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  1. Terapia antiangiogenica oltre i farmaci anti-VEGF Filippo de Braud & Francesco Agustoni S.C. Oncologia Medica Fondazione IRCCS Istituto Nazionale Tumori Modena, 18-19/11/2011

  2. Warren Lewis described the vasculature of spontaneously occurring rat tumours each tumour type has different vascular architecture the growth and morphology of tumour blood vessels are therefore influenced by the tumour environment 1927: tumour environment influences vasculature Lewis. Johns Hopkins Hospital Bulletin 1927

  3. Gordon Ide and colleagues used a transparent chamber to observe growth of a transplanted tumour in the ear of a rabbit tumour growth is accompanied by extensive formation of new vessels if blood vessel growth does not occur, the tumour fails to grow 1939: tumour angiogenesis observed in vivo Ide, et al. Am J Roentgenol 1939

  4. A diffusible, endothelial-specific mitogen is identified and named vascular endothelial growth factor (VEGF)1 VEGF and VPF are cloned independently by separate groups2,3 they turn out to be the same molecule 1989: one molecule, multiple rolesNapoleaone Ferrara et al. 1. Ferrara N, et al. Biochem Biophys Res Comm 19892. Leung DW, et al. Science 1989; 3. Keck PJ, et al. Science 1989

  5. Angiogenesis is a balance between… PRO-ANGIOGENIC FACTORS VEGF FGF PDGF EGF TGF-α TGF-β IL-8 Leptin Angiogenin ANTI-ANGIOGENIC FACTORS Angiostatin Endostatin Thrombospondin-1 Angiopoietin-2 IFN-α IL-2

  6. TARGET THERAPIES

  7. Whytargetingtumorvasculature? • Tumors secrete angiogenic factors (1979, J. Folkman) • Tumor neo-angiogenesis and vascular integrity is essential for tumor growth • The cellular and stromal components of the tumor’s new and established vessels are a target for cancer therapy

  8. Variety of approaches to targeting VEGF and the VEGFR system 1. Ellis, Hicklin. Nat Rev 20082. Schenone, et al. Curr Med Chem 20073. Taylor, et al. Biochem Biophys Res Commun 2008

  9. Tumour characteristics and environment promote VEGF expression PDGF IGF-1 H2O2 EGF IL-8 Binding and activation of VEGFR VEGF release bFGF Hypoxia  COX-2  NO  Oncogenes  –P P– Increased expression (MMP, tPA, uPA, uPAr, eNOS, etc.) –P P– Survival Proliferation Migration Permeability Adapted from Ferrara et al. Oncologist 2004 and Ferrara et al. Nature Med 2003

  10. Regulationof VEGF in tumorcells Activated Signaling Pathways/ Transcription Factors • Src • COX-2 • Bcl-2 • AKT/PKB • AP-1 • SP-1 • NF-kB • HIF Oncogenes / Tumor Suppressor Genes • Ras • Src • PTEN • p53 • HER-2 • c-Jun Enviromental Factors, Growth Factors, Cytokines and their Receptors • Hypoxia • Low pH • IL-1β • EGFR • IL-6 • C-MET • PDGFR

  11. Signaling Pathways Activated by VEGF

  12. VEGF-targetedtherapies VEGFR-TKI Sorafenib Telatenib Regorafenib Sunitinib SU14813 Pazopanib Valatinib (ZD ZD6474 (Vandetanib) AG-013736 (Axitinib) AMG 706 VEGF-antibodies Bevacizumab VEGF-Trap (Aflibercept)

  13. Recombinant humanised monoclonal anti-VEGF antibody developed from murine anti-VEGF MAb A4.6.11 93% human, 7% murine recognises all major isoforms of human VEGF, Kd = 8 x 10–10M terminal half-life 17–21 days 1997: humanisation of A4.6.1 produces bevacizumab 1. Presta, et al. Cancer Res 1997

  14. BevacizumabMoA: early and continued benefits EARLY EFFECTS CONTINUED EFFECTS Regression Normalisation Inhibition 1 2 3 Decreases tumour size Improves delivery of chemotherapy Suppresses new vessel growth Suppresses regrowth via vessel ‘scaffolds’ Enables metastectomyIncreases PFSIncreases OS Willett, et al. Nat Med 2004; Gerber, Ferrara. Cancer Res 2005

  15. = VEGF-Trap

  16. VEGF-Trap • VEGF-Trapis a fusionprotein, madefrom key domainsfrom VEGFR1 and VEGFR2 and from the FC fragmentofhuman IgG1 • Itonlyincludeshumanaminoacidsequences • High affinity block on all VEGF-A isoformsaswellas the placentalgrowthfactor (PIGF) • Smallersizethanmonoclonal antibody (MW 115.000) • Long eliminationhalf-life in men (20 days)

