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Monoclonal antibody therapy in Surgical Malignancy: Does it work and how?

Monoclonal antibody therapy in Surgical Malignancy: Does it work and how?. Dr. Jeremy Yip RHTSK. Targeted Therapies. The aim of such therapies was to disrupt the signalling processes that the cell depends upon for growth and survival. MAbs. Small Molecules.

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Monoclonal antibody therapy in Surgical Malignancy: Does it work and how?

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  1. Monoclonal antibody therapy in Surgical Malignancy: Does it work and how? Dr. Jeremy Yip RHTSK

  2. Targeted Therapies • The aim of such therapies was to disrupt the signalling processes that the cell depends upon for growth and survival. MAbs Small Molecules Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  3. MAbs Goodin S. Development of monoclonal antibodies for treatment of colorectal cancer. Am J Health-Syst Pharm. 2008,65 (Suppl 4):S3-7

  4. MAbs Goodin S. Development of monoclonal antibodies for treatment of colorectal cancer. Am J Health-Syst Pharm. 2008,65 (Suppl 4):S3-7

  5. MAbs http://approachepilepsy.com/home/modules/Drugs-MM/images/MonoclonalAb.jpg

  6. MAbs http://approachepilepsy.com/home/modules/Drugs-MM/images/MonoclonalAb.jpg

  7. MAbs for Solid Tumors VEGF EGFR Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  8. EGFR • One of the ErbB family of tyrosine kinase receptors involved in growth and differentiation. • Known to be present on the surface of healthy cells and is abnormally expressed and activated in many tumor types including colorectal tumors. • Activation of EGFR by its ligands-EGF and transforming growth factor α, initiate downstream signaling mechanisms which in turn result in cellular growth, differentiation, and proliferation. Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  9. Cetuximab http://www.nature.com/nrd/journal/v3/n7/images/nrd1445-f1.jpg

  10. Cetuximab Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  11. Borner et al. 2008 • Cetuximab increases median overall survival 4 months • Median time to progression also increase under 2 months Borner M, et al. Adding cetuximab to capecitabine pluse oxaliplatin (XELOX) in first line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK. Annals of Oncology 2008;19:1288-1292

  12. Cetuximab • Extent of EGFR expression ≠ response/overall survival • Patients with no detectable EGFR have been shown to respond to cetuximab. Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221 Chung KY, Shia J, Kemeny NE. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. Journal of Clinical Oncology 2005;23:1803-10

  13. VEGF • Central to the entire angiogenic process. • VEGF molecule interacts with cell surface VEGF receptors • growth and differentiation of vascular endothelial cells. • formation of new blood vessels. Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  14. VEGF • Expressed by 40-60% of colorectal cancers • correlates with disease recurrence and survival • VEGF is involved in the angiogenic switch to vascular malignant growth of micrometastases, which can cause tumor relapse. Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221 Diaz-Rubio E., Schmoll Hans-Joachim. The Future Development of Bevacizumab in Colorectal Cancer. Oncology 2005;69(suppl 3):34-45

  15. Bevacizumab (Avastin) Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  16. Kabbinavar et al. Randomized trial of 104 previously untreated metastatic colorectal cancer to study the efficacy and safety of bevacizumab. Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  17. Benefit not as pronounced with given with newer generation of chemotherapy. Clinical studies with Avastin Avastin consistently extended median overall survival of metastatic CRC by approximately 4-5 months when given with earlier generation chemotherapy Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  18. Saltz LB et al. 2005 Increase response rate when Cetuximab and Avastin are given together. Study limited by small size. Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  19. Adjuvant Therapy • AVANT • NSABP CO8 • PETACC8 Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  20. HER2 • ~ 25-30% of breast tumors overexpress human epidermal growth factor receptor 2 • HER2 is part of the tyrosine kinase family, and overexpression is associated with aggressive disease and a poor prognosis. McKeage K, Lyseng-Williamson KA. Trastuzumab A pharacoeconomic review of its use in early breast cancer. Pharmacoeconomics 2008; 26(8) 699-719.

  21. Herceptin McKeage K, Lyseng-Williamson KA. Trastuzumab A pharacoeconomic review of its use in early breast cancer. Pharmacoeconomics 2008; 26(8) 699-719.

