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  1. John Mackey, MD Professor of Oncology University of Alberta Edmonton, Canada Angiogenesis: Using Old and New Approaches

  2. Faculty Disclosure John R. Mackey, MD, FRCP (C), has disclosed that he has received consulting fees from Eli Lilly and Roche and CME honoraria from Amgen.

  3. Overview • Angiogenesis and the VEGF/VEGF-R pathway • New mechanisms and new agents • The metastatic / adjuvant gulf • Toward predictive biomarkers

  4. Angiogenesis • Physiologic process of new blood vessel formation • Principally driven by interactions between vascular endothelial growth factors and 3 high-affinity VEGF receptors Folkman J. Semin Oncol. 2002;29(suppl 6):15-18. Hicklin DJ, et al. J Clin Oncol. 2005;23:1011-1027.

  5. VEGF Family of Ligands and Receptors VEGF- A121 VEGF- A145 VEGF- A165 VEGF- A189 VEGF- A206 VEGF- B167 VEGF- B186 PlGF- 1,2 VEGF- C VEGF- D VEGF- E Y s-s s-s NRP-1 NRP-2 VEGFR-1 (Flt-1) VEGFR-2 (Flk-1/KDR) VEGFR-3 (Flt-4) Vasculogenesis Angiogenesis Lymphangiogenesis

  6. An Obvious Target . . .

  7. P P P P P P P P P P P P Agents Targeting the VEGF Pathway VEGF-A Anti-VEGFR2antibodies(ramucirumab) Anti-VEGFantibodies(bevacizumab) SolubleVEGFreceptors(aflibercept) VEGFR-1 VEGFR-2 VEGFR-3 Endothelial cell Agents in yellow = FDA approved Small-molecule inhibitors of VEGFR(PTK-787, AZD2171, motesanib,sunitinib, sorafenib, pazopanib,axitinib, others)

  8. Agents Targeting the VEGF Pathway • Small-molecule VEGFR inhibitors • Vatalanib (PTK787) • AZD2171 • Sunitinib (SU11248) • Sorafenib (BAY 43-9006) • Motesanib (AMG 706) • Pazopanib • AG-013736 • Others • Anti-VEGF antibodies • Bevacizumab • Anti–VEGFR-2 antibodies • Ramucirumab (IMC-1121B) • Soluble VEGF receptors • Aflibercept (VEGF Trap)

  9. AntiangiogenicRisk:Benefit Ratio Efficacy Toxicity

  10. Antiangiogenic Class Toxicities • Hypertension • Clotting • Bleeding • Congestive heart failure (when combined with anthracyclines) • Financial • Agent-specific toxicities • Motesanib: cholecystitis • Pigmentation changes: sunitinib, pazopanib Gressett SM, et al. Ann Pharmacother. 2009;43:490-501. Blumenschein GR Jr, et al. Ann Oncol. 2011;[Epub ahead of print]. Rosenbaum SE, et al. Support Care Cancer. 2008;16:557-566. Bible KC, et al. Lancet Oncol. 2010;11:962-972.

  11. Therapeutic Efficacy • Modest, in general … • Colorectal carcinoma – M1 • Non-small-cell lung carcinoma – M1 • Renal cell carcinoma – M1 • Breast cancer – M1 • No evidence of adjuvant efficacy thus far • 2 negative studies in M0 CRC (C-08, AVANT)

  12. Adjuvant Antiangiogenic Therapy?

  13. Bevacizumab • Best studied agent • Modest efficacy in a number of indications • Resistance mechanisms • Upregulation of ligand • Insoluble VEGF remains and promotes angiogenesis?[1] • VEGFR-1 polymorphisms (constitutive activation)?[2] • No validated predictive marker • Potential high serum VEGF levels? 1. Chen TT, et al. J Cell Biol. 2010;188:595-609. 2. Lambrechts D, et al. ECCO-ESMO 2009. Abstract 16LBA.

  14. New Data on Newer Agents • Ramucirumab • Aflibercept

  15. Ramucirumab • Fully humanized antibody directed against the VEGFR-2 • Potential for immune-mediated destruction of angiogenic vessels • Circumvents insoluble VEGF activation of VEGFR-2 • In phase II trials for MBC, advanced GI cancers, metastatic GU cancers, recurrent ovarian cancer, prostate cancer, metastatic RCC • In phase III trials for refractory metastatic gastric adenocarcinoma, advanced NSCLC, relapsed hepatocellular carcinoma, metastatic CRC Spratlin and Mackey. Future Oncol. 2010;6:1085-1094.

