Lee Ellis, MD, UT MDACC Anti-VEGF Therapy Goes Mainstream Lee M. Ellis, MD UT MD Anderson Cancer Center Houston, TX ASCO 2005 “Advancing the science of

Lee Ellis, MD, UT MDACC

Anti-VEGF Therapy Goes Mainstream

Lee M. Ellis, MD

UT MD Anderson Cancer Center

Houston, TX

ASCO 2005

“Advancing the science of clinical oncology”


What Have We Learned Today About Anti-VEGF Therapy?

• Bevacizumab (BV) improves effects of chemo in– NSCLC (first line)– mCRC (second line)

• Dosing of BV (10 vs 5 mg/kg) is probably not an issue in mCRC

• BV, as monotherapy, remains unproven in mCRC– Although OS was comparable to FOLFOX, we do not have data

on therapy after progression (PFS of BV < FOLFOX)

• PTK/ZK does not improve the effects of FOLFOX in mCRC front line

• No drug is without toxicity


Points for Discussion

• Biology

• Brief review of trials

• Mechanisms of Action

• PTK/ZK: Why different results than BV

• Toxicities


VEGF-A

VEGF-R1(Flt-1)

MigrationInvasion

VEGF-R3(Flt-4)

Lymphangio-genesis

VEGF-R2(KDR/Flk-1)Proliferation

SurvivalPermeability

Cell membrane

VEGF Family and Receptors

PlGF VEGF-B VEGF-C, D

VEGF-R

Functions

NeuropilinSurvivalMigration


Anti-VEGF Therapy is Not Synonymous With Anti-Angiogenic Therapy

Anti-VEGF Anti-angiogenic

Target Endothelial and tumors cells

Endothelial cells

Inhibits permeability Yes ??

Inhibits further blood vessel growth (hard to prove)

Yes TBD

Effects blood flow and function (Nitric oxide?)

Yes TBD


Phase III Trials: Chemo +/- Anti-VEGF Therapy

Trial Year Malignancy Setting Primary Endpoint Met?

Capecitabine +/-BV

2002 mBreast Ca

Refractory NO

Paclitaxel +/- BV 2005 mBreast Ca

Front Line YES

5-FU/LV +/- SU5416

2002 mCRC Front Line NO

IFL +/- BV 2003 (AV2107)

mCRC First Line YES

FOLFOX +/- BV 2005

(ECOG 3200)

mCRC Refractory YES

FOLFOX +/-PTK/ZK

2005

(CONFIRM-1)

mCRC First Line NO

Carbo/Paclitaxel +/- BV

2005

(ECOG 4599)

NSCLC First Line YES

We owe it to our patients to publish the results…good or bad!


Progression Free Survival

0

1

2

3

4

5

6

7

8

PFS (months)

C + P C + P +BV

FOLFOX FOLFOX+ BV

FOLFOX FOLFOX+ PTK/ZK

ECOG 4599NSCLC

CONFIRM-1mCRC 1st

(Central Rad Review)

ECOG 3200mCRC 2nd

**

* P < 0.05


Response Rates

0

5

10

15

20

25

30

35

40

45

50

Response Rates (CR + PR) (%)

C + P C + P +BV

FOLFOX FOLFOX+ BV

FOLFOX FOLFOX+ PTK/ZK

ECOG 4599NSCLC

CONFIRM-1mCRC 1st

(Central Rad Review)

ECOG 3200mCRC 2nd

**

* P < 0.05


Phase III Trials: Chemo +/- BV

Trial Disease Site Front Line or Refractory

RR + BV

Capecitabine +/-BV

mBreast Ca Refractory 10%

Paclitaxel +/- BV mBreast Ca Front Line Monday

IFL +/- BV mCRC First Line 10%

FOLFOX +/- BV mCRC

ECOG 3200

Refractory 13%*

Carbo/Paclitaxel +/- BV

NSCLC

ECOG 4599

First Line 15

* Single agent BV RR in ECOG 3200 = 3%



• Biology




• Toxicities


Proposed Mechanisms of Action of Anti-VEGF Rx

• Anti-angiogenic– Difficult to demonstrate in patients

• How does one explain the increase in RR with chemo when, as a single agent, responses are rare?– “Normalization” of the vasculature with improved

delivery of chemo and O2 (transient)• Jain Science 2005, Yang Cancer 2005

– Vascular “constriction” (Sunday 11:15)

– Direct effect on tumor cells


VEGF-A

VEGF-R1(Flt-1)

MigrationInvasion

VEGF-R3(Flt-4)