  17. TKI antiangiogenicdrugs

  18. Targeting Angiogenesis: Multiple Tyrosine Kinase Inhibition • Multitargeted agents have demonstrated higher response rates than single target agents • Targeting a single receptor or enzyme may not sustain an antitumor response • Targeting multiple receptors or enzymes can be achieved with: • A combination of agents • A single agent with specificity for multiple receptors or steps in tumor signaling pathways • A single, multitargeted agent has several potential advantages: • Reduced toxicity • Simplified dosing • Flexibility to administer with other treatment regimens • Increased convenience and patient compliance

  19. Activity spectrum of TKI

  20. Effectof TKI on cellularkinases Pazopanib

  21. Sunitinib Simultaneously Inhibits RTKs on Tumor Cells, Pericytes and Endothelial Cells Antiangiogenic effects Antitumor effects VASCULARENDOTHELIAL CELL TUMOR CELL PERICYTE Cross-talk VEGF VEGF VEGF PDGF RTKs expressed by tumor cells PDGFR KIT VEGFR-2 PDGFRs VEGFR-3 VEGFR-1 Sunitinib Sunitinib Sunitinib Sunitinib

  22. Sorafenib targets both tumor cells proliferation and tumor angiogenesis Tumor cell Endothelial cell Sorafenib inhibits proliferation and survival in tumor cells Sorafenib inhibits proliferation and/or survival in endothelial cells

  23. Ras-GDP Ras-GTP SOS Raf SH3 Tyr SH2 P SH3 RKI Raf P Tyrosine kinase receptor MEK MEK P ERK ERK P Transcription elk-l Sorafenib targets tumors at several molecular levels Growth factor • Sorafenib: potent inhibitor of Raf kinase • ~70% of melanomas contain B-Raf mutations • Overall 30% of cancers display Ras mutations • Preclinical activity in tumors exhibiting Ras mutations • Sorafenib: potent inhibitor of VEGFR-2 • VEGFs probably important in pathogenesis and prognosis of MBC • Potential use in multiple cancer types through inhibition of angiogenesis • Additional activities against other proto-oncogenic proteins (VEGFR3, PDGFRb,-p38) Potential use in large spectrum of cancers Cell Cell proliferation

  24. Successfullcompletedphase III trialswithanti-VEGFpathwaysagents

  25. Unsuccessfull or terminatedphase III trialswithanti-VEGFpathwaysagents

  26. VEGF pathway-targeteddrugscurrently in neoadjuvantclinicaltrials

  27. Potential mechanisms of resistance to VEGF inhibitors 1Oromi A et al Cell 2005 3Du R Cancer Cell 2008 2Ebos JM et al PNAS 2007 CAFs SDF1a Osteopontin BMDCs • PDGF • MMP9 SDF1a Bone marrow derived cells (i.e myeloid suppressive cells) Cancer associated fibroblasts Adapted from Casanovas O Cancer Cell 2005

  28. FGF/FGFR network Characteristics: • 18 ligands • 4 TKI receptors: FGFR1, FGFR2, FGFR3, FGFR4 • One non-TKI receptor: FGFRL1 • Regulatory activity of cell proliferation, survival, migration and angiogenesis

  29. Mechanisms of pathogenic cancer cell FGF signalling

  30. Anti FGFR/FGFs Monoclonal Antibodies

  31. FGFR TKI

  32. ALK-1: Biology and Signaling In Angiogenesis • ALK-1 (activin receptor like kinase I) is a TGFβ receptor mostly restricted to endothelial cells in adults • 2 known ligands • TGFb-1, 3 (low affinity) • BMP-9 and BMP-10 (high affinity) • ALK-1 is required for vascular development, and its loss of function is linked to hereditary hemorrhagic telangectasia (HHT-2) in humans, which is associated with increased ALK-1 expression, plasma VEGF and TGFb • Hypothesis in cancer: ALK-1 is pro-angiogenic by contributing to vascular maturation/stabilization • PF-03446962 is a fully human IgG2 mAb that inhibits ALK-1

  33. Different Vessel Phenotype Between Anti-ALK-1 and Anti-VEGF Control Combination • Human foreskin/SCID mice chimera model implanted with human melanoma • Human CD31 (EC) co-staining with desmin (perivascular and smooth muscle cells) 1.8 1.6 1.4 1.2 1.0 SMCs and PCs Tumor Weight (g) 0.8 ** 0.6 0.4 0.2 Endothelial cells 0.0 Control (No Dose) Anti-huALK1 (10 mg/kg, QW) Bevacizumab (5 mg/kg, Q5D) Combination Bevacizumab Anti-ALK1 Combo

