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Anti-Angiogenic Therapy in Metastatic Colorectal Cancer
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
ROHCE Meeting - Asyut – 06/12/2017
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Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag, Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Ely Lilly.
Speaker Disclosures:
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Definition of Cancer:
“Large family of diseases that involve abnormalcell growth with the potential to invade orspread to other parts of the body”
World Health Organization. February 2014.
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The Cell Cycle:G0
G1
SG2
M
Class Example Method of Action Cycle Specific
Alkylating agents Cytoxan Effects DNA chemically All
Antimetabolites 5-FUGemzar
Substitutes for normal cell building blocks
S
Anthracyclines Adriamycin DNA damage or inhibit topoisomerase All
Anti-tumor Antibiotics Bleomycin DNA damage All
Topoisomerase Inhibitors Irinotecan Complex DNA and topoisomerasetogether
SG-2
Vinca Alkaloids Vincristine Binds to tubulin, interferes with mitosis M
Taxanes TaxolTaxotere
Prevents microtubules from disassociating
M
Chow. 2010, Nature Education 3(9):7
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Could we do better?
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Biography of cancer:
Normal Mother Cells Normal Daughter Cells
Abnormal Daughter Cells
Programed Cell Death: APOPTOSIS
RESISTANCE TO APOPTOSIS
Continued Un-opposed Proliferation
Malignant TumorPROGRESSION, Invasion &
MetastasesANGIOGENESIS
• Life• Growth• Maintenance
P53
+++Growth Signals
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Formation of Blood Vessels:Hemangioblast
Endothelial Cells Hematopoeitic
Extensive Branching 1ry Capillary
Network
Lamalice et al. Circ Res.2007;100:782-794
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Formation of New Blood Vessels = Angiogenesis
Physiological
Wound Healing
Placental Implantation
Growth
Pathological
Pre-Eclampsia
Diabetic Retinopathy
Tumors
Formation of Blood Vessels:
Lamalice et al. Circ Res.2007;100:782-794
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Control of Angiogenesis:
Growth Factor
Monoclonal Antibody
Normally Existing
++ By The Tumor
TK
1
2
3
Activated Receptor
Cross Talk with Nucleus
Malignant Cascade
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Hypoxia
HIF
VEGF Gene
VEGF/R VEGFR on Nearby Vessels VEGFR on Tumor Vessels
Angiogenic Switch:
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Tyrosine Kinase Receptors
VEGFR - 1 VEGFR - 2 VEGFR - 3 NRP - 1 NRP - 2
VEGFs
VEGF - A VEGF - B VEGF - C VEGF - D PlGF
VEGF & VEGFR: “The Key & Lock”
Bates Cardiovascular Research (2010) 87, 262–271
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VEG
FR
AKT
Grb SOS
mTOR
Protein Synthesis
HIF-1@Metabolism
Growth
Angiogenesis
RAS
RAF
Mek
Erk
Cell Cycle Progression , Proliferation & Angiogenesis
1. Avastin [package insert]. South San Francisco, CA: Genentech; 2009. 2. Escudier B et al; TARGET Study Group. N Engl J Med. 2007;356:125-134. 3. Escudier B et al. J Clin Oncol. 2009;27:3312-3318. 4. Nexavar [package insert]. Wayne, NJ: Bayer
Healthcare Pharmaceuticals; 2007.
Bevacizumab
RAD 001
TKI, Proliferation Cascades & Angiogenesis:
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New Blood
Vessel
Proliferation
Release of GFsReceptor
Activation
Degradation &
Proteolytic Enz.
Disruption of
ECM & Wall
Invasion &
Migration
Mechanism of Angiogenesis:
Dovrak etal. Am J Pathol. 1995;146(5):1029.
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VEGF A:
• Stimulation of Endothelium Proliferation.
• Enhanced Endothelial Survival.
• Control of Vascular Permeability.
• Enhanced ECM Degradation Vascular Migration.
Dovrak etal. Am J Pathol. 1995;146(5):1029.
