Transcript Monoclonal Antibody Therapy in Surgical Malignancy: Does it Work

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):S3-7
MAbs
Goodin S. Development of monoclonal antibodies for treatment of colorectal cancer. Am J Health-Syst Pharm. 2008,65 (Suppl 4):S3-7
MAbs
http://approachepilepsy.com/home/modules/Drugs-MM/images/MonoclonalAb.jpg
MAbs
http://approachepilepsy.com/home/modules/Drugs-MM/images/MonoclonalAb.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
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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: 209221
Cetuximab
http://www.nature.com/nrd/journal/v3/n7/images/nrd1445-f1.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
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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
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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: 209221
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: 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.
5mg/kg + 5-FU/LV
10mg/kg + + 5-FU/LV
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 CO8
•
PETACC8
Pickering L., Rudman S., Ross PJ., Leslie MD. Targeted therapy in colorectal carcinoma: more than a theory. Colorectal Disease. 2008, 10: 209221
HER2
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~ 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.
Herceptin
McKeage 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 HER2-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 HER2-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 HER2-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.
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.
What’s Ahead?
•
Subsets of patient?
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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: 209221
Conclusion
•
Monoclonal antibody therapy shows promise.
•
High cost
•
Further research required.
Thank you
http://images.encarta.msn.com/xrefmedia/aencmed/targets/illus/ilt/T059309A.gif
Goodin S. Development of monoclonal antibodies for treatment of colorectal cancer. Am J Health-Syst Pharm. 2008,65 (Suppl 4):S3-7
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
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3 types
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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
Unconjugated MAbs
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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
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Prevent protein expression - bring about anti-idiotype antibody formation and subsequently cell death.
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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):S3-7
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 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: 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)
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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
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.
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
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
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
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 HER2, lead to G1 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 HER2-Positive Breast Cancer. NEJM 353;16:1659-72
NSABP B-31 and NCCTG N9831
Trials
•
Herceptin given with chemotherapy improves the
outcome in women with HER2-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.
McKeage 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
McKeage 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 HER2 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 HER2 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 $US38,723
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
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