  16. TRIO-012 Ramucirumab Study • Patient population • Women with HER2-negative, unresectable, locally recurrent or metastatic breast cancer with or without measurable lesions • No previous chemotherapy for metastatic or locally recurrent and inoperable breast cancer • Study plan Progressive disease Or unacceptable toxicity Or withdrawn consent Docetaxel 75 mg/m² IV q3w RANDOMIZATION ….. 2/3 F/UP Blinded ramucirumab 10 mg/kg IV q3w Docetaxel 75 mg/m² IV q3w ….. 1/3 Blinded placebo IV q3w Mackey J, et al. Clin Breast Cancer. 2009;9:258-261.

  17. Aflibercept • Fusion protein decoy receptor: binds VEGF-A, VEGF-B, and placental growth factor • Achieved primary endpoint (OS) in VELOUR phase III clinical trial for second-line treatment of mCRC • 1266 mCRC patients FOLFIRI vs FOLFIRI + aflibercept improved OS Regeneron [press release]. Available at: Accessed May 25, 2011.

  18. Motesanib • Small molecule inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, and KIT • Increases activity of paclitaxel in MBC in randomized phase II setting, but with significant GI toxicity Martin MM, et. al. Lancet Oncol. 2011;12:369-376.

  19. TRIO-010 Motesanib Study Paclitaxel 90 mg/m² IV weekly for 3/4 wks Roll-over (optional) RANDOM I ZAT I ON Arm A Open-label motesanib 125 mg PO daily PD Blinded placebo PO daily Paclitaxel 90 mg/m² IV weekly for 3/4 wks Arm B • Treatment until • Progressive disease • Unacceptable toxicity • Consent withdrawal Blinded motesanib 125 mg PO daily Paclitaxel 90 mg/m² IV weekly for 3/4 wks Arm C Open-label bevacizumab 10 mg/kg on Week 1 and Week 3 N = 282 • Stratified by: • Previous taxane CT vs other vs none • Number of metastatic sites (< 3 vs ≥ 3) • Hormone receptor status (positive vs negative) Martin MM, et. al. Lancet Oncol. 2011;12:369-376.

  20. Vascular Disrupting Agents • drugs designed to damage the established vasculature of tumors causing central necrosis • Flavinoid compounds • ASA404 Phase III (NSCLC) • microtubule destabilizers • CA4P Phase II/III • AVE8062 Phase III; sarcoma) • ABT-751 Phase II (multiple histologies) • Dolastatin Phase II • Oxi4503 Phase I • Due to residual rim of viable cells, combination therapy may be required

  21. Angipoietin -TIE Receptor Pathway • TIE-1 and TIE-2 are cell-surface receptors that bind and are activated by angiopoietins (ANGPT1, ANGPT2, and ANGPT4) • Play crucial role in angiogenic switch • Agents targeting ANG1 anad ANGPT2 are in phase II clinical trials and early reports suggest anti-tumor activity and a safety profile distinct from anti-VEGFA agents • Substantial combination benefit of targeting both ANGPT2 and VEGFA pathways preclinically

  22. Agents Targeting the ANGPT-TIE Pathway

  23. How Can We Move Beyond Empiricism? • Predictive assays

  24. Therapeutic Predictive Assays • Prognostic biomarker • “How bad is my cancer, Doc?” • Predictive biomarker • “Is this drug going to work?”

  25. Exposure Biomarkers • Measure biologic response after administration of the drug • Include: • Treatment-emergent hypertension • Changes in serum VEGF, shed VEGFR-2, PIGF • Changes in dynamic-contrast MRI • Have been useful in defining pharmacodynamically appropriate doses and schedules • Do not address whether or not to start antiangiogenic therapy in a given patient Rini B, et al. J Natl Cancer Inst. 2011;103:763-773. Schneider BP. J Clin Oncol. 2008;26:4672-4678. Vlahovic G, et al. J Thoracic Oncol. 2007;8:S745.

