treatment paradigms in recurrent gbm: today’s options and tomorrow’s promising directions

Thursday, November 20, 2008Henderson, Nevada

Treatment Paradigms inRecurrent GBM:Today’s Options and Tomorrow’s Promising Directions

This program is supported by an educational grant from

Timothy Cloughesy, MDProfessor and DirectorDepartment of Neurology, Neurological Services, Neuro-Oncology ProgramJonsson Comprehensive Cancer CenterDavid Geffen School of Medicine at UCLALos Angeles, California

Clinical Explorations With Targeted Agents in Recurrent GBM

clinicaloptions.com/oncology

Treatment Paradigms in Recurrent GBM

What Are the Targets?

Genetic abnormalities or pathways activated as a consequence of genetic abnormalities

– RTK/MAPK/PI3K

– P53

– RB1

– Or critical messengers of those pathways

End biologic processes

– Invasion

– Angiogenesis

– Cell survival

– Cell metabolism

Unique cell populations

– Stem cells

– Endothelial cell

Immune therapies



Wen PY, et al. N Engl J Med. 2008;359:492-507.



Cancer Genome Atlas Research Network. Nature. 2008;[E-pub ahead of print].

PTENMutation, homozygous

deletion in 18%Mutation in 2% Mutation in 15%

Amplification in 2%

Mutation in 1%

Mutation, homozygous deletion in 36%

EGFR ERBB2 PDGFRA MET

Mutation, amplification

in 45%

Mutation in 8%

Amplificationin 13%

Amplificationin 4%

RTK/RAS/PI(3)Ksignaling altered

in 88%

Proliferationsurvival

translation

NF1 RAS PI(3)K

AKT

FOXO

p53signaling altered in

87%Homozygous deletion,

mutation in 49%

Amplification in 7%

Amplification in 14%

Mutation, homozygous

deletion in 35%

CDKN2A (ARF)

MDM2MDM4

TP53

Activated oncogenes

ApoptosisSenescence

RBsignaling

alteredin 78%

Homozygous deletion,mutation in 52%

Homozygous deletion in 47%

Homozygous deletion in 2%

Amplificationin 18%

Amplificationin 2%

Amplificationin 1%

Homozygous deletion,mutation in 11%

CDKN2A(P16/

INK4a)CDKN2B CDKN2C

CDK4CCND

2CDK6

RB1

G1/S progression

a

b c



Results of Targeted Therapy

RTK (imatinib, gefitinib, erlotinib, AEE788, dasatinib, XL184)

FTI (tipifarnib)

Avb3 integrins (cilengitide)

Multikinase (sorafenib, sunitinib)

SRC (dasatinib)

mTOR (temsirolimus, sirolimus, everolimus)

PI3K (XL765, BEZ235)

PKC (enzastaurine, tamoxifen)

VEGF/R (PTK, AEE788, pazopanib, bevacizumab, AZD2171, aflibercept, CT-322)

Temozolomide



6-Month PFS and OS: Historical Data

*Patients from NABTC phase II studies between February 1998 - December 2002.†Patients from 8 phase II studies with 225 recurrent GBM and 150 recurrent AA.

1. Lamborn KR, et al. Neuro Oncol. 2008;10:162-170.2. Wong ET, et al. J Clin Oncol. 1999;17:2572-2578.

Grade IV Glioma*[1] GBM/AA†[2]

6-mo PFS 6, % (95% CI) TMZ: 28 (21-36)Other: 9 (6-13)

Total: 16 (12-20)

GBM: 15 (10-19)AA: 31 (24-39)

Total: 21 (17-26)

Median survival, wks (95% CI) TMZ: 40 (33-47)Other: 26 (23-29)Total: 30 (27-33)

GBM: 25 (21-28)AA: 47 (38-64)

Total: 30



How Will We Become Successful Using Targeted Agents? Single agents will not be enough

Need combinations

– AIDS

– Lymphoma

– Leukemia

Need rational combinations

– Based on understanding mechanisms of resistance



Studying Targeted Therapies

Is the target present?

Does drug hit the target?

Is target altered?

Impact on downstream signaling?

End biologic effect?

Feedback loop?



First Things First

Is the target present or active?

– Do we know how to prescreen?

Does the drug get to the target?

