Monoclonal antibody therapy in Surgical Malignancy Does it

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 Pickering L. , Rudman S. , Ross PJ. , Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209221

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

MAbs http: //approachepilepsy. com/home/modules/Drugs-MM/images/Monoclonal. Ab. jpg

MAbs for Solid Tumors EGFR VEGF Pickering L. , Rudman S. , Ross PJ. , Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209221

EGFR • One of the Erb. B 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: 209221

Cetuximab http: //www. nature. com/nrd/journal/v 3/n 7/images/nrd 1445 -f 1. jpg

Cetuximab Study Treatment Response Rate Saltz Irinotecan + Cetuximab 19% Cetuximab alone 11% Irinotecan + Cetuximab 23% 4. 1 months 8. 6 months Cetuximab alone 11% 1. 5 months 6. 9 months BOND Progression free survival Overall Survival Pickering L. , Rudman S. , Ross PJ. , Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209221

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

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: 209221 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

VEGF • Central to the entire angiogenic process. • VEGF molecule interacts with cell surface VEGF receptors Øgrowth and differentiation of vascular endothelial cells. Øformation 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: 209221

VEGF • Expressed by 40 -60% of colorectal cancers Øcorrelates • 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: 209221 Diaz-Rubio E. , Schmoll Hans-Joachim. The Future Development of Bevacizumab in Colorectal Cancer. Oncology 2005; 69(suppl 3): 34 -45

Bevacizumab (Avastin) Pickering L. , Rudman S. , Ross PJ. , Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209221

Kabbinavar et al. Randomized trial of 104 previously untreated metastatic colorectal cancer to study the efficacy and safety of bevacizumab. 5 mg/kg + 5 -FU/LV 10 mg/kg + + 5 -FU/LV Pickering L. , Rudman S. , Ross PJ. , Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209221

Clinical studies with Avastin Benefit not as pronounced with given with newer generation of chemotherapy. 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: 209221

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: 209221

Adjuvant Therapy • AVANT • NSABP CO 8 • PETACC 8 Pickering L. , Rudman S. , Ross PJ. , Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209221

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

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

Herceptin Plosker GL, Keam, SJ. Trastuzumab A review of its use in the management of HER 2 -positive metastatic and early-stage breast cancer. Drugs 2006; 66(4)449 -475.

NSABP B-31 Plosker GL, Keam, SJ. Trastuzumab A review of its use in the management of HER 2 -positive metastatic and early-stage breast cancer. Drugs 2006; 66(4)449 -475.

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 HER 2 -positive metastatic and early-stage breast cancer. Drugs 2006; 66(4)449 -475.

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. Mc. Keage 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 HER 2 -positive metastatic and early-stage breast cancer. Drugs 2006; 66(4)449 -475.

What’s Ahead? • Subsets of patient? • Combination? • Timing? • Sequence? • At what cost? • Bevacizumab • • £ 60, 000 -75, 000 per QUALY ≈ HKD 680, 000 -850, 000 Cetuximab • £ 20, 000 -37, 000 per QUALY ≈ HKD 226, 000 -419, 000 Pickering L. , Rudman S. , Ross PJ. , Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209221

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

Thank you

http: //images. encarta. msn. com/xrefmedia/aencmed/targets/illus/ilt/T 059309 A. gif

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

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

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

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): S 3 -7

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 antibodydependent 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): S 3 -7

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: 209221

Cetuximab • human-mouse chimeric Ig. G 1 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: 209221 http: //cancercommentary. com/wp-content/uploads/2007/01/erbitux. jpg

Pickering L. , Rudman S. , Ross PJ. , Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209221

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: 209221

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.

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.

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: 209221

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

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

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

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

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: 209221

HER 2 status • Herceptin has the greatest effect in tumors that overexpress HER 2 at a 3 -positive by IHC or that are FISH positive. • recommendation in the UK is that HER 2 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. Mc. Keage K, Lyseng-Williamson KA. Trastuzumab A pharacoeconomic review of its use in early breast cancer. Pharmacoeconomics 2008; 26(8) 699 -719.

