Targeting Tumor Angiogenesis: What Have We Learned So Far?

Lee M. Ellis, MDDepartments of Cancer Biology and Surgical Oncology

UT MD Anderson Cancer CenterHouston, Texas, USA

Tuesday June 8 Education Session

Tumor Biology

Overview: What Have We Learned So Far?

• Current State in the Clinic– Where have we done well and where have we

failed

• Potential Mechanisms of Action of Anti-VEGF Therapy

• Biomarkers

VEGFR-1(Flt-1)

NRP-1/NRP-2 NRP-2

VEGF-D

VEGF-CVEGF-B VEGF-A

PlGF

VEGFR-2(Flk-1/KDR)

VEGFR-3(Flt-4)

VasculogenesisAngiogenesis

Lymphangiogenesis

BEVACIZUMAB*

VEGF-TRAP

18F1 1121B

TG-403

Tyrosine Kinase InhibitorsSunitinib*Sorafenib*Pazopanib*

AxitinibMotesanibCedirinibBrivinib

Many, many others

VEGF Targeted Agents in the Clinic or In Clinical Trials

Ellis, Hicklin Nat Rev Ca. 2008* FDA approved agents

The Scorecard: Phase III Trials Chemo +/- Anti-VEGF Rx in Solid Malignancies

Trial Disease Site Line of Therapy

1o Endpoint Met

RR Anti-VEGF Rx

PFS

mos

5FU/LCV +/- SU5416 mCRC First Line No ? ?

IFL +/- BV mCRC First Line Yes 10% 4.4

FOLFOX +/- PTK/ZK mCRC First Line No -4% 0.2

XELOX/FOLFOX +/- BV mCRC First Line Yes 0 1.4

FOLFOX +/- BV mCRC Refractory Yes 14% 2.6

FOLFOX +/- PTK/ZK mCRC Refractory No ? 1.5

FOLFIRI+/- Sunitinib mCRC First Line No ? ?

Chemo +/ Cedirinib vs Chemo + BV**

mCRC First Line No ? ?

Chemo +/- BV/BV Adjuvant CRC - No NA NA

5FU/Cisplatin +/- BV Gastric First Line No 9 1.4

** head to head comparison BV=Bevacizumab, RR= response rate, PFS=Progression free survival

06/10

The Scorecard: Phase III Trials Chemo +/- Anti-VEGF Rx in Solid Malignancies

Trial Disease Site Line of Therapy

1o Endpoint Met

RR Anti-VEGF Rx

PFS

mos

Paclitaxel +/- BV mBreast Ca Front Line Yes 22% 5.9

Docetaxel +/- BV mBreast Ca Front Line Yes 11% 0.7-0.8

Capecitabine +/-BV* mBreast Ca Refractory No 10% 0.7

Chemo +/- BV mBreast Ca Front Line Yes 12-13% 1.2-2.9

Chemo +/- Sunitinib mBreast Ca Front Line No ? ?

Chemo +/- Sunitinib mBreast Ca Refractory No ? ?

Carbo/Paclitaxel +/- BV +/- BV

Ovarian First Line No/Yes ? 4

Carbo/Paclitaxel +/- BV Melanoma First Line (Phase 2)

No 1.4

06/10

The Scorecard: Phase III Trials Chemo +/- Anti-VEGF Rx in Solid Malignancies

Trial Disease Site Line of Therapy

1o Endpoint Met

RR Anti-VEGF Rx

PFS

mos

Gemcitabine +/- BV* Pancreatic Ca First Line No 1% 0

Gemcitabine +/- Axitinib Pancreatic Ca First Line No ? ?

Gem +/- VEGF-Trap Pancreatic Ca First Line No ? ?

Gemcitabine/Erlotinib +/- BV*

Pancreatic Ca First Line No ? ?

Chemo +/- BV Prostate Ca Hormone-refractory

No ? ?

Carbo/Paclitaxel +/- BV NSCLC First Line Yes 15% 1.9

Gem/Cis +/- BV NSCLC First Line Yes 10-14% 0.4-0.6

Carbo/Paclitaxel +/- Sorafenib

NSCLC First Line No 3 -0.8

BV=Bevacizumab, RR= response rate, PFS=Progression free survival

06/10

The Scorecard: Phase III Trials “Standard of Care” vs Single Agent Anti-VEGF Rx in Solid Malignancies

Trial Disease Site Line of Rx 1o Endpt Met

RR Anti-VEGF Rx

PFS

mos

Sorafenib vs Placebo RCC Refractory Yes 8% 2.7

Sunitinib vs IFN RCC First Line Yes 31% 5.9

IFN +/- BV RCC First Line Yes 18% 4.8

Pazopanib vs Placebo RCC Both Yes 27% 5.0

Sorafenib vs Placebo HCC First Line Yes 2% 3.0

Sorafenib vs Placebo HCC First Line Yes 2% 1.4

Sunitinib vs Sorafenib** HCC First Line No ? ?