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Angiogenesis in Malignancy:
Monoclonal Antibody
Soluble Receptor
TKI
Tumor GFEndogenous GF HIF, COX2,IL-6β
EGF/RPDGF/ROthers
mTOR Inhibitors
Miles et al. J Clin Oncol. 2011;29(1):83. Epub 2010 Nov 22.
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Tribute to History of Angiogenesis:
1787Angiogenesis in Reindeer
Antler
Dr. John Hunter
1971Angiogenesis Dependent
Tumor Growth
Dr. Judah Folkman
1975
1st
Angiogenesis Inhibitor
(in Cartilage)
Dr. Henry Brem
19841st Angiogenic
Factor (bFGF)
Dr. Michael Klagsbrun
1989Discovery
OfVEGF
Dr. Napoleon Ferrara
1997Angio- &
EndostatinCR in Cancer
Dr. Michael O’Reilly
1999Dr.
Richard Klaussner
Director of the U.S. NCI
designates the development of
anti-angiogenic therapies for cancer as a national priority.
2003
2017
1st
Line
2nd
Line
3rd
Line
• Beyond Progression• Maintenance• Tumor Shrinkage• RAS Wild/Mutant• ≅ Anti-EGFR MoAb• Not Adjuvant ttt.
No Predictive Markers
BRAF Mutant
Triplet + Bevacizumab
Right & Left Sided Colon Cancer
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Phase III Trials: Anti-Angiogenic Therapies in mCRC
J.M. Clarke et al. / Cancer Treatment Reviews 40 (2014) 1065–1072
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Anti-Angiogenic Agents in Maintenance Trials:
Aprile et al. Clinical Colorectal Cancer, 2016. Vol. 15, No. 1, 7-15
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Antiangiogenic Therapy in BRAF Mutated Patients:
Roma et al. CANCER BIOLOGY & THERAPY 2016, VOL. 17, NO. 8, 840–848Cremollini et al. Lancet Oncol 2015; 16: 1306–15
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Tomasello et al. JAMA Oncol. 2017;3(7):e170278. doi:10.1001/jamaoncol.2017.0278
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First Head-to-Head Comparisons of First-Line Bevacizumab Versus EGFR Inhibitors in KRAS WTmCRC
1. Schwartzberg LS, et al. J Clin Oncol. 2014;32(21):2240-2247. 2. Heinemann V, et al. Lancet Oncol. 2014;15(10):1065-1075.3. Venook A, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA3.
PEAK1
Phase II
Untreated –Unresectable mCRC
N = 285
Bevacizumab + mFOLFOX6
Panitumumab + mFOLFOX6
FIRE-32
Phase III
Untreated mCRC
N = 592
Bevacizumab + FOLFIRI
Cetuximab + FOLFIRI
CALGB-804053
Phase III
Untreated mCRC
N = 1200
Bevacizumab +
FOLFIRI or FOLFOX
Cetuximab
+ FOLFIRI or FOLFOX
No Hypothesis
OAS
ORR
DP
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FIRE-3 Trial: FOLFIRI + Either Cetuximab orBevacizumab in KRAS WT mCRC
Heinemann V, et al. Lancet Oncol. 2014;15(10):1065-1075.
HR 0.77P .011
Parameter Chemo + CET Chemo + Bev P
ORR (%) 62 58 .183
PFS (ms) 10 10.3 .547
OAS Dif. = 8.5 ms
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Anti-EGFR or Anti-VEGF/R in RAS-Wild mCRC: Evidence from Literature:
Anti-EGFR > Anti-VEGF A1. ORR2. OAS
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Stintzing et al. Lancet Oncol 2016; 17: 1426–34
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Modest et al. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology
Item Arm A Arm B HR P
PFS 6.5 m 4.7 m 0.68 < .001
OAS 16.3 m 13.2 m 0.70 .0021
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• 52.2% in Arm B Anti-EGFR MOAb• 30.2% in 2nd Line • 22% in 3rd Line
• No Reporting on Associated Chemotherapy
• Is Chemotherapy Sequence the BEST??
