008

  4. 06/10 The Scorecard: Phase III Trials Chemo +/- Anti-VEGF Rx in Solid Malignancies

  5. 06/10 The Scorecard: Phase III Trials Chemo +/- Anti-VEGF Rx in Solid Malignancies

  6. 06/10 The Scorecard: Phase III Trials Chemo +/- Anti-VEGF Rx in Solid Malignancies BV=Bevacizumab, RR= response rate, PFS=Progression free survival

  7. The Scorecard: Phase III Trials “Standard of Care” vs Single Agent Anti-VEGF Rx in Solid Malignancies ** head to head comparison

  8. What Have We Learned So Far? • The efficacy of VEGF-targeted therapy is • Tumor specific • Context specific • Agent specific • This is not a simple field to understand • You cannot make broad generalizations across drugs, tumor types, or stage of tumors

  9. What Have We Learned So Far? • Despite similar primary targets (VEGFRs), all drugs in this class are NOT created equal • If we “hit” too many targets, is this a bad thing? • CAIRO-2 and PACCE Trials • Activation of compensatory pathways?

  10. Kinase Inhibition Profiles of VEGFR Targeted Agents Bevacizumab VEGF-Trap Karaman et al. Nat Biotech 2008

  11. Phase III Trial Summary: TKIs vs MoAB (Bev)Excluding head to head comparisons and continuation studies Highly Angiogenic Tumors

  12. MoABs vs TKIs Differences in Specificity Half-life/exposure (metabolism) Tissue Penetration • Despite many hypothetical discussions about the advantages of TKIs regarding their ability to target all 3 VEGFR TKRs, and PDGFR, etc., in the tumor types that are NOT highly angiogenic, we cannot ignore the clinical data. • My personal view, backed by some preclinical data, is that targeting PDGFR does not add to efficacy, and in some ways, may decrease efficacy

  13. ASCO 2009/2010: For Solid Tumors “Requiring” Multiagent Therapy, Single Agent Bevacizumab May Demonstrate Some Activity as “Maintenance Therapy” • But the question remains, how much benefit will patients receive • CRC • Ovarian Cancer

  14. Validation, Validation, Validation! Single agent maintenance therapy is not FDA-approved. We must study this concept in more clinical trials before changing practice.

  15. Overview: What Have We Learned So Far? • Current State in the Clinic • Potential Mechanisms of Action of Anti-VEGF Therapy • Biomarkers

  16. Summary of PFS and RRs with VEGF-Targeted Therapies

  17. With Such Varied Results With VEGF-Targeted Therapies, There Must be Multiple Mechanisms of Action of This Class of Drugs

  18. Potential Mechanisms of Action of VEGF Targeted Therapies(When it works) • 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

  19. Anti-VEGF Therapy: My Theory on Different Mechanisms of Action in Different Tumor Systems Renal Cell Carcinoma Colon Carcinoma

  20. Overview: What Have We Learned So Far? • Current State in the Clinic • Potential Mechanisms of Action of Anti-VEGF Therapy • Biomarkers

  21. A Few DefinitionsA “marker” is not a “marker” is not a “marker” • Prognostic marker • associated with clinical outcome, independent of specific treatment • Predictive marker • identifies groups receiving different degrees of benefit from a therapy • specific for a given treatment (i.e., Ras for EGFR MoABs in CRC, HER2 expression for trastuzumab in breast cancer) • Surrogate / activity marker • modulated by treatment • may be on target tissue (tumor) or surrogate tissue (i.e., lymphocytes, skin) • might or might not correlate with clinical activity

  22. We Do Not Have Any Predictive Biomarkers!!!! Comment: We should never subject patients to biopsies for any biomarker study until we have shown proof of principle in preclinical models.