Sunitinib vs Placebo Pancreatic NET

First Line Yes 9% 5.9

** head to head comparison

What Have We Learned So Far?

• The efficacy of VEGF-targeted therapy is – Tumor specific– Context specific– Agent specific

• This is not a simple field to understand– You cannot make broad generalizations across

drugs, tumor types, or stage of tumors

What Have We Learned So Far?

• Despite similar primary targets (VEGFRs), all drugs in this class are NOT created equal

– If we “hit” too many targets, is this a bad thing?

• CAIRO-2 and PACCE Trials• Activation of compensatory pathways?

Kinase Inhibition Profiles of VEGFR Targeted Agents

BevacizumabVEGF-Trap

Karaman et al. Nat Biotech 2008

Phase III Trial Summary: TKIs vs MoAB (Bev)Excluding head to head comparisons and continuation studies

Disease MoAB (Bev) TKI

Pancreatic 0/2 (VEGF Trap 0/1) 0/1

Melanoma 0/1 NA

Gastric 0/1 NA

Prostate 0/1 NA

CRC 3/3 0/4

Breast 3/4 0/2

NSCLC 2/2 0/1

Hepatocellular NA 2/2

Renal Cell 1/1 3/3

Pancreatic NET NA 1/1

Total Percent 9/16 (56%) 6/14 (43%)

Excluding HCC/RCC/pNET

8/15 (53%) 0/8 (0%)

Highly Angiogenic Tumors

MoABs vs TKIs

Differences in

Specificity

Half-life/exposure (metabolism)

Tissue Penetration

• Despite many hypothetical discussions about the advantages of TKIs regarding their ability to target all 3 VEGFR TKRs, and PDGFR, etc., in the tumor types that are NOT highly angiogenic, we cannot ignore the clinical data.

• My personal view, backed by some preclinical data, is that targeting PDGFR does not add to efficacy, and in some ways, may decrease efficacy

ASCO 2009/2010: For Solid Tumors “Requiring” Multiagent Therapy, Single Agent Bevacizumab May Demonstrate

Some Activity as “Maintenance Therapy”

• But the question remains, how much benefit will patients receive

• CRC

• Ovarian Cancer

Tumor Trial Benefit Observed

Remaining Questions

CRC NSABP C-08/adjuvant Separation of curves while Bev administered as single agent

Is it feasible to give Bev for an extended period (yrs) in a population where 97% may not benefit from Rx?

mCRC MACRO/maintenance Bev following XeLOX/Bev vs XeLOXBev continuation

Non-inferior to XeLOX/Bev after first 6 cycles

Too few patients to draw firm conclusions of non-inferiority

Ovarian ECOG/maintenance Bev following C/T/Bev vs C/T alone

Improved PFS OS not improved - is this due to access to Bev after progression or does this fit with other Bev trials where PFS does not always translate into OS? Eisenhower discussion

Validation, Validation, Validation!

Single agent maintenance therapy is not FDA-approved.

We must study this concept in more clinical trials before changing practice.

Overview: What Have We Learned So Far?

• Current State in the Clinic• Potential Mechanisms of Action of Anti-VEGF

Therapy• Biomarkers

Summary of PFS and RRs with VEGF-Targeted Therapies

Cancer Type How Utilized or Studied

Increase PFS Over Standard Care

Increase RR FDA Approval

CRC + Chemo 0-4 months 0-10% Y

NSCLC + Chemo 0-2 months 3-15% Y

Breast Cancer + Chemo 1-6 months 10-22% Y

Renal Cell Ca Single agent 3-6 months 8-30% Y

GBM (Phase 2) Single agent 1-2 months 15-20% Y

HCC Single agent 1.4-3 months 2% Y

Ovarian After chemo/Bev

4 months ? pending

Prostate + Chemo ? ? N

Pancreas + Chemo 0 0-1% N

Melanoma + Chemo 0-1.4 2-9% N

With Such Varied Results With VEGF-Targeted Therapies, There Must be Multiple Mechanisms of Action of This Class of Drugs

Potential Mechanisms of Action of VEGF Targeted Therapies

(When it works)

• Anti-angiogenic• “Normalization” of the vasculature • Direct effect on tumor cells• Vascular “constriction” • Offset effects of stress• Reverse immuno-suppression due to VEGF• Disruption of the cancer stem cell niche

Anti-VEGF Therapy: My Theory on Different Mechanisms of Action in Different Tumor Systems

Renal Cell Carcinoma Colon Carcinoma

Overview: What Have We Learned So Far?

• Current State in the Clinic• Potential Mechanisms of Action of Anti-VEGF

Therapy• Biomarkers

• Prognostic marker– associated with clinical outcome, independent of specific treatment

• Predictive marker– identifies groups receiving different degrees of benefit from a therapy – specific for a given treatment (i.e., Ras for EGFR MoABs in CRC, HER2

expression for trastuzumab in breast cancer)

• Surrogate / activity marker– modulated by treatment– may be on target tissue (tumor) or surrogate tissue (i.e., lymphocytes, skin)– might or might not correlate with clinical activity

A Few DefinitionsA “marker” is not a “marker” is not a “marker”

We Do Not Have Any Predictive Biomarkers!!!!

