Angiogenesis: Angiogenesis: Using Old and New ApproachesUsing Old and New Approaches

John Mackey, MD

Professor of Oncology

University of Alberta

Edmonton, Canada

Faculty DisclosureFaculty 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

AngiogenesisAngiogenesis

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

s-s

VEGF- B167

VEGF- B186

PlGF- 1,2

VEGF- A121

VEGF- A145

VEGF- A165

VEGF- A189

VEGF- A206

VEGF- E VEGF- CVEGF- D

VEGFR-1(Flt-1)

VEGFR-2(Flk-1/KDR)

VEGFR-3(Flt-4)

NRP-1

s-s

NRP-2

Vasculogenesis

Angiogenesis

Lymphangiogenesis

YY

An Obvious Target . . .An Obvious Target . . .

Agents Targeting the VEGF PathwayAgents Targeting the VEGF Pathway

VEGFR-3VEGFR-2VEGFR-1

Endothelial cell

VEGF-A

PP

PP P

PPP

PP

PP

Anti-VEGFantibodies

(bevacizumab)

Anti-VEGFR2antibodies

(ramucirumab)

Small-molecule inhibitors of VEGFR (PTK-787, AZD2171, motesanib,

sunitinib, sorafenib, pazopanib, axitinib, others)

Agents in yellow = FDA approved

SolubleVEGF

receptors(aflibercept)

Agents Targeting the VEGF PathwayAgents 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

AntiangiogenicAntiangiogenicRisk:Benefit RatioRisk:Benefit Ratio

Toxicity Efficacy

Antiangiogenic Antiangiogenic Class ToxicitiesClass 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 EfficacyTherapeutic 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?Adjuvant Antiangiogenic Therapy?

BevacizumabBevacizumab

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 AgentsNew Data on Newer Agents

Ramucirumab

Aflibercept

RamucirumabRamucirumab

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.

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

RA

ND

OM

IZA

TIO

N

F/UP

Progressivedisease

Or unacceptable

toxicityOr

withdrawnconsent

Docetaxel 75 mg/m² IV q3w

Blinded ramucirumab 10 mg/kg IV q3w

…..

…..

2/3

1/3Docetaxel 75 mg/m² IV q3w

Blinded placebo IV q3w

TRIO-012 Ramucirumab StudyTRIO-012 Ramucirumab Study

Mackey J, et al. Clin Breast Cancer. 2009;9:258-261.

AfliberceptAflibercept

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.

MotesanibMotesanib

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. 2011;12:369-376.

RANDOMIZATION

Arm A

Paclitaxel90 mg/m² IV weekly for 3/4 wks

Blinded placeboPO daily

Arm BBlinded motesanib 125 mg PO daily

Arm COpen-label bevacizumab

10 mg/kg on Week 1 and Week 3

Paclitaxel90 mg/m² IV weekly for 3/4 wks

Open-label motesanib125 mg PO daily

N = 282Stratified by: Previous taxane CT vs other vs none Number of metastatic sites (< 3 vs ≥ 3)Hormone receptor status (positive vs negative)

PD

Treatment until- Progressive disease - Unacceptable toxicity- Consent withdrawal

Roll-over (optional)

Paclitaxel90 mg/m² IV weekly for 3/4 wks

TRIO-010 Motesanib StudyTRIO-010 Motesanib Study

Martin MM, et. al. Lancet Oncol. 2011;12:369-376.

Vascular Disrupting AgentsVascular 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 PathwayAngipoietin -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 PathwayAgents 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?How Can We Move Beyond Empiricism?

Predictive assays

Therapeutic Predictive AssaysTherapeutic Predictive Assays

Prognostic biomarker

– “How bad is my cancer, Doc?”

Predictive biomarker

– “Is this drug going to work?”

Exposure BiomarkersExposure 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 MarkersTumor-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]

Blood-Based BiomarkersBlood-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 BiomarkersHost-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/ SNPs Relate to Survival in MBC/ Bevacizumab? Bevacizumab? Small subset, tumor DNA, unclear how many SNPs

evaluated

Schneider BP, et al. Clin Cancer Res. 2009;15:5297-5302.

The State of PublishedThe State of PublishedAntiangiogenic TrialsAntiangiogenic TrialsIn general . . .

Unselected cancers

Treat entire population with novel therapy

Minimal and/or retrospective tissue collection

Unplanned retrospective subset analysis

Ongoing Antiangiogenic Trials . . .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 Will We Find a Predictive Marker for Antiangiogenic Therapy?Antiangiogenic Therapy?

“It’s difficult to make predictions, especially about the future.”

A Tale of 2 TrialsA 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 Preconditions for a VEGF Pathway Predictive BiomarkerPredictive 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 TrialWhy 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 TrialWhy 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 StudyUniversity of Alberta Breast StudyCase-Control SelectionCase-Control Selection

Biomarker SelectionBiomarker Selection

Triple-Negative Cohort: Proangiogenic Factor (Non-VEGF Related)

FundingFunding

Raymond Lai, MD, PhD

Cheryl Santos, MSc

Kathryn Graham, PhD

Roger Tsang, MD

CollaboratorsCollaborators

Prediction on Predictive Assays for VEGF Prediction on Predictive Assays for VEGF Pathway Inhibitors . . .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 non-VEGF proangiogenic pathways

Take Home MessagesTake 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