Angiogenesis: Using Old and New Approaches

1
Angiogenesis Using Old and New Approaches

• John Mackey, MD
• Professor of Oncology
• University of Alberta
• Edmonton, Canada

2
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.

3
Overview

• Angiogenesis and the VEGF/VEGF-R pathway
• New mechanisms and new agents
• The metastatic / adjuvant gulf
• Toward predictive biomarkers

4
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. 200229(suppl
6)15-18. Hicklin DJ, et al. J Clin Oncol.
2005231011-1027.
5
VEGF Family of Ligands and Receptors
VEGF- A121 VEGF- A145 VEGF- A165 VEGF- A189 VEGF-
A206
VEGF- B167 VEGF- B186 PlGF- 1,2
VEGF- C VEGF- D
VEGF- E
Y
s-s
s-s
VEGFR-1 (Flt-1)
VEGFR-2 (Flk-1/KDR)
VEGFR-3 (Flt-4)
NRP-1
NRP-2
Vasculogenesis Angiogenesis
Lymphangiogenesis
6
An Obvious Target . . .
7
Agents Targeting the VEGF Pathway
VEGF-A
Anti-VEGFR2antibodies(ramucirumab)
Anti-VEGFantibodies(bevacizumab)
SolubleVEGFreceptors(aflibercept)
VEGFR-3
VEGFR-2
VEGFR-1
Endothelial cell
Agents in yellow FDA approved
Small-molecule inhibitors of VEGFR (PTK-787,
AZD2171, motesanib,sunitinib, sorafenib,
pazopanib, axitinib, others)
8
Agents Targeting the VEGF Pathway

• Anti-VEGF antibodies
• Bevacizumab
• AntiVEGFR-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

9
AntiangiogenicRiskBenefit Ratio
Efficacy
Toxicity
10
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.
200943490-501. Blumenschein GR Jr, et al. Ann
Oncol. 2011Epub ahead of print. Rosenbaum SE,
et al. Support Care Cancer. 200816557-566.
Bible KC, et al. Lancet Oncol. 201011962-972.
11
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)

12
Adjuvant Antiangiogenic Therapy?
13
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. 2010188595-609.
2. Lambrechts D, et al. ECCO-ESMO 2009. Abstract
16LBA.
14
New Data on Newer Agents

• Ramucirumab
• Aflibercept

15
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.
201061085-1094.
16
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
• Study plan

Progressive disease Or unacceptable toxicity Or
withdrawn consent
Docetaxel 75 mg/m² IV q3w
RANDOMIZATION
..
2/3
F/UP
Blinded ramucirumab 10 mg/kg IV q3w
Docetaxel 75 mg/m² IV q3w
..
1/3
Blinded placebo IV q3w
Mackey J, et al. Clin Breast Cancer.
20099258-261.
17
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?Re
leaseID571966. Accessed May 25, 2011.
18
Motesanib

• Small molecule inhibitor of VEGFR-1, VEGFR-2,
  VEGFR-3, 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. 201112369-376.
19
TRIO-010 Motesanib Study
Paclitaxel 90 mg/m² IV weekly for 3/4 wks
Roll-over (optional)
RANDOM I ZAT I ON
Arm A
Open-label motesanib 125 mg PO daily
PD
Blinded placebo PO daily
Paclitaxel 90 mg/m² IV weekly for 3/4 wks
Arm B

• Treatment until
• Progressive disease
• Unacceptable toxicity
• Consent withdrawal

Blinded motesanib 125 mg PO daily
Paclitaxel 90 mg/m² IV weekly for 3/4 wks
Arm C
Open-label bevacizumab 10 mg/kg on Week 1 and
Week 3
N 282

• Stratified by
• Previous taxane CT vs other vs none
• Number of metastatic sites (lt 3 vs 3)
• Hormone receptor status (positive vs negative)

Martin MM, et. al. Lancet Oncol. 201112369-376.
20
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

21
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

22
Agents Targeting the ANGPT-TIE Pathway
23
How Can We Move Beyond Empiricism?

• Predictive assays

24
Therapeutic Predictive Assays

• Prognostic biomarker
• How bad is my cancer, Doc?
• Predictive biomarker
• Is this drug going to work?

25
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.
2011103763-773. Schneider BP. J Clin Oncol.
2008264672-4678. Vlahovic G, et al. J Thoracic
Oncol. 20078S745.
26
Tumor-Based Predictive Markers

• Baseline tumor VEGF levels
• Prognostic but not predictive
• Low levels of carbonic anhydrase IX1
• Von Hippel-Lindau loss of function mutations in
  M1 renal cell carcinoma2
• HER2 positivity in breast cancer
• Associated with high levels of VEGF,
  independently prognostic3

1. Hong YS, et. al. BMC Cancer. 20099246 2.
Choueri et. al. J Urol 2008. 3. Konecny GE, et.
al. Clin Cancer Res. 2004101706-1716
27
Blood-Based Biomarkers

• Baseline circulating VEGF levels
• Variably prognostic, but not predictive1
• Circulating endothelial cell enumeration
• May be prognostic in some malignancies2,3
• Not yet shown to be predictive

1. Kaseb AO, et al. Cancer. 20091154895-4906.
2. Batchelor T, et al. ASCO 2007. Abstract
2001.3. Ramalingam SS, et al. ASCO 2008.
Abstract 8078.
28
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 combination1
• Constitutive activation of VEGFR-1 pathway?2

1. Schneider BP, et al. Clin Cancer Res.
2009155297-5302. 2. Lambrechts D, et al.
ECCO-ESMO 2009. Abstract 16LBA.
29
SNPs Relate to Survival in MBC/ Bevacizumab?

• Small subset, tumor DNA, unclear how many SNPs
  evaluated

Schneider BP, et al. Clin Cancer Res.
2009155297-5302.
30
The State of PublishedAntiangiogenic Trials

• In general . . .
• Unselected cancers
• Treat entire population with novel therapy
• Minimal and/or retrospective tissue collection
• Unplanned retrospective subset analysis

31
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

32
Will We Find a Predictive Marker for
Antiangiogenic Therapy?

• Its difficult to make predictions, especially
  about the future.

33
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.go
v. NCT00528567.
34
Preconditions for a VEGF Pathway Predictive
Biomarker

• Agent inhibits this pathway
• Pretreatment biology drives the therapeutic
  response
• Compensatory non-VEGFmediated 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

35
Why BETH Should Be a Positive Trial

• Preselected population with VEGF-driven
  biology1
• Preclinical (and apparent clinical) synergy
  between HER2 inhibitors and antiangiogenic
  therapy2-4

1. Konecny GE, et. al. Clin Cancer Res.
2004101706-1716. 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.
36
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

37
University of Alberta Breast StudyCase-Control
Selection
38
Biomarker Selection
39
Triple-Negative Cohort Proangiogenic Factor
(Non-VEGF Related)
40
Funding
Collaborators

• Raymond Lai, MD, PhD
• Cheryl Santos, MSc
• Kathryn Graham, PhD
• Roger Tsang, MD

41
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 nonVEGFR-1 pathway
  or non-VEGF proangiogenic pathways

42
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