New Perspectives in Cancer Therapy

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

3. A 72-year-old man presented for evaluation of progressive dyspnea and cough. He reported smoking one to two packs of cigarettes a day since the age of 15 years. Standard chest radiography showed a suspicious lesion in the right thoracic cavity. Computed tomography of his chest revealed bullous emphysema (thick arrow), a tumor involving the middle lobe of the right lung (thin arrow), and a pack of cigarettes in his shirt pocket (asterisk). Biopsy of the lesion confirmed the presence of non-small-cell lung cancer.A 72-year-old man presented for evaluation of progressive dyspnea and cough. He reported smoking one to two packs of cigarettes a day since the age of 15 years. Standard chest radiography showed a suspicious lesion in the right thoracic cavity. Computed tomography of his chest revealed bullous emphysema (thick arrow), a tumor involving the middle lobe of the right lung (thin arrow), and a pack of cigarettes in his shirt pocket (asterisk). Biopsy of the lesion confirmed the presence of non-small-cell lung cancer.

4. Change in the US Death Rates* by Cause, 1950 & 2002 Compared to the rate in 1950, the cancer death rate was about the same in 2002, while rates for other major chronic diseases decreased during this period. Compared to the rate in 1950, the cancer death rate was about the same in 2002, while rates for other major chronic diseases decreased during this period.

5. Fight Against Cancer Surgery Radiotherapy Chemotherapy Targeted Therapy Agents

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

8. Hanahan D, Cell 2000

9. The EGFR (erbB) Family and Ligands The EGFR family consists of four members, HER1/erbB-1 through HER4/erbB-4. They all share the same structure – an extracellular domain that interacts with specific ligands, a short transmembrane domain and a tyrosine kinase domain within the cell, which is the activator of downstream signaling. Each receptor has some homology with the others but they vary in terms of ligand binding and tyrosine kinase activity.The EGFR family consists of four members, HER1/erbB-1 through HER4/erbB-4. They all share the same structure – an extracellular domain that interacts with specific ligands, a short transmembrane domain and a tyrosine kinase domain within the cell, which is the activator of downstream signaling. Each receptor has some homology with the others but they vary in terms of ligand binding and tyrosine kinase activity.

10. Família EGFR (Her)

11. Trastuzumab – mecanismo de ação

12. Trastuzumab in Breast Cancer

13. Trastuzumab – metastatic breast cancer

14. Trastuzumab – metastatic breast cancer

15. Trastuzumab – adjuvant treatment

16. Trastuzumab – adjuvant treatment

17. EGFR Signaling Pathways

18. EGFR Expression in Human Cancer Overexpression associated with: Invasion Metastasis Advanced disease Poor outcome Resistance to chemotherapy, hormonotherapy radiotherapy EGFR is generally expressed in a wide range of human solid tumors. Expression is very variable due to the different detection assays used, since there is no standardized method of measuring EGFR expression.EGFR is generally expressed in a wide range of human solid tumors. Expression is very variable due to the different detection assays used, since there is no standardized method of measuring EGFR expression.

19. Disease-free Survival and EGFR and TGF-a Levels in Head and Neck Cancer

20. EGFR Mab Currently Approved

21. Cetuximab (Erbitux®) IgG1 (chimerized antibody) Exclusive for EGFR and its heterodimers Prevents ligand binding to EGFR High affinity. Kd = 0.39 nM (M-225 Kd = 1 nM) 1 log > natural ligand Stimulates receptor internalization Blocks receptor dimerization, tyrosine kinase phosphorylation, signal transduction M225, a murine monoclonal antibody, competitively binds to the EGFR and inhibits EGFR pathways. Clinical trials using murine monoclonal antibodies have been complicated by the development of the human antimouse antibody (HAMA) immune response. The HAMA response not only carries the risk of serious allergic reactions but also increases the clearance of the murine proteins. Thus, the clinical utility of murine monoclonal antibodies has been limited. Cetuximab is a human:murine chimeric anti-EGFR IgG monoclonal antibody that binds exclusively to the EGFR. Chimeric antibodies are composed of the variable regions of murine antibody (the regions responsible for antigen binding) and the constant region of the human Fc fragment.[1] Chimeric monoclonal antibodies have demonstrated specificity and a diminished incidence of immunologic reactions.[2,3] Cetuximab binds to the EGFR with a binding affinity that is approximately one log higher than natural ligands.[4] Cetuximab prevents binding of endogenous ligands and induces receptor internalization, which ultimately blocks the activities of the EGFR pathway. Owens RJ, Young RJ. The genetic engineering of monoclonal antibodies. J Immunol Methods 1994; 168:149–165. Shitara K, Kuwana Y, Nakamura K, et al. A mouse/human chimeric anti-(ganglioside GD3) antibody with enhanced tumor activities. Cancer Immunol Immunother. 1993; 36:373–380. LoBuglio AF, Wheeler RH, Trang J, et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci U S A. 1989; 86:4220–4224. Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995; 1:1311–1318.M225, a murine monoclonal antibody, competitively binds to the EGFR and inhibits EGFR pathways. Clinical trials using murine monoclonal antibodies have been complicated by the development of the human antimouse antibody (HAMA) immune response. The HAMA response not only carries the risk of serious allergic reactions but also increases the clearance of the murine proteins. Thus, the clinical utility of murine monoclonal antibodies has been limited. Cetuximab is a human:murine chimeric anti-EGFR IgG monoclonal antibody that binds exclusively to the EGFR. Chimeric antibodies are composed of the variable regions of murine antibody (the regions responsible for antigen binding) and the constant region of the human Fc fragment.[1] Chimeric monoclonal antibodies have demonstrated specificity and a diminished incidence of immunologic reactions.[2,3] Cetuximab binds to the EGFR with a binding affinity that is approximately one log higher than natural ligands.[4] Cetuximab prevents binding of endogenous ligands and induces receptor internalization, which ultimately blocks the activities of the EGFR pathway. Owens RJ, Young RJ. The genetic engineering of monoclonal antibodies. J Immunol Methods 1994; 168:149–165. Shitara K, Kuwana Y, Nakamura K, et al. A mouse/human chimeric anti-(ganglioside GD3) antibody with enhanced tumor activities. Cancer Immunol Immunother. 1993; 36:373–380. LoBuglio AF, Wheeler RH, Trang J, et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci U S A. 1989; 86:4220–4224. Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995; 1:1311–1318.

22. Panitumumab (Vectibix®) fully human IgG2? 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. Mechanism of Action of anti-EGFR Monoclonal Antibodies This and the next slide show simple examples of the difference in mechanism of action between moAbs and TKIs. In this slide it is shown that ligand binding is blocked by an anti-EGFR moAb. The moAb-EGFR is internalized, but cannot signal within the cell. In this way, the signal transduction cascade is blocked. With a moAb such as cetuximab, ligand activation of the receptor, and therefore intracellular signaling, are blocked.This and the next slide show simple examples of the difference in mechanism of action between moAbs and TKIs. In this slide it is shown that ligand binding is blocked by an anti-EGFR moAb. The moAb-EGFR is internalized, but cannot signal within the cell. In this way, the signal transduction cascade is blocked. With a moAb such as cetuximab, ligand activation of the receptor, and therefore intracellular signaling, are blocked.

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”)

28. Cetuximab in Colorectal Cancer (“Bond Trial”)

30. Panitumumab in Colon/Rectal Cancer

31. Panitumumab vs. BSC

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

36. K-RAS mutation detection PCR test for mutation in codons 12 and 13 kras

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