Lymphangio-genesis

VEGF-R2(KDR/Flk-1)Proliferation

SurvivalPermeability

Cell membrane

VEGF Family and Receptors

PlGF VEGF-B VEGF-C, D

VEGF-R

Functions

NeuropilinSurvivalMigration


HT

-29

KM

12S

ML

M2

KM

12L

4

SW

480

SW

620

GE

O

RK

O

VEGFR1

-Actin

Parikh et al. Am J Path 2004

VEGFR1

NRP-1

VEGFR1 and NRP-1 on CRC Cells

Fan et al. Oncogene, 2005


Copyright ©2004 by the National Academy of Sciences

Castro-Rivera, Emely et al. (2004) PNAS 101, 11432-11437

Expression of VEGFR-1, VEGFR-2, and NP-1, in

Lung Cancer Cells In Vitro

Anti-VEGF Antibody Decreases Number of Lung

Cancer Cells In Vitro

VEGFR and NRP-1 on Lung Cancer Cells

VEGFR-1

VEGFR-2

Neuropilin-1


Dynamic Effect of Anti-VEGF Therapy

Acute Chronic

• Decreased flow due to vasoconstriction

• Direct effect on tumor cells• Paradoxical transient increase

in chemo delivery

• Inhibition of blood vessel growth



• Biology




• Toxicities


Addition of BV to Chemo Improves EfficacyAddition of PTK/ZK Does Not

• PK?

• Antibody vs TKI?

• VEGF Receptor target profile– TKIs do not target Neuropilin on tumor cells


Morgan, B. et al. J Clin Oncol; 21:3955-3964 2003

• Imaging done 2-9 hrs post dosing• Half-life PTK/ZK = 3-6 hrs• How long is the target affected?

With Daily Dosing, We Do Not Know if the Target Was Inhibited for the Entire Dosing Period?

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Pre PTK/ZK Rx Post PTK/ZK Rx(Day 2)

CRC Liver Metastases: DCE-MRI Ki (perfusion/permeability)


Partial Inhibition of VEGFR is Ineffective!! Stress Induction of VEGF

• VEGF-R inhibition (stress) leads to a compensatory increase in VEGF levels– PTK/ZK leads to an increase in plasma VEGF in

Phase I study in a dose dependent manner • Drevs et al. Ann Onc 2005

– Increases in plasma VEGF with VEGFR-2 MoAB• Bocci….Hicklin, Kerbel. Cancer Res 2004


JCO June 20, 2005

Recent studies with TKIs: Longer half-lives or BID dosing


Just because a trial does not meet its primary endpoint does not mean

that the drug is not active!

• Capecitabine +/ BV in refractory breast cancer• PTK/ZK has activity, but in this population with

daily dosing, it did not significantly improve the effects of FOLFOX– LDH as a predictive marker could be explored in

prospective trials, but it is not ready for prime time.• Await OS data, and CONFIRM-2 data

• Consider alternative dosing schedules after validation of PK



• Biology




• Toxicities


Adverse Events in Anti-VEGF + Chemo Trials

• NSCLC (ECOG 4599) C/P +/-BV

– HTN 6%– Hemoptysis and death (5 pts)

• mCRC 2nd line (ECOG 3200) FOLFOX +/-BV vs BV

– HTN 6-7%– Hemorrhage 2-3.5%

• mCRC 1st line (CONFIRM-1) FOLFOX +/- PTK/ZK

– HTN 21%– Dizziness 7-8%

VEGF Plays Important Roles in Physiology!!!

Does HTN contribute to hemorrhage or dizziness, or are they independent effects?


Although Progress Has Been Made, Our Work Is Not Done!!

• Improvements in survival are good, but not good enough (~2 mos) (our patients expect more)

• Identify predictive markers for – efficacy – adverse events

• Determine the role of combination therapy with other biologics– Will the addition of EGFR inhibitors improve efficacy even

further?• BV + cetuximab in mCRC • BV + erlotinib in NSCLC


Take Home Messages• The addition of BV to chemo improves efficacy

– First and second line mCRC– First line NSCLC and Breast Cancer– Be cognizant of HTN, bowel perforations and hemorrhage

(infrequent, but important)

• The role of tyrosine kinase inhibitors targeting VEGFR (PTK/ZK) remains undefined in mCRC– Await overall survival data in CONFIRM-1, and outcomes of

CONFIRM-2 Trials

• Ongoing studies in other malignancies with TKIs– RCC and GIST


Documents

Lee Ellis, MD, UT MDACC Anti-VEGF Therapy Goes Mainstream Lee M. Ellis, MD UT MD Anderson Cancer Center Houston, TX ASCO 2005 “Advancing the science of