Antiangiogenic Therapy in colorectal cancer

Anti-Angiogenic Therapy in Metastatic Colorectal Cancer

Mohamed Abdulla M.D.

Prof. of Clinical Oncology

Cairo University

ROHCE Meeting - Asyut – 06/12/2017

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:

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.

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

Could we do better?

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

Formation of Blood Vessels:Hemangioblast

Endothelial Cells Hematopoeitic

Extensive Branching 1ry Capillary

Network

Lamalice et al. Circ Res.2007;100:782-794

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

Control of Angiogenesis:

Growth Factor

Monoclonal Antibody

Normally Existing

++ By The Tumor

TK

1

2

3

Activated Receptor

Cross Talk with Nucleus

Malignant Cascade

Hypoxia

HIF

VEGF Gene

VEGF/R VEGFR on Nearby Vessels VEGFR on Tumor Vessels

Angiogenic Switch:

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

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:

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.

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.

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.

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

Phase III Trials: Anti-Angiogenic Therapies in mCRC

J.M. Clarke et al. / Cancer Treatment Reviews 40 (2014) 1065–1072

Anti-Angiogenic Agents in Maintenance Trials:

Aprile et al. Clinical Colorectal Cancer, 2016. Vol. 15, No. 1, 7-15

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

Tomasello et al. JAMA Oncol. 2017;3(7):e170278. doi:10.1001/jamaoncol.2017.0278

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

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

Anti-EGFR or Anti-VEGF/R in RAS-Wild mCRC: Evidence from Literature:

Anti-EGFR > Anti-VEGF A1. ORR2. OAS

Stintzing et al. Lancet Oncol 2016; 17: 1426–34

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

• 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??

CALGB 80405: OAS

Alan P. Venook, MD et al. JAMA June 20, 2017 Volume 317, Number 23

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)

Petrelli et al. Jama Oncology. 2017 Vol 3 Number 2

66 RCT = 1437846 Colon Cancer Patients

Location as an Independent Prognostic Factor:

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

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.

4. Pre-Neoplastic Lesions:

Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017

Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017

Molecular Alterations in CRC:

Molecular Alterations in CRC:

Stintzing et al. European Journal of Cancer 84 (2017) 69e80

Molecular Alterations in CRC:

Stintzing et al. European Journal of Cancer 84 (2017) 69e80

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.

Right Versus Left Sided Colon Cancer OAS & Anti-EGFR:

Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564

Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564

Right Versus Left Sided Colon Cancer PFS & Anti-EGFR:

TEJPAR et al. JAMA Oncology February 2017 Volume 3, Number 2

Kerr et al.Lancet Oncol 2016; 17: 1543–57

Adverse Events with Anti-Angiogenic Therapy:

CartwrightTH. Clinical Colorectal Cancer, 2013 Vol. 12, No. 2, 86-94

Anti-Angiogenic Therapy: Drug Interactions:

CartwrightTH. Clinical Colorectal Cancer, 2013 Vol. 12, No. 2, 86-94

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

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.