  22. Herceptin Plosker GL, Keam, SJ. Trastuzumab A review of its use in the management of HER2-positive metastatic and early-stage breast cancer. Drugs 2006;66(4)449-475.

  23. NSABP B-31 Plosker GL, Keam, SJ. Trastuzumab A review of its use in the management of HER2-positive metastatic and early-stage breast cancer. Drugs 2006;66(4)449-475.

  24. NSABP B-31 Absolute difference in disease free survival of 18% at 4 years Plosker GL, Keam, SJ. Trastuzumab A review of its use in the management of HER2-positive metastatic and early-stage breast cancer. Drugs 2006;66(4)449-475.

  25. Herceptin Adjuvant Trial • Disease-free survival rates at 2 years were 86% and 77% for patients in the 1 year trastuzumab group and those in the control group. • Using Kaplan-Meier estimates, this equates to an absolute disease-free survival benefit with Herceptin of 6.3% (80.6% vs. 74.3%) at 3 years. • Overall survival 59 vs. 90 deaths; HR 0.66. Absolute overall survival benefits of 2.7% at 3 years. McKeage K, Lyseng-Williamson KA. Trastuzumab A pharacoeconomic review of its use in early breast cancer. Pharmacoeconomics 2008; 26(8) 699-719. Plosker GL, Keam, SJ. Trastuzumab A review of its use in the management of HER2-positive metastatic and early-stage breast cancer. Drugs 2006;66(4)449-475. Piccart-Gebhart MJ, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast caner. NEJM 2005;353(16):1659-72

  26. What’s Ahead? • Subsets of patient? • Combination? • Timing? • Sequence? • At what cost? • Bevacizumab • £60,000-75,000 per QUALY ≈ HKD680,000-850,000 • Cetuximab • £20,000-37,000 per QUALY ≈ HKD226,000-419,000 Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  27. Conclusion • Monoclonal antibody therapy shows promise. • High cost • Further research required.

  28. Thank you

  29. http://images.encarta.msn.com/xrefmedia/aencmed/targets/illus/ilt/T059309A.gifhttp://images.encarta.msn.com/xrefmedia/aencmed/targets/illus/ilt/T059309A.gif

  30. Goodin S. Development of monoclonal antibodies for treatment of colorectal cancer. Am J Health-Syst Pharm. 2008,65 (Suppl 4):S3-7

  31. Takeuchi EE, Alison DL. What’s new in oncology: targeted therapy. Continuing Education in Anaesthesia, Critical Care & Pain. 2008; 8(1):36-8

  32. MAbs for Solid Tumors • Epidermal growth factor receptors are overexpressed or overactive in several solid cancers (e.g. breast, colon, lung, kidney and H&N cancers) • Vascular endothelial growth factor leads to formation of new blood vessels and the maintenance of existing blood vessels, resulting in tumor growth and metastasis. Takeuchi EE, Alison DL. What’s new in oncology: targeted therapy. Continuing Education in Anaesthesia, Critical Care & Pain. 2008; 8(1):36-8

  33. Cytotoxic monoclonal antibodies • 3 types • Unconjugated monoclonal antibodies are used in colorectal cancer and work by directly causing tumor cell death. • Conjugated monoclonal antibodies or immunotoxins are monoclonal antibodies conjugated with a potent toxin. • Radioimmunoconjugated (RICs) - monoclonal antibodies conjugated with radioisotopes. Goodin S. Development of monoclonal antibodies for treatment of colorectal cancer. Am J Health-Syst Pharm. 2008,65 (Suppl 4):S3-7

  34. Unconjugated MAbs • direct effect on tumor cell, including the induction of apoptosis. (Interference with EGFR) • direct antitumor effect by increasing the effect of or overcome resistance to a second agent • Prevent protein expression - bring about anti-idiotype antibody formation and subsequently cell death. • Indirect effects involve the monoclonal antibody binding to the cancer cell and inducing antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity by activating the host’s immune system to induce tumor lysis. Goodin S. Development of monoclonal antibodies for treatment of colorectal cancer. Am J Health-Syst Pharm. 2008,65 (Suppl 4):S3-7

