Angiogenesis:
Using Old and New Approaches
John Mackey, MD
Professor of Oncology
University of Alberta
Edmonton, Canada
Faculty Disclosure
John R. Mackey, MD, FRCP (C), has disclosed that he has
received consulting fees from Eli Lilly and Roche and CME
honoraria from Amgen.
Overview
 Angiogenesis and the VEGF/VEGF-R pathway
 New mechanisms and new agents
 The metastatic / adjuvant gulf
 Toward predictive biomarkers
Angiogenesis
 Physiologic process of new blood vessel formation
 Principally driven by interactions between vascular
endothelial growth factors and 3 high-affinity VEGF
receptors
Folkman J. Semin Oncol. 2002;29(suppl 6):15-18.
Hicklin DJ, et al. J Clin Oncol. 2005;23:1011-1027.
VEGF Family of Ligands and Receptors
VEGF- A121
VEGF- A145
VEGF- A165
VEGF- A189
VEGF- A206
VEGF- B167
VEGF- B186
PlGF- 1,2
VEGF- E
VEGF- C
VEGF- D
Y
s-s
VEGFR-1
(Flt-1)
NRP-1
Vasculogenesis
Angiogenesis
VEGFR-2
(Flk-1/KDR)
s-s
VEGFR-3
(Flt-4)
NRP-2
Lymphangiogenesis
An Obvious Target . . .
Agents Targeting the VEGF Pathway
VEGF-A
Anti-VEGF
antibodies
(bevacizumab)
Soluble
VEGF
receptors
(aflibercept)
Anti-VEGFR2
antibodies
(ramucirumab)
VEGFR-1
P
P
P
P
VEGFR-2
P
P
P
P
VEGFR-3
P
P
P
P
Endothelial cell
Agents in yellow = FDA approved
Small-molecule inhibitors of VEGFR
(PTK-787, AZD2171, motesanib,
sunitinib, sorafenib, pazopanib, axitinib, others)
Agents Targeting the VEGF Pathway
 Anti-VEGF antibodies
– Bevacizumab
 Anti–VEGFR-2 antibodies
– Ramucirumab (IMC-1121B)
 Soluble VEGF receptors
– Aflibercept (VEGF Trap)
 Small-molecule VEGFR
inhibitors
– Vatalanib (PTK787)
– AZD2171
– Sunitinib (SU11248)
– Sorafenib (BAY 43-9006)
– Motesanib (AMG 706)
– Pazopanib
– AG-013736
– Others
Antiangiogenic
Risk:Benefit Ratio
Toxicity
Efficacy
Antiangiogenic
Class Toxicities
 Hypertension
 Clotting
 Bleeding
 Congestive heart failure (when combined with
anthracyclines)
 Financial
 Agent-specific toxicities
– Motesanib: cholecystitis
– Pigmentation changes: sunitinib, pazopanib
Gressett SM, et al. Ann Pharmacother. 2009;43:490-501. Blumenschein GR Jr, et al. Ann Oncol. 2011;[Epub ahead of print].
Rosenbaum SE, et al. Support Care Cancer. 2008;16:557-566. Bible KC, et al. Lancet Oncol. 2010;11:962-972.
Therapeutic Efficacy
 Modest, in general …
 Colorectal carcinoma – M1
 Non-small-cell lung carcinoma – M1
 Renal cell carcinoma – M1
 Breast cancer – M1
 No evidence of adjuvant efficacy thus far
– 2 negative studies in M0 CRC (C-08, AVANT)
Adjuvant Antiangiogenic Therapy?
Bevacizumab
 Best studied agent
 Modest efficacy in a number of indications
 Resistance mechanisms
– Upregulation of ligand
– Insoluble VEGF remains and promotes angiogenesis?[1]
– VEGFR-1 polymorphisms (constitutive activation)?[2]
 No validated predictive marker
– Potential high serum VEGF levels?
1. Chen TT, et al. J Cell Biol. 2010;188:595-609.
2. Lambrechts D, et al. ECCO-ESMO 2009. Abstract 16LBA.
New Data on Newer Agents
 Ramucirumab
 Aflibercept
Ramucirumab
 Fully humanized antibody directed against the VEGFR-2
 Potential for immune-mediated destruction of angiogenic
vessels
 Circumvents insoluble VEGF activation of VEGFR-2
 In phase II trials for MBC, advanced GI cancers,
metastatic GU cancers, recurrent ovarian cancer, prostate
cancer, metastatic RCC
 In phase III trials for refractory metastatic gastric
adenocarcinoma, advanced NSCLC, relapsed
hepatocellular carcinoma, metastatic CRC
Spratlin and Mackey. Future Oncol. 2010;6:1085-1094.