– BBB vs BTB

– Small molecule vs antibody

– Empiric data with rituximab and bevacizumab

– How do we measure (peak or trough levels)

– PK

– Impact of EIAED and other inducers

– MTD: if agent hits multiple targets, off-target toxicity may limit escalation of dose



Prescreen for EGFR Inhibition

18/132 (13.6 %) glioblastomas0/11 WHO grade III gliomas1/8 (12.5 %) GBM cell lines

FISH WT EGFR EGFRvIII

p-EGFR



Selected Trial of Erlotinib in Patients With Malignant GliomasPhase Description n (Eval) Activity Summary

I Monotherapy (100-500 mg/day) or in combination with TMZ in patients with newly

diagnosed malignant glioma

57 8 PR (14.0%), 2 SD > 6 mos (3.5%)

I 150-20 mg/day in combination with RT in patients with GBM

19 9 SD (47%)

I/II Monotherapy (150 mg/day) in patients with recurrent malignant glioma not on EIAEDs

GBM: 30 AA: 15

1 CR (2%), 3 PR (6%), 16 SD (33%)

II Monotherapy (150-500 mg/day) in patients with GBM at first relapse

48 1 CR (2%), 3 PR (6%), 16 SD (33%)

II Monotherapy (150 mg/day) in patients with recurrent GBM

16 4 PR (25%), 4 SD (25%)

II 50-150 mg/day in combination with temozolomide and concurrent RT in patients with newly diagnosed GBM

9 3 SD (33%)

Halatsch ME, et al. Cancer Treatment Rev. 2006;32:74-89.



Selected Trial of Gefitinib in Patients With Malignant GliomasPhase Description n (Eval) Activity Summary

I Monotherapy (250-1250 mg/day) or in combination with temozolomide in

patients with malignant glioma

28 1 CR (4%), 14 SD (50%)

I/II Monotherapy (500-1500 mg/day) in patients with recurrent malignant glioma

or unresectable meningioma progressing after RT

GBM: 38 AG: 17

MEN: 10

GBM: 5 PR (13%) AG: 2 PR (12%) MEN: No response

II Monotherapy (500-1000 mg/day) in patients with GBM at first relapse

53 No response or improvement in OS

II Monotherapy (500-1000 mg/day) in patients with newly diagnosed GBM

96 No improvement in OS or PFS

Halatsch ME, et al. Cancer Treatment Rev. 2006;32:74-89.



Targeting VEGF

*N = 68. Response to therapy determined by neurologic examination and MRI using the Macdonald criteria. Noncontrast T1 and T2 images and FLAIR images also were evaluated.

†N = 31. Response to therapy determined by radiographic imaging.

BEVASCO 2008*

AZD2171 AACR 2008†

NABTC Targeted

Enzastaurin ASCO 2008

CCNU ASCO 2008

mPFS, wks 23 17 6-8 6 6

mTTS 39.0 32.0 26.0 25.0 30.5

6-mo PFS, % 43 26 9 15 19

RR, % 28 56 NA 3 4

Wagner SA, et al. ASCO 2008. Abstract 2021.Batchelor T, et al. AACR 2008. Abstract LB-247.Fine HA, et al. ASCO 2008. Abstract 2005.



First Things First




– BBB vs BTB




– PK


– MTD: if agent hits multiple targets, off target toxicity may limit escalation of dose



R115777 Plasma Concentration vs Time

Group A (non-EIAEDs) 300 mg

Group B (EIAEDs) 600 mg

2422201816141210864201

10

100

1000

Hour

R11

5777

Pla

sma

Co

nc.

(n

g/m

L)

Dose (mg) 300 300 600 No. pts (group) 5 2A 2BCmax (ng/mL) 882 722 543AUC12h (μg x hr/mL) 3.76 3.93 2.24

Karp JE, et al. Blood. 2001;97:3361-3369.



NABTC 99-01 Tipifarnib

Phase II trial of tipifarnib in recurrent malignant glioma (GBM: n = 67; AG: n = 22)

– Group A: Patients not on EIAEDs

– Group B: Patients on EIAEDs

PR reported in only in GBM patients (4 in Group A; 1 in Group B)

Exploratory analysis of GBM patients showed a significant difference (P = .01) in PFS favoring Group A (n = 36) to Group B (n = 31)

Cloughesy TF, et al. J Clin Oncol. 2006;24:3651-3656.



