1. An update on biological therapies in colorectal cancer Mount Vernon Cancer Network Sept 05 Mark Harrison

2. Biological therapies 1.What have we got now 2.What’s coming soon 3.What’s on the horizon

3. Adhesion Signalling Growth factors Apoptosis Angiogenesis P16, SMAD4,E-Cadherin Hmsh2, Hmlh1 APCK-rasp53

4. Antibody receptor antagonists Tyrosine kinase inhibitors Antisense Hormones Apoptosis agonists Angiogenesis inhibitors Metalloproteinase inhibitors Matrix degradation Immune system activation

11. Where to use these agents? Adjuvant5-FU, Capecitabine, Oxaliplatin 1 st line metastatic5-FU, Capecitabine, Oxaliplatin, Irinotecan 2 nd line metastatic5-FU, Capecitabine, Irinotecan, Oxaliplatin 3 rd line metastaticMMC, other 4 th line metastaticOther

16. Cetuximab Combination RR 22.9% TTP4.1 months OS8.6 months Cetuximab RR 10.8% TTP1.5 months OS6.9 months Side effects – rash, fever, nausea and vomiting

17. Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan- Refractory Metastatic Colorectal Cancer N. Engl. J. Med., Jul 2004; 351: 337 - 345. David Cunningham et al Phase II Trial of Cetuximab in Patients With Refractory Colorectal Cancer That Expresses the Epidermal Growth Factor Receptor JCO Apr 1 2004: 1201-1208. Leonard B. Saltz et al

18. Cetuximab Current studies COIN (NCRN) – first line metastatic 3 way randomisation Xelox for 18 weeks Xelox until disease progression Xelox + Cetuximab until disease progression

20. Microvascular Corrosion Cast Showing Difference Between Blood vessels of Normal Colon and Colonic carcinoma Konerding et al BJC 1999, 80; 724-32

21. Angiogenesis is involved throughout tumour formation, growth and metastasis Adapted from Poon RT-P, et al. J Clin Oncol 2001;19:1207–25 Stages at which angiogenesis plays a role in tumour progression Premalignant stage Malignant tumour Tumour growth Vascular invasion Dormant micrometastasis Overt metastasis (Avascular tumour) (Angiogenic switch) (Vascularised tumour) (Tumour cell intravasation) (Seeding in distant organs) (Secondary angiogenesis)

22. Approaches to anti-vascular therapy Inhibit tumour angiogenesis Disrupt tumour vasculature

25. VEGF is central to angiogenesis VEGF is a homodimeric ligand that binds to VEGF receptors (VEGFRs) on vascular endothelial cells to stimulate cell survival and growth VEGF is a critical regulator of normal and abnormal angiogenesis VEGF = vascular endothelial growth factor 1 Carmeliet P, et al. Nature 1996;380:435–9 2 Ferrara N, et al. Nature 1996;380:439–42 The loss of a single VEGF allele causes embryonic lethality in mice 1,2

26. VEGF is central to angiogenesis (cont’d) Regulates new blood vessel growth by controlling endothelial cell activation, survival, migration and proliferation 1 Promotes survival of immature vasculature 1 Promotes vascular permeability 1 Stimulates lymphangiogenesis –growth of new lymphatic vessels often accompanies angiogenesis 2 –VEGF overexpression leads to functionally abnormal lymphatic vessels in experimental models 2 Affects the immune response 1 –  dendritic cell maturation –  survival and migration of immune cells 1 Ferrara N, Davis-Smyth T. Endocr Rev 1997;18(1):4–25 2 Nagy JA, et al. J Exp Med 2002;196(11):1497–506

27. Many new drugs target the VEGF pathway VEGFR-2 VEGFR-1 P P P P P P P P Endothelial cell Small-molecule VEGFR inhibitors (tyrosine kinase inhibitors) Ribozymes Anti-VEGFR antibodies Soluble VEGFRs Anti-VEGF antibodies VEGF

28. Bevacizumab (Avastin TM ): an anti-VEGF antibody Recombinant humanised monoclonal antibody targeting the angiogenic factor VEGF Similar to Herceptin ® : 93% human, 7% murine

29. Preclinical studies have confirmed the specificity and activity of bevacizumab Bevacizumab inhibits tumour growth in mice Tumour volume (mm 3 ) VEGF MAbControl MAb Warren RS, et al. J Clin Invest 1995;95:1789–97 Time (days) Control Control MAb (200µg) Bevacizumab (10µg) Bevacizumab (50µg) Bevacizumab (100µg) Bevacizumab (200µg) 1,600 1,200 800 400 0 071421 MAb = monoclonal antibody