TRIO-012 Ramucirumab Study
 Patient population
 Women with HER2-negative, unresectable, locally recurrent or
metastatic breast cancer with or without measurable lesions
 No previous chemotherapy for metastatic or locally recurrent and
inoperable breast cancer
RANDOMIZATION
 Study plan
Docetaxel 75 mg/m² IV q3w
2/3
1/3
…..
Blinded ramucirumab 10 mg/kg
IV q3w
Docetaxel 75 mg/m² IV q3w
Blinded placebo IV q3w
Mackey J, et al. Clin Breast Cancer. 2009;9:258-261.
…..
Progressive
disease
Or
unacceptable
toxicity
Or
withdrawn
consent
F/UP
Aflibercept
 Fusion protein decoy receptor: binds VEGF-A, VEGF-B,
and placental growth factor
 Achieved primary endpoint (OS) in VELOUR phase III
clinical trial for second-line treatment of mCRC
– 1266 mCRC patients FOLFIRI vs FOLFIRI + aflibercept
improved OS
Regeneron [press release]. Available at:
http://investor.regeneron.com/releasedetail.cfm?ReleaseID=571966. Accessed May 25, 2011.
Motesanib
 Small molecule inhibitor of VEGFR-1, VEGFR-2, VEGFR3, PDGFR, and KIT
 Increases activity of paclitaxel in MBC in randomized
phase II setting, but with significant GI toxicity
Martin MM, et. al. Lancet Oncol. 2011;12:369-376.
TRIO-010 Motesanib Study
R
A
N
D
O
M
I
Z
A
T
I
O
N
Arm A
Paclitaxel
90 mg/m² IV weekly for 3/4 wks
Blinded placebo
PO daily
Arm B
Paclitaxel
90 mg/m² IV weekly for 3/4 wks
Blinded motesanib
125 mg PO daily
Arm C
N = 282
Roll-over (optional)
PD
Open-label motesanib
125 mg PO daily
Treatment until
Paclitaxel
90 mg/m² IV weekly for 3/4 wks
Open-label bevacizumab
10 mg/kg on Week 1 and Week 3
Stratified by:
 Previous taxane CT vs other vs none
 Number of metastatic sites (< 3 vs ≥ 3)
 Hormone receptor status (positive vs negative)
Martin MM, et. al. Lancet Oncol. 2011;12:369-376.
- Progressive disease
- Unacceptable toxicity
- Consent withdrawal
Vascular Disrupting Agents
 drugs designed to damage the established vasculature of
tumors causing central necrosis
– Flavinoid compounds
– ASA404
Phase III (NSCLC)
– microtubule destabilizers
– CA4P
Phase II/III
– AVE8062
Phase III; sarcoma)
– ABT-751
Phase II (multiple histologies)
– Dolastatin
Phase II
– Oxi4503
Phase I
 Due to residual rim of viable cells, combination therapy
may be required
Angipoietin -TIE Receptor Pathway
 TIE-1 and TIE-2 are cell-surface receptors that bind and
are activated by angiopoietins (ANGPT1, ANGPT2, and
ANGPT4)
 Play crucial role in angiogenic switch
 Agents targeting ANG1 anad ANGPT2 are in phase II
clinical trials and early reports suggest anti-tumor activity
and a safety profile distinct from anti-VEGFA agents
 Substantial combination benefit of targeting both ANGPT2
and VEGFA pathways preclinically
Agents Targeting the ANGPT-TIE Pathway
Compound
Target
Status
AMG-386
ANGPT1 and 2
phase II studies report
OS advantage in ovarian
CA; phase III
PF-4856884
ANGPT2
phase II
CEP-11981
TIE2 and VEGF-R
phase I
ANGPT2 aptamer
ANGPT2
preclinical
How Can We Move Beyond Empiricism?
 Predictive assays
Therapeutic Predictive Assays
 Prognostic biomarker
– “How bad is my cancer, Doc?”
 Predictive biomarker
– “Is this drug going to work?”
Exposure Biomarkers
 Measure biologic response after administration of the drug
 Include:
– Treatment-emergent hypertension
– Changes in serum VEGF, shed VEGFR-2, PIGF
– Changes in dynamic-contrast MRI
 Have been useful in defining pharmacodynamically
appropriate doses and schedules
 Do not address whether or not to start antiangiogenic
therapy in a given patient
Rini B, et al. J Natl Cancer Inst. 2011;103:763-773. Schneider BP. J Clin Oncol. 2008;26:4672-4678.
Vlahovic G, et al. J Thoracic Oncol. 2007;8:S745.