First Things First




– BBB vs BTB




– PK


– MTD: if agent hits multiple targets, off target toxicity may limit escalation of dose



Collins I, et al. Nat Chem Biol. 2006;2:689-700.

MAPK

RTK

TK TKL

CK

PKA

CAMK

CLK

CDK

Lapatinib

RTK

TK TKL

CK

PKA

CAMK

CLK

CDK

Imatinib

MAPK

RTK

TK TKL

CK

PKA

CAMK

CLK

CDK

Staurosporine

MAPK

RTK

TK TKL

CK

PKA

CAMK

CLK

CDK

Sorafenib

MAPK

Kd

< 1 nM1-10 nM10-100 nM100 nM - 1 µM1-10 µM



Considerations

Is the target inhibited?

– All of the above plus potency, reversible vs irreversible

– VEGFR inhibitors prior to AZD2171 not as potent KDR IC50 < 1 nmol



Schold SC Jr, et al. Neuro-Oncology. 2004;6:28-32.Lassman AB, et al. Clin Cancer Res. 2005;11:7841-7850.

Examples of Measuring Drug Hitting Target

140120100806040200

70

BG Dose (mg/m2)

Dete

cta

ble

AG

T (

%)

60

50

40

30

20

10

90

80

100

CTumor:

Drug:Sensitivity:

pEGFR

EGFR

pERK

pAKT

GAPDH

- - - - - -- - - - - -

24 25 26 27 28 29

E E E G E

I I I I I

12 13 14 10 15

G

I

16

G

S

11

E

S

9

E

S

18

E

S

19

E

I

17

E

S

20



Considerations

Impact on downstream signaling

Biologic effect

Feedback loop



Rapamycin in Recurrent PTEN-Deficient Glioblastoma: Phase I

Cloughesy TF, et al. PLoS Medicine. 2008;5:139-151.

IHC-based screening for PTEN protein expression in newly diagnosed GBM

(N = 165)PTEN deficient

(67/165 = 40.6%)PTEN positive

(98/165 = 59.4%)

Other eligibility criteria

Exclude fromclinical trialNo Yes

Exclude fromclinical trial

Enroll at tumorrecurrence (n = 15)

TTP

Tumorrecurrenc

e

Tumorfailure

Surgery 2 (S2)Initial diagnosisSurgery 1 (S1)

Postoprecovery

Rapamycin Rapamycin




Plasma (ng/mL)

Tumor (nM)

Pa

tie

nt

#

15

10 mg cohort

5 mg cohort

2 mg cohort

Rapamycin Concentration

0

1413121110

987654321

0.1 1 10 100

02

.01

.51

.00

.5

Su

rge

ry 2

/S

urg

ery

1

pSer 235/236 S6

P = .028

NoRapa

RapaPatients

02

.01

.51

.00

.5

Su

rge

ry 2

/S

urg

ery

1

pSer 240/244 S6

P = .002

NoRapa

RapaPatients

Rapamycin

mTOROther

kinasesOther

S6K1

S235/236 S240/244

S6 ribosomal protein

IHC

Immunoblot

Pt #1 Pt #2 Pt #3

S1 S2 S1 S2 S2S1IB: pS235/236 S6RP

IB: total S6RP

IB: tubulin

Pt #1

S1 S2

pS

23

5/2

36

-S6

RP

Me

al

Sa

tura

tio

n p

er

Ce

ll20

4060

80

Pt #2

S1S2

2040

6080

100

120

Pt #3

S1

2040

6080

100

0

S2

A

B

C



Rapamycin in Recurrent PTEN-Deficient Glioblastoma: Ph I Results

S6 Inhibition pSer240/244 pSer235/236 pSer235/236 or pSer240/244

≥ 25% P = .56 P = .29 P = .46

≥ 30% P = .56 P = .29 P = .46

≥ 35% P = .56 P = .29 P = .46

≥ 40% P = 1 P = .29 P = .46

≥ 45% P = .27 P = .21 P = .029

≥ 50% P = .19 P = .21 P = .0047


Ki67 Response Stratified by % S6 Inhibition




15131297310

50

Patient #

pP

RA

S40 I

HC

(A

rbit

rary

U

nit

s)

40

30

20

10

1110862 4 5

NS NSNS NS

Surgery 1 (S1)Surgery 2 (S2)

NSNS

1.0

0.8

0.6

0.4

0.2

00 100 200 300 400 500

TTP (Days)

P = .049

pPRAS40 not induced (n = 7)pPRAS40 induced (n = 7)

C

B

Pt 2 Pt 5Surgery 1 Surgery 2 Surgery 1 Surgery 2 Surgery 1 Surgery 2

Pt 11

P-AKT(Ser473)

P-PRAS40(Thr246)

A

Rapamycin

Growth factorreceptor IRS

S6K1

OtherT246

mTOR

PTENPI3K

PIP 2

PIP 3

S473

PRAS40

Akt



Multitargeted Approaches and Defining Mechanisms of Resistance?