  23. Negative (mostly unpublished) VEGF Tissue, plasma, anywhere TSP VEGFRs Ras, Raf, P53 Possible/requires further study SNPs (VEGF, VEGFR-1) Imaging of vascular flow and function in metastasis Yao et al. NETs, Saturday A Snapshot of Predictive Marker Studies for VEGF Targeted Therapies • A predictive marker must be strong enough to allow a “go/no go” for a particular drug for a particular patient • Would you deny a patient therapy based on a “negative” biomarker? • - Mut Kras for EGFR MoABs in mCRC

  24. ASCO 2010 Circulating vascular endothelial growth factor (VEGF) as a biomarker for bevacizumab-based therapy in metastatic colorectal, non-small cell lung, and renal cell cancers: Analysis of phase III studies. C. Bernaards, et al. “Conclusions: Measurement of baseline circulating VEGF levels may be useful as a prognostic biomarker, but not as a predictive biomarker for bevacizumab-based treatment benefit in metastatic colorectal, lung, and renal cell cancers. Despite innumerable studies of circulating VEGF and it’s lack of validity as a predictive biomarker, invesigators will continue to study this until we get a false positive.

  25. SNPs: VEGF Polymorphisms and Predictive Value in ECOG-2100 (Pac +/- Bev Metastatic Breast Cancer) Kaplan-Meier curve for overall survival (OS) in experimental arm by genotype; (A) vascular endothelial growth factor (VEGF)-2578 C/A; (B) VEGF-1154 G/A • Caveats: • Predictive for OS, but not PFS • Small numbers • Did not include Pac Rx alone group Schneider, et al. J Clin Oncol; 2008

  26. VEGFR-1 SNPs in Pancreatic Cancer SNPs are exploratory and require unbiased validation in larger studies! We should do our best to associate SNPS to biology. Bev Group Lambrechts et al. ESMO 2009

  27. A Few DefinitionsA “marker” is not a “marker” is not a “marker” From a practical perspective, a surrogate marker is only of use to an oncologist if it is strong enough to force an oncologist to alter Rx. • Prognostic marker • Predictive marker • Surrogate / activity marker • modulated by treatment • may be on target tissue (tumor) or surrogate tissue (i.e., lymphocytes, skin) • might or might not correlate with clinical activity

  28. After a Decade of Studies and MILLIONS of $$ Spent in Search of Biomarkers for Anti-angiogenic Therapy ~$40-50 George Sledge

  29. Grade 3/4 Hypertension Is Associated With Improved Median OS in E2100 Median OS: 25.3 mo vs. 38.7 mo p=0.002 Schneider et al; J Clin Oncol, 2008

  30. Hypertension is a Biomarker of Efficacy in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib Brian Rini et al (2010)

  31. Overall Survival and HTN After One Cycle of Therapy: ECOG 4599 High blood pressure (HBP) by the end of cycle 1 was defined as > 150/100 at any previous time or at least a 20-mmHg increase in diastolic blood pressure from baseline. Dahlberg et al. J Clin Oncol; 28: 2010

  32. ASCO 2010 Analysis of early hypertension (HTN) and clinical outcome with bevacizumab (BV). H. Hurwitz, et al. “…The primary HTN endpoint was an SBP increase 20 mmHg or DBP increase 10 mmHg within the first 60 days of Tx. ….Conclusions: HTN during Tx does not predict clinical benefit from BV based on PFS or OS.….”

  33. What We Know (and don’t know) in 2010About VEGF Targeted Therapy What We (Think) We Know Single agent anti-VEGF therapy is effective in the most angiogenic tumors RCC, HCC, GBM (NETs?) And….it may have utility as “maintenance therapy” (Ovarian, colorectal cancers-ASCO 2010) Not all anti-VEGF therapies are created equal This is both good and bad The benefits of therapy at times may be statistically significant, but clinically marginal What We Do Not Know (but still think we do know) How it works The best agents to partner with VEGF-targeted therapies Biomarkers to select patients (SNPs?) If it will work in the adjuvant setting (presumed micromets) in diseases other than CRC (C-08 -) Long term effects of VEGF inhibition on the CV system and CNS (relevant to adjuvant studies) If it will work through multiple lines of therapy (CRC trials)

  34. Despite Incremental Gains in Many Tumor Types, We Have Not Done As Well as We Had Hoped.We Must Be More Creative in Drug Combinations and Biomarker Discovery!! “Me too” drugs and trials are unlikely to significantly advance the field It is time to move new approaches forward!!