1

Targeted Therapy:Novel Approaches to Cancer Treatment

Narin Voravud, M.D.Medical Oncology Unit, Department of Medicine,

Faculty of Medicine, Thai Red Cross Society and King Chulalongkorn Memorial Hospital, Chulalongkorn University

Bangkok, Thailand

The 