Comment: We should never subject patients to biopsies for any biomarker

study until we have shown proof of principle in preclinical models.

A Snapshot of Predictive Marker Studies for VEGF Targeted Therapies

• Negative (mostly unpublished)

– VEGF • Tissue, plasma, anywhere

– TSP– VEGFRs– Ras, Raf, P53

• Possible/requires further study– SNPs (VEGF, VEGFR-1)– Imaging of vascular flow and

function in metastasis• Yao et al. NETs, Saturday

• A predictive marker must be strong enough to allow a “go/no go” for a particular drug for a particular patient• Would you deny a patient therapy based on a “negative” biomarker?

- Mut Kras for EGFR MoABs in mCRC

ASCO 2010

“Conclusions: Measurement of baseline circulating VEGF levels may be useful as a prognostic biomarker, but not as a predictive biomarker for bevacizumab-based treatment

benefit in metastatic colorectal, lung, and renal cell cancers.

Circulating vascular endothelial growth factor (VEGF) as a biomarker for bevacizumab-based therapy in metastatic colorectal, non-small cell lung, and renal cell cancers: Analysis of phase III studies.C. Bernaards, et al.

Despite innumerable studies of circulating VEGF and it’s lack of validity as a predictive biomarker, invesigators will continue to study

this until we get a false positive.

Schneider, et al. J Clin Oncol; 2008

Kaplan-Meier curve for overall survival (OS) in experimental arm by genotype; (A) vascular endothelial growth factor (VEGF)-2578 C/A; (B) VEGF-1154 G/A

SNPs: VEGF Polymorphisms and Predictive Value in ECOG-2100

(Pac +/- Bev Metastatic Breast Cancer)

Caveats: • Predictive for OS, but not PFS• Small numbers• Did not include Pac Rx alone group

VEGFR-1 SNPs in Pancreatic Cancer

Bev Group

Lambrechts et al. ESMO 2009

SNPs are exploratory and require unbiased validation in larger studies!

We should do our best to associate SNPS to biology.

• Prognostic marker• Predictive marker• Surrogate / activity marker

– modulated by treatment

– may be on target tissue (tumor) or surrogate tissue (i.e., lymphocytes, skin)

– might or might not correlate with clinical activity

A Few DefinitionsA “marker” is not a “marker” is not a “marker”

From a practical perspective, a surrogate marker is only of use to an oncologist if it is strong enough to force an oncologist to alter Rx.

After a Decade of Studies and

MILLIONS of $$ Spent in Search of

Biomarkers for Anti-angiogenic Therapy

George Sledge

~$40-50

Grade 3/4 Hypertension Is Associated With Improved Median OS in E2100

Median OS:

25.3 mo vs. 38.7 mop=0.002

Schneider et al; J Clin Oncol, 2008

Hypertension is a Biomarker of Efficacy in Patients with Metastatic Renal Cell Carcinoma

Treated with Sunitinib Brian Rini et al (2010)

Dahlberg et al. J Clin Oncol; 28: 2010

Overall Survival and HTN After One Cycle of Therapy: ECOG 4599

High blood pressure (HBP) by the end of cycle 1 was defined as > 150/100 at any previous time or at least a 20-mmHg increase in diastolic blood pressure from baseline.

ASCO 2010Analysis of early hypertension (HTN) and clinical outcome with bevacizumab (BV). H. Hurwitz, et al.

“…The primary HTN endpoint was an SBP increase 20 mmHg or DBP increase 10 mmHg within the first 60 days of Tx.

….Conclusions: HTN during Tx does not predict clinical benefit from BV based on PFS or OS.….”

What We Know (and don’t know) in 2010About VEGF Targeted Therapy

What We (Think) We Know – Single agent anti-VEGF

therapy is effective in the most angiogenic tumors• RCC, HCC, GBM (NETs?)

• And….it may have utility as “maintenance therapy” (Ovarian, colorectal cancers-ASCO 2010)

– Not all anti-VEGF therapies are created equal• This is both good and bad

– The benefits of therapy at times may be statistically significant, but clinically marginal

What We Do Not Know (but still think we do know)

– How it works– The best agents to partner with VEGF-

targeted therapies– Biomarkers to select patients (SNPs?)– If it will work in the adjuvant setting

(presumed micromets) in diseases other than CRC (C-08 -)

– Long term effects of VEGF inhibition on the CV system and CNS (relevant to adjuvant studies)

– If it will work through multiple lines of therapy (CRC trials)

Despite Incremental Gains in Many Tumor Types, We Have Not Done As Well as We Had Hoped.

We Must Be More Creative in Drug Combinations and Biomarker Discovery!!

It is time to move new approaches forward!!

“Me too” drugs and trials are unlikely to significantly advance the field