NSABP B-31 Romond E? H, Perez EA, et al. Trastuzumab plus Adjuvant Chemotherapy for Operable HER 2 -Positive Breast Cancer. NEJM 353; 16: 1673 -84

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): S 15 -21

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

Breast Cancer • Trastuzumab (Herceptin) is the first HER-directed therapy to gain approval from the U. S. FDA for the treatment of patients with metastatic breast cancer. In preclinical studies, trastuzumab has been demonstrated to downregulate HER 2, lead to G 1 growth arrest and apoptosis, act as an angiogenic inhibitor, and have synergistic effect with doxorubicin, taxanes, vinorelbine, and flavopiridol in breast cancer cells. Response rates to trastuzumab given as a single agent ranged from 12% to 40%. Book

Hussain SA, et al. Molecularly targeted therapeutics for breast cancer. Biodrugs 2007; 21(4): 215 -224

HERA • 2005 • 127 disease-free survival events vs 220 in the trastuzumab and observation groups. • • Unadjusted hazard ratio of the risk o an event in trastuzumab group as compared to observation group 0. 54 which corresponded to an absolute benefit in disease-free survival of 8. 4% at two years Hazard ratio for time to distant recurrence in the trastuzumab group as compared with the observaion group was 0. 49 Piccart-Gebhart MJ, et al. Trastuzumab after Adjuvant Chemotherapy in HER 2 -Positive Breast Cancer. NEJM 353; 16: 1659 -72

NSABP B-31 and NCCTG N 9831 Trials • Herceptin given with chemotherapy improves the outcome in women with HER 2 -positive early breast cancer compared with those receiving conventional chemotherapy alone. • Disease-free survival events in the Herceptin treatment group was 133 compared with 261 in those receiving chemotherapy alone. (HR 0. 48) • • absolute disease-free survival benefit in favor of herceptin of 11. 8% at 3 years and 18. 2% at 4 years. Absolute overall survival benefit of 2. 6% at 3 years. Mc. Keage K, Lyseng-Williamson KA. Trastuzumab A pharacoeconomic review of its use in early breast cancer. Pharmacoeconomics 2008; 26(8) 699 -719.

C/I of Herceptin • LVEF <55% • history of documented congestive heart failure (CHF) • high risk uncontrolled arrhythmias • angina pectoris requiring medication • clinically significant valvular disease • evidence of transmural infarction on ECG Mc. Keage K, Lyseng-Williamson KA. Trastuzumab A pharacoeconomic review of its use in early breast cancer. Pharmacoeconomics 2008; 26(8) 699 -719. • poorly controlled hypertension.

Brain metastases • Symptomatic brain metastases occur in 10 to 16% of patients with metastatic breast cancer. • Survival after diagnosis of brain metastases usually in the region of 3 to 7 months. Church DN, et al. Extended survival in women with brain metastases from HER 2 overexpressing breast cancer. American Journal of Clinical Oncology. 2008; 31(3) 250 -4

Survival after Herceptin Church DN, et al. Extended survival in women with brain metastases from HER 2 overexpressing breast cancer. American Journal of Clinical Oncology. 2008; 31(3) 250 -4

Small molecules • Unlike MAbs, small molecule agents can permeate through plasma membranes and interact with the cytoplasmic domains of cell surface receptors and various intracellular signalling molecules that regulate cell proliferation, differentiation and apoptosis. • Protein tyrosine kinases are crucial mediators in such signalling pathways and many are deregulated in malignant cells, making them targets for therapeutic agents. Takeuchi EE, Alison DL. What’s new in oncology: targeted therapy. Continuing Education in Anaesthesia, Critical Care & Pain. 2008; 8(1): 36 -8

Glivec • first small molecule tyrosine kinase inhibitor to be approved for human cancer treatment in CML in 2001. • Selectively and competitively inhibiting the protein-tyrosine kinase activity associated with KIT receptors and platelet-derived growth factor receptor-α • resulting in inhibition of cell proliferation and apoptosis induction in-vitro in GIST cell lines, and arrest of tumor cell proliferation and decrease in tumor volume in-vivo. Takeuchi EE, Alison DL. What’s new in oncology: targeted therapy. Continuing Education in Anaesthesia, Critical Care & Pain. 2008; 8(1): 36 -8 Siddiqui MAA, Scott LJ. Imatinib A review of its use in the management of gastrointestinal stromal tumors. Drugs 2007; 67(5): 805 -820

Johnston SRD et al. Cancer Biology Clinical applications, Lumey Surgery 2003

GIST • characteristic feature of GIST is the expression of the KIT protein, a receptor tyrosine kinase encoded by the protooncogene KIT and activated by stem cell factor (SCF). • 5 -year survival rate in patients with radial resection have ranged from 48% to 65%. Siddiqui MAA, Scott LJ. Imatinib A review of its use in the management of gastrointestinal stromal tumors. Drugs 2007; 67(5): 805 -820

Glivec • QUALY $US 38, 723 Siddiqui MAA, Scott LJ. Imatinib A review of its use in the management of gastrointestinal stromal tumors. Drugs 2007; 67(5): 805 -820

Glivec Siddiqui MAA, Scott LJ. Imatinib A review of its use in the management of gastrointestinal stromal tumors. Drugs 2007; 67(5): 805 -820 69