1. New Perspectives in Cancer Therapy Óren Smaletz Programa de Oncologia Hospital Israelita Albert Einstein

2. Disclosure of Potential Conflicts of Interest Honoraria: Pfizer, Merck KGaA Research Funding: Pfizer Scientific Funding: Merck KGaA, Roche CFM Resolution nº 1.595/2000 SBOC/SBC oct/2007

3. McMullan D and Cohen G. N Engl J Med 2006;354:397 A 72-year-old man presented for evaluation of progressive dyspnea and cough

4. Change in the US Death Rates* by Cause, 1950 & 2002 * Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2002 Mortality Data: US Mortality Public Use Data Tape, 2002, NCHS, Centers for Disease Control and Prevention, 2004 Heart Diseases Cerebrovascular Diseases Pneumonia/ Influenza Cancer 1950 2002 Rate Per 100,000

5. Fight Against Cancer Surgery Radiotherapy Chemotherapy Targeted Therapy Agents

6. FDA Approved New Molecules for Solid Tumor Use per Year

7. Schrag, D., New Engl J Med 2004

8. Hanahan D, Cell 2000

9. EGF TGF  Amphiregulin  -cellulin HB-EGF Epiregulin Heregulins NRG2 NRG3 Heregulins  -cellulin Cysteine-rich domains Tyrosine kinase domain HER1 EGFR ErbB-1 HER2/neu ErbB-2 HER3 ErbB-3 HER4 ErbB-4 C-terminus 100 44 82 33 36 59 24 48 79 28 The EGFR (erbB) Family and Ligands

10. Família EGFR (Her) Hudis NEJM 2007

11. Trastuzumab – mecanismo de ação Hudis NEJM 2007

12. Trastuzumab in Breast Cancer

13. Trastuzumab – metastatic breast cancer Slamon, NEJM 2001

14. Trastuzumab – metastatic breast cancer Slamon, NEJM 2001

15. Trastuzumab – adjuvant treatment

17. EGFR Signaling Pathways Membrane Extracellular Intracellular Signaling Molecules Cellular effects + proliferation - apoptosis + angiogenesis + metastasis K R K K R K pY Substract pY K R K R R R

18. EGFR Expression in Human Cancer Overexpression associated with: Invasion Metastasis Advanced disease Poor outcome Resistance to chemotherapy, hormonotherapy radiotherapy *lowest to highest published range of expression TumorsExpression (%)* NSCLC50-90 Colorectal45-80 Gastric30-60 Pancreatic30-50 Ovarian35-60 Prostate40-70 Breast14-91 Head and Neck70-100 Kidney80-100

19. Rubin Grandis J et al. JNCI 1998; 90: 824–832. Disease-free Survival and EGFR and TGF-  Levels in Head and Neck Cancer 0123456/0 0.0 0.2 0.4 0.6 0.8 1.0 Years after surgery Proportion Surviving EGFR low medium high p=.0001 123456 Years after surgery TGF  high medium low p=.0001

20. EGFR Mab Currently Approved Clinical activity randomized trials FDAANVISADosage CetuximabHead & Neck Colon/Rectal YYYY YYYY 400 mg/m2 i.v. initial dose followed by 250 mg/m2 weekly PanitumumabColon/RectalYN6 mg/kg i.v. every 14 days

21. Cetuximab (Erbitux®) IgG1 (chimerized antibody) Exclusive for EGFR and its heterodimers Prevents ligand binding to EGFR High affinity. K d = 0.39 nM (M-225 K d = 1 nM) 1 log > natural ligand Stimulates receptor internalization Blocks receptor dimerization, tyrosine kinase phosphorylation, signal transduction

22. Panitumumab (Vectibix®) fully human IgG2κ mAb high affinity (Kd ~ 0.05 nM) Upon binding, internalized and donwregulates EGFR Prevents – receptor dimerization – EGFR-tyrosine autophosphorylation – activation of downstream signaling molecules

23. Apoptosis Nucleus Mechanism of Action of anti-EGFR Monoclonal Antibodies Metastasis X TGF  Membrane Angiogenesis X Cetuximab Panitumumab Cell proliferation X X Cancer Cell

24. Cetuximab in Colorectal Cancer (“Bond Trial”) Eligibility criteria  Pretreated metastatic colorectal cancer with irinotecan  All patients had to be EGF-R positive  Primary end-point  Tumor response

25. Cetuximab in Colorectal Cancer (“Bond Trial”) Irinotecan pre- treated Metastatic CRC EGFR positive Cetuximab and Irinotecan 218 patients Cetuximab 111 patients

28. Cetuximab in Colorectal Cancer (“Bond Trial”) NOR (%)TTP (months) Survival (months) C225 and Irinotecan 21822.94.18.6 C22511110.81.56.9 p = 0.007 Cunningham et al., New Engl J Med 2004

30. Panitumumab in Colon/Rectal Cancer 463 EGFR +, M1 Colon/Rectal Cancer, POD on standard chemoRX Panitumumab + BSC BSC Primary Endpoint: PFS Minimum f/u 12 months Van Cutsem et al., J Clin Oncol 2007

31. Panitumumab vs. BSC Van Cutsem st al. J Clin Oncol 2007

33. Panitumumab vs. BSC

35. EGFR and K-RAS K-RAS mutation present in 40-45% patients When K-ras gene is mutated, K-ras protein (p21 ras) is active independently of EGFR activation Khambata-Ford et al. JCO 2007

36. K-RAS mutation detection PCR test for mutation in codons 12 and 13 kras Chen et al. Clin Chem 2004

37. pre-treated Metastatic CRC (no other option available) Cetuximab + BSC 287 patients BSC 285 patients

38. Karapetis et al. New Engl J Med 2008

39. Take Home Message Moleculat Targeted Therapy – showtime Benefit is evident – as well as costs Who should receive? – Clinical oncology os meeting science

40. Thank you osmaletz@einstein.br