Tumor-Based Predictive Markers
 Baseline tumor VEGF levels
– Prognostic but not predictive
 Low levels of carbonic anhydrase IX[1]
 Von Hippel-Lindau loss of function mutations in M1 renal
cell carcinoma[2]
 HER2 positivity in breast cancer
– Associated with high levels of VEGF, independently
prognostic[3]
1. Hong YS, et. al. BMC Cancer. 2009;9:246 2. Choueri et. al. J Urol 2008. 3. Konecny GE, et. al. Clin
Cancer Res. 2004;10:1706-1716
Blood-Based Biomarkers
 Baseline circulating VEGF levels
– Variably prognostic, but not predictive[1]
 Circulating endothelial cell enumeration
– May be prognostic in some malignancies[2,3]
– Not yet shown to be predictive
1. Kaseb AO, et al. Cancer. 2009;115:4895-4906. 2. Batchelor T, et al. ASCO 2007. Abstract 2001.
3. Ramalingam SS, et al. ASCO 2008. Abstract 8078.
Host-Based Predictive Biomarkers
 Angiogenesis is a response of normal stroma to signals
from the cancer
 Germ-line genetic variability may contribute to efficacy and
toxicity
 E2100 MBC paclitaxel ± bevacizumab
– VEGF-2578AA and VEGF-1154AA genotypes had higher
OS in combination[1]
 Constitutive activation of VEGFR-1 pathway?[2]
1. Schneider BP, et al. Clin Cancer Res. 2009;15:5297-5302. 2. Lambrechts D, et al. ECCO-ESMO 2009.
Abstract 16LBA.
SNPs Relate to Survival in MBC/
Bevacizumab?
 Small subset, tumor DNA, unclear how many SNPs
evaluated
Schneider BP, et al. Clin Cancer Res. 2009;15:5297-5302.
The State of Published
Antiangiogenic Trials
In general . . .
 Unselected cancers
 Treat entire population with novel therapy
 Minimal and/or retrospective tissue collection
 Unplanned retrospective subset analysis
Ongoing Antiangiogenic Trials . . .
 Molecular rationale
 Up-front tumor and somatic tissue accrual
 Molecular stratification prior to therapy
– (If any hint of predictive marker)
 Prespecified statistical assessment of biomarker
performance
Will We Find a Predictive Marker for
Antiangiogenic Therapy?
“It’s difficult to make predictions,
especially about the future.”
A Tale of 2 Trials
 Adjuvant chemotherapy in operable breast cancer
 Standard therapy vs standard therapy + 1 yr of
bevacizumab N ~ 3000 patients
ClinicalTrials.gov. NCT00625898.
ClincialTrials.gov. NCT00528567.
Preconditions for a VEGF Pathway
Predictive Biomarker
 Agent inhibits this pathway
 Pretreatment biology drives the therapeutic response
 Compensatory non-VEGF–mediated pathways are
irrelevant
 Randomized clinical trials with appropriate biologic
samples
 Clinical efficacy signal is sufficiently strong in the sensitive
subpopulation to drive a statistically significant interaction
test
Why BETH Should Be a Positive Trial
 Preselected population
with VEGF-driven
biology[1]
 Preclinical (and apparent
clinical) synergy between
HER2 inhibitors and
antiangiogenic therapy[2-4]
1. Konecny GE, et. al. Clin Cancer Res. 2004;10:1706-1716. 2. Peagram M, et al. SABCS 2006. Abstract 301.
3. Blackwell KL, et al. SABCS. Abstract 61. 4. Slamon DJ, et al. SABCS 2008. Abstract 4114.
Why BEATRICE May Be a Negative Trial
 VEGF does not appear to be the key angiogenic driver of
relapse in triple-negative breast cancer
– Alberta Breast Cancer Relapse Study
– Mackey J, et. al. unpublished
University of Alberta Breast Study
Case-Control Selection
Biomarker Selection
Triple-Negative Cohort: Proangiogenic Factor
(Non-VEGF Related)
Funding
Collaborators
 Raymond Lai, MD, PhD
 Cheryl Santos, MSc
 Kathryn Graham, PhD
 Roger Tsang, MD
Prediction on Predictive Assays for VEGF
Pathway Inhibitors . . .
 HER2 will be the marker of selective benefit from adjuvant
antiangiogenic therapy in breast cancer
 Multiplex solutions required for other cancers
– Integrate tumor factors
– Identify VEGF-dependent cancers
– Integrate host factors
– Constitutive upregulation of non–VEGFR-1 pathway or nonVEGF proangiogenic pathways
Take Home Messages
 Antiangiogenic agents have modest population benefit in
some metastatic settings
 Progress will require better agents or more appropriately
selected patient populations
 No predictive biomarker has been validated
 The most promising candidates include
– HER2 positivity in breast cancer
– Multiplexed approaches
– Identifying VEGF-driven tumors
– Integration with host factors