30. VEGF is a significant indicator of outcome in CRC VEGF inhibition has the potential to improve survival in patients with CRC CRC = colorectal cancer IHC = immunohistochemical studies; MVA = multivariate analysis; NBH = Northern blot hybridisation; UVA = univariate analysis

31. In combination with 5-FU/LV in advanced CRC Development of bevacizumab in CRC As single agent and in combination with chemotherapy in solid tumours In combination with IFL in metastatic CRC In combination with other chemotherapy regimens (FOLFOX, FOLFIRI, XELOX) in metastatic CRC Phase IVPhase IIIPhase IIPhase I

32. May receive bevacizumab past disease progression May receive bevacizumab past disease progression No bevacizumab past disease progression Phase III trial of IFL ± bevacizumab: study design IFL: bolus 5-FU 500mg/m 2 leucovorin 20mg/m 2 irinotecan 125mg/m 2 given 4/6 weeks Bolus IFL + bevacizumab (n=402) Previously untreated metastatic CRC 5-FU/LV + bevacizumab (n=110) Bolus IFL + placebo (n=411) 5-FU/LV: bolus 5-FU 500mg/m 2 leucovorin 500mg/m 2 given 6/8 weeks Bevacizumab: 5mg/kg every 2 weeks Hurwitz H, et al. Proc Am Soc Clin Oncol 2003;22:3646

33. Phase III trial of IFL ± bevacizumab: effect of bevacizumab on clinical endpoints Hurwitz H, et al. Proc Am Soc Clin Oncol 2003;22:3646

34. Phase III trial of IFL ± bevacizumab: patient characteristics Hurwitz H, et al. Proc Am Soc Clin Oncol 2003;22:3646

35. Phase III trial of IFL ± bevacizumab: effect of bevacizumab on overall survival Probability of survival 1.0 0.8 0.6 0.4 0.2 0 010203040 Survival (months) IFL + placebo IFL + bevacizumab Hazard ratio = 0.66, p=0.00003 Median survival 15.6 (IFL + placebo) vs 20.3 months (IFL + bevacizumab) Kaplan-Meier curve Hurwitz H, et al. Proc Am Soc Clin Oncol 2003;22:3646

36. Is this state of the art ?

37. First line metastatic disease 5-FU, Capecitabine, Oxaliplatin NICE NCRN trial (COIN)

38. Hazard ratio (arm 1 vs 2): 0.71 Hazard ratio (arm 1 vs 3): 0.81 Overall survival: 15.1 vs 20.5 vs 18.3 months 1.0 0.8 0.6 0.4 0.2 0 Probability of survival 010203040 Survival (months) Phase III trial of IFL ± bevacizumab: survival for 5-FU/LV arm (n=314) IFL + placebo IFL + bevacizumab 5-FU/LV + bevacizumab Hurwitz H, et al. Proc Am Soc Clin Oncol 2003;22:3646

39. Many phase II/III trials of bevacizumab in metastatic CRC are ongoing

40. Many new drugs target the VEGF pathway VEGFR-2 VEGFR-1 P P P P P P P P Endothelial cell Small-molecule VEGFR inhibitors (tyrosine kinase inhibitors) Ribozymes Anti-VEGFR antibodies Soluble VEGFRs Anti-VEGF antibodies VEGF

41. Angiogenesis Inhibitors in Clinical Trials 2 Receptor tyrosine kinase inhibitors PTK787/ZK22854VEGFR-1,2,3,PDGFR,cKit,c-FMS SU11248VEGFR-1,2, PDGFR,c-Kit, Flt-3,c-Fms BAY43-9006b-raf, VEGFR-2, 3, PDGFR, Flt-3, c-Kit ZD6474VEGFR2, EGFR CP547,632VEGFR-2, FGFR AZD2171VEGFR-1, VEGFR-2, VEGFR-3 BIBF1120VEGFR-1,3, FGFR-1,3, PDGFR BMS582664VEGFR-2, FGFR-1 AG013736VEGFR, PDGFR

42. Antibody receptor antagonists Tyrosine kinase inhibitors Antisense Hormones Apoptosis agonists Angiogenesis inhibitors Metalloproteinase inhibitors Matrix degradation Immune system activation