XL 765, BEZ235


Rapamycin


S6K1

OtherT246

mTOR

PTENPI3K

PIP 2

PIP 3S473

AGENT

PRAS40

Akt



If We Hit Target, Why Do We Fail? Mechanisms of Resistance Adaption (upfront)

– Feedback loops

– Multiple RTK activation

– Heterogeneity—selection

– PTEN

– Stem cell population

Late (acquired) mutation, selection

– RTK mutation in kinase domain

– MET RTK activation



Adaptive (Upfront) Resistance

Feedback Loop Multiple RTK Activation


GefitinibTumor growth

TimeE

rbB3

ErbB

3EGFR

ErbB

3

MET PDGFR

Rapamycin


S6K1

OtherT246

mTOR

PTENPI3K

PIP 2

PIP 3S473

PRAS40

Akt




– Feedback loops



– PTEN







Adaptive (Upfront) Resistance

Lethaltumor

Cure

Antiangiogenictherapy

Life-span

Time

Tumor size

RelapseTumor

Resistant cancer cells

a

b

cd



Context-Dependent Sensitivity

EGFR inhibition

– Lack of activation of AKT

– PTEN and EGFRviii

– KRAS WT better outcome in metastatic CRC with cetuximab

mTOR inhibition

– PTEN-deficient tumors

– Identification of feedback loop

Growth factorsIntegrins

ECM

Growth factorsPlasma membrane

Adhesion, migrationinvasion, growth

Apoptosisgrowth

F-ac

tin, c

ytos

kele

ton

Othereffects

PTEN

PIP3

Akt/PKB

P13-kSignaling andcytoskeletal

complex

Shc FAK P13-k

SosRaf

MEK

ERK

RasCasSncGrb2

SosGrb2




– Feedback loops



– PTEN







Late (Acquired) Resistance

GefitinibTumor growth

Time

ErbB

3

ErbB

3EGFR

ErbB

3

MET PDGFR

NSCLC Glioblastoma

EGFRCR1

CR2

EGFTransmembranedomain

Tyrosinekinasedomain

ATP-binding cleftof the kinase

Y

Y

Y

Y

P-loop

A-loopATP

TKI

G719S,G719C

L858R, L861QT790M

Δ6-273(EGFRvIII)(Δ6-185)

Δ521-603

ΔE746-A750ΔL747-P753insSΔL747-T751insS

L2

L1



mTOR

S6K

Cyclin D1

Rapamycin

RTKiOther

Adhesion, migrationinvasion, growth

PTEN

Othereffects

ApoptosisGrowth

Akt/PKB

P13-kP13-k

CasSnc

Sos

Grb2Ras

Raf

MEK

ERK

Sos

Grb2Shc FAK

PIP3

Growth factorsIntegrins

ECM

Growth factors

Plasma membrane

Signaling andcytoskeletal

complexFTI

F-ac

tin, c

ytos

kele

ton

Sorafenib



Promise and Problems With Combinations Need to understand single agent effects before moving to

combination

Single-agent MTD not met in combination studies due to toxicity

– Erlotinib and CCI-779

– CCI-779 MTD 15 mg, which is less than 1/10 MTD single agent

– Sorafenib and erlotinib

– Erlotinib MTD 100 mg, which is 50% single-agent MTD

Need to study potent selective inhibitors before considering multikinase inhibitors

Karaman MW, et al. Nat Biotech. 2008;26:127-132.



How Will We Evaluate Targets?

Need to choose and study agents carefully

Biopsy-treat-biopsy

– Optimize molecular/tissue evaluations

Each study should provide insight to future studies or combinations (know why you failed)

Do not ignore success

– Anti-VEGF, temozolomide, CCNU?



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