  34. Key Preclinical Data • Proangiogenic factors (VEGF and/or bFGF) are required for ALK-1 to sustain tumor vessel growth • In vitro, the proliferation of endothelial cells resistant to VEGFR TKI (sunitinib) was significantly reduced after PF-03446962 administration • In tumors resistant to VEGFR TKI • ALK-1 gene was upregulated; VEGFR-2 was downregulated • ALK-1 protein was localized within the mature vasculature of the tumor • Resistant tumors responded to single agent anti–ALK-1 better than VEGFR TKI-sensitive tumors The vascular phenotype after ALK-1 blockade is different than anti-VEGF, confirming a different and potentially complementary mechanism of action

  35. Thanks… Filippo de Braud & Francesco Agustoni S.C. Oncologia Medica Fondazione IRCCS Istituto Nazionale Tumori Modena, 18-19/11/2011

  36. CLINICAL OUTCOMES

  37. Breast Cancer

  38. Bevacizumab as first-line • Bevacizumab in LR/mBC Overview of three randomised phase III trials • E2100 (bevacizumab combined with weekly paclitaxel) Trial design, patient population, efficacy, safety, summary • AVADO (bevacizumab combined with 3-weekly docetaxel) Trial design, patient population, efficacy, safety, summary • RIBBON-1 (bevacizumab combined with either taxane/anthracycline or capecitabine) Trial design, patient population, efficacy (capecitabine cohort), efficacy (taxane/anthracycline cohort), safety, summary 44

  39. Three Randomised Trials of First-Line Bevacizumab-Based Therapy in LR/mBC: Similar Trial Designs 1Miller et al. NEJM 2007; 2Miles et al. ASCO 2008; 3Robert et al. ASCO 2009 45

  40. Consistent Benefit with Bevacizumab-Based Therapy: Significant Improvement in PFS & ORR aIRF assessment; bPFS censored for non-protocol therapy before disease progression; c15 mg/kg q3w; dExploratory p value 1Klencke et al. ASCO 2008; 2Gray et al. JCO 2009; 3Avastin SmPC 2009; 4Robert et al. ASCO 2009

  41. Secondary Endpoint: Overall Survival a15 mg/kg q3w; bExploratory p value 1Cameron EJC Suppl 2008; 2Avastin SmPC 2009; 3Roche data on file 2009; 4Robert et al. ASCO 2009

  42. RIBBON-2: Study Design CHOICE OF CHEMOTHERAPY BY INVESTIGATOR • Previously treated • mBC (n=684) • Stratification factors: • Investigator choice ofchemotherapy on study • Interval from mBCdiagnosis to first PD • ER and PR status RANDOMISE 2:1 Chemotherapy+ Bevacizumab Treat until PD TaxaneorGemcitabine or Capecitabine or Vinorelbine Chemotherapy+ placebo Primary endpoint: investigator-assessed PFS pooled across the chemotherapy cohorts Treatment • taxane (paclitaxel 90mg/m2/wk for 3 of 4 wk; paclitaxel 175mg/m2, nab-paclitaxel 260mg/m2, or docetaxel 75–100mg/m2 q3w) • gemcitabine (1,250mg/m2 on days 1 and 8 q3w) • capecitabine (2,000mg/m2 days 1–14 q3w) • vinorelbine (30mg/m2/wk) • Bevacizumab or placebo (15mg/kg q3w or 10mg/kg q2w, depending on chemotherapy regimen) Brufsky, et al. SABCS 2009

  43. RIBBON-2: Bevacizumab Significantly Improves PFS in Second-line mBC 1.0 0.8 0.6 0.4 0.2 0 Chemo/Placebo (n=225) Chemo/Bev (n=495) Median PFS, 7.2 vs. 5.1 months HR=0.78, p = 0.0072 Proportion of progression-free 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Duration of PFS Number at risk:Chemo/Placebo Chemo/Bev 225 165 129 93 77 44 33 19 12 8 5 4 3 1 1 0 0 0 459 381 334 254 190 130 87 47 27 18 9 5 2 1 1 0 0 0 Brufsky, et al. SABCS 2009

  44. Phase II Trial of Sunitinib in Patients with Previously-Treated Metastatic Breast Cancer Kathy D. Miller, MD American Society of Clinical Oncology (ASCO) 42nd Annual Meeting 2005 May 13–17, Orlando, FL