  35. Colorectal Cancer • Chemotherapeutic options have extended beyond treatment with 5-FU alone: the benefits of oxaliplatin in combination with a fluoropyrimidine (F-FU or Xeloda) and irinotecan either alone or in combination with 5-FU are well recognized. • Clinical trial data indicate that following the diagnosis of advanced colorectal cancer access to all three active chemotherapeutic agents has almost doubled median survival from 10-12 months to more than 20 months. Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  36. Cetuximab • human-mouse chimeric IgG1 monoclonal antibody against the extracellular binding domain of the EGFR. • Competitively inhibits endogenous ligand binding and binds with high affinity to EGFR. Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221 http://cancercommentary.com/wp-content/uploads/2007/01/erbitux.jpg

  37. Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  38. Cetuximab (Erbitux) • Acneiform skin reaction, in up to 85% of patients • Severity of rash has now been correlated with an increased likelihood of clinical response. • Rash can be treated effectively with standard acne therapies and are rarely an indication to stop treatment. Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  39. Karapetis et al. 2008 • Benefit of cetuximab treatment was confined to patients who had a tumor with no K-ras mutation. • It had little or no effect in the presence of a K-ras mutation. Karapetis CS., Khambata-Ford S., Jonker DJ., et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359:1757-65. http://www.nature.com/modpathol/journal/v21/n2s/images/3801018f1.jpg

  40. Karapetis CS., Khambata-Ford S., Jonker DJ., et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359:1757-65.

  41. Saltz LB et al. 2005 Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  42. Bevacizumab • Consistently extend median overall survival of metastatic CRC patients by approximately 4-5 months, compared with chemotherapy alone. Diaz-Rubio E., Schmoll Hans-Joachim. The Future Development of Bevacizumab in Colorectal Cancer. Oncology 2005;69(suppl 3):34-45

  43. Bevacizumab • One of the most serious complication with Avastin is perforation of a viscus. • Avastin is therefore not indicated in squamous cell NSCLC that has a tendency to cavitate and may cause serious bleeding. Takeuchi EE, Alison DL. What’s new in oncology: targeted therapy. Continuing Education in Anaesthesia, Critical Care & Pain. 2008; 8(1):36-8

  44. AVANT • Open label, three arm phase II study Diaz-Rubio E., Schmoll Hans-Joachim. The Future Development of Bevacizumab in Colorectal Cancer. Oncology 2005;69(suppl 3):34-45

  45. NSABP • US Cooperative Group phase III study that is examining the benefit of adding Avastin to FOLFOX in 2600 patients. • resected stage II or III colon cancer will be stratified depending on the number of nodes involved. Diaz-Rubio E., Schmoll Hans-Joachim. The Future Development of Bevacizumab in Colorectal Cancer. Oncology 2005;69(suppl 3):34-45

  46. NICE • bevacizumab • £60,000-75,000 per QUALY • cetuximab • £20,000-37,000 per QUALY Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209-221

  47. HER2 status • Herceptin has the greatest effect in tumors that overexpress HER2 at a 3-positive by IHC or that are FISH positive. • recommendation in the UK is that HER2 status is determined in all primary breast tumors either by immunohistochemistry (IHC) or fluorescence in-situ hybridization (FISH), and that borderline IHC samples IHC 2 positive are retested by FISH. McKeage K, Lyseng-Williamson KA. Trastuzumab A pharacoeconomic review of its use in early breast cancer. Pharmacoeconomics 2008; 26(8) 699-719.

  48. NSABP B-31 Romond E?H, Perez EA, et al. Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer. NEJM 353;16:1673-84

  49. NSABP B-31 Romond E?H, Perez EA, et al. Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer. NEJM 353;16:1673-84

  50. Target therapy • The optimal combinations, timing, and sequence of agents and the subset of patients who stand to benefit most from a particular therapeutic intervention remain to be determined. • bevacizumab • £60,000-75,000 per QUALY • cetuximab • £20,000-37,000 per QUALY Hecht JR. Current and emerging therapies for metastatic colorectal cancer: Applying research findings to clinical practice.Am J Health-Syst Pharm 2008;65 (Spple 4): S15-21

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