angiogenesis: using old and new approaches john mackey, md professor of oncology university of...
TRANSCRIPT
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