  26. Tumor-Based Predictive Markers • Baseline tumor VEGF levels • Prognostic but not predictive • Low levels of carbonic anhydrase IX[1] • Von Hippel-Lindau loss of function mutations in M1 renal cell carcinoma[2] • HER2 positivity in breast cancer • Associated with high levels of VEGF, independently prognostic[3] • 1. Hong YS, et. al. BMC Cancer. 2009;9:246 2. Choueri et. al. J Urol 2008. 3. Konecny GE, et. al. Clin Cancer Res. 2004;10:1706-1716

  27. Blood-Based Biomarkers • Baseline circulating VEGF levels • Variably prognostic, but not predictive[1] • Circulating endothelial cell enumeration • May be prognostic in some malignancies[2,3] • Not yet shown to be predictive 1. Kaseb AO, et al. Cancer. 2009;115:4895-4906. 2. Batchelor T, et al. ASCO 2007. Abstract 2001.3. Ramalingam SS, et al. ASCO 2008. Abstract 8078.

  28. Host-Based Predictive Biomarkers • Angiogenesis is a response of normal stroma to signals from the cancer • Germ-line genetic variability may contribute to efficacy and toxicity • E2100 MBC paclitaxel ± bevacizumab • VEGF-2578AA and VEGF-1154AA genotypes had higher OS in combination[1] • Constitutive activation of VEGFR-1 pathway?[2] 1. Schneider BP, et al. Clin Cancer Res. 2009;15:5297-5302. 2. Lambrechts D, et al. ECCO-ESMO 2009. Abstract 16LBA.

  29. SNPs Relate to Survival in MBC/ Bevacizumab? • Small subset, tumor DNA, unclear how many SNPs evaluated Schneider BP, et al. Clin Cancer Res. 2009;15:5297-5302.

  30. The State of PublishedAntiangiogenic Trials In general . . . • Unselected cancers • Treat entire population with novel therapy • Minimal and/or retrospective tissue collection • Unplanned retrospective subset analysis

  31. Ongoing Antiangiogenic Trials . . . • Molecular rationale • Up-front tumor and somatic tissue accrual • Molecular stratification prior to therapy • (If any hint of predictive marker) • Prespecified statistical assessment of biomarker performance

  32. “It’s difficult to make predictions, especially about the future.” Will We Find a Predictive Marker for Antiangiogenic Therapy?

  33. A Tale of 2 Trials • Adjuvant chemotherapy in operable breast cancer • Standard therapy vs standard therapy + 1 yr of bevacizumab N ~ 3000 patients NCT00625898. NCT00528567.

  34. Preconditions for a VEGF Pathway Predictive Biomarker • Agent inhibits this pathway • Pretreatment biology drives the therapeutic response • Compensatory non-VEGF–mediated pathways are irrelevant • Randomized clinical trials with appropriate biologic samples • Clinical efficacy signal is sufficiently strong in the sensitive subpopulation to drive a statistically significant interaction test

  35. Why BETH Should Be a Positive Trial • Preselected population with VEGF-driven biology[1] • Preclinical (and apparent clinical) synergy between HER2 inhibitors and antiangiogenic therapy[2-4] 1. Konecny GE, et. al. Clin Cancer Res. 2004;10:1706-1716. 2. Peagram M, et al. SABCS 2006. Abstract 301. 3. Blackwell KL, et al. SABCS. Abstract 61. 4. Slamon DJ, et al. SABCS 2008. Abstract 4114.

  36. Why BEATRICE May Be a Negative Trial • VEGF does not appear to be the key angiogenic driver of relapse in triple-negative breast cancer • Alberta Breast Cancer Relapse Study • Mackey J, et. al. unpublished

  37. University of Alberta Breast StudyCase-Control Selection

  38. Biomarker Selection

  39. Triple-Negative Cohort: Proangiogenic Factor (Non-VEGF Related)

  40. Funding • Raymond Lai, MD, PhD • Cheryl Santos, MSc • Kathryn Graham, PhD • Roger Tsang, MD Collaborators

  41. Prediction on Predictive Assays for VEGF Pathway Inhibitors . . . • HER2 will be the marker of selective benefit from adjuvant antiangiogenic therapy in breast cancer • Multiplex solutions required for other cancers • Integrate tumor factors • Identify VEGF-dependent cancers • Integrate host factors • Constitutive upregulation of non–VEGFR-1 pathway or non-VEGF proangiogenic pathways

  42. Take Home Messages • Antiangiogenic agents have modest population benefit in some metastatic settings • Progress will require better agents or more appropriately selected patient populations • No predictive biomarker has been validated • The most promising candidates include • HER2 positivity in breast cancer • Multiplexed approaches • Identifying VEGF-driven tumors • Integration with host factors