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CALGB 80405: OAS
Alan P. Venook, MD et al. JAMA June 20, 2017 Volume 317, Number 23
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80405: (KRAS WT) Overall Survival by Sidedness
Presented by:ASCO ANNUAL MEETING ‘16
SideN
(Events)
Median
(95% CI)
HR
(95% CI)p
Left 732 (550)33.3
(31.4-35.7) 1.55
(1.32-1.82)
<
0.0001Right 293 (242)
19.4
(16.7-23.6)
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Petrelli et al. Jama Oncology. 2017 Vol 3 Number 2
66 RCT = 1437846 Colon Cancer Patients
Location as an Independent Prognostic Factor:
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Right versus Left Colon:Why different disease entities?
Different:• Blood Supply• LN Drainage
1. Embryologic Origin2. Blood Supply & Nodal Drainage
3. Microbiome Difference
4. Precancerous Lesions.
6. Histopathology & Natural History
5. Consensus Molecular Subtypes.
Stintzing et al. European Journal of Cancer 84 (2017) 69e80
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3. Microbiome Difference:
Right Colon Cancer Left Colon Cancer
Prevotella, Pyramido-bacterium, Selenomonas and Peptostreptococcus.
Fusobacterium, Escherichia-Shigellaand Leptotrichia
Escherichia coli phylogroup B2. Helicobacter pylori infection
Dense Bacterial Aggregates
1. E-Cadherin2. IL-63. STAT3
Cellular Proliferation
Invasion of Colonic Mucous LayerProinflammatory Genes
Flemer et al. Tumour-associated and non-tumour- associated microbiota in colorectal cancer. Gut 2017;66(4): 633e43.
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4. Pre-Neoplastic Lesions:
Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017
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Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017
Molecular Alterations in CRC:
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Molecular Alterations in CRC:
Stintzing et al. European Journal of Cancer 84 (2017) 69e80
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Molecular Alterations in CRC:
Stintzing et al. European Journal of Cancer 84 (2017) 69e80
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5. Consensus Molecular Subtypes (CMS):
RIG
HT
CO
LON
LEFT
CO
LON
BETTER OUTCOME
WORSE OUTCOME
Guinney et al. Nature Medicine. 21,1350-1356 (2015)Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017.
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Right Versus Left Sided Colon Cancer OAS & Anti-EGFR:
Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564
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Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564
Right Versus Left Sided Colon Cancer PFS & Anti-EGFR:
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TEJPAR et al. JAMA Oncology February 2017 Volume 3, Number 2
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Kerr et al.Lancet Oncol 2016; 17: 1543–57
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Adverse Events with Anti-Angiogenic Therapy:
CartwrightTH. Clinical Colorectal Cancer, 2013 Vol. 12, No. 2, 86-94
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Anti-Angiogenic Therapy: Drug Interactions:
CartwrightTH. Clinical Colorectal Cancer, 2013 Vol. 12, No. 2, 86-94
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Treatment Platform in mCRC:mCRC
RAS Mutant
RAS Wild
BRAF Mutant
FOLFOX/FOLFIRI/ FOLFOXIRI
+ Bevacizumab
FOLFOXIRI + Bevacizumab
Right Colon Left Colon
FOLFOX/FOLFIRI + Anti-EGFR/VEGF
Alternate Doublet + Biologic
Regorafinib or TAS102 or
Trial
Anti-EGFR + BRAF +/- MEK Inhibitor +/-
Cytotoxic
Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564
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Art of Today:
• Angiogenesis is an appealing target in cancer management.
• Anti-Angiogenic Therapies had contributed positively in treatment platform of mCRC.
• Anti-Angiogenic Therapies are proved effective in different treatment scenarios (Bevacizumab 1st Line & beyond progression, 2nd & 3rd Lines Aflibercept, Ramucirumab & Regorafinib).
• Care must be taken for toxicity and drug to drug interactions.
• More work is mandatory for biomarker assessment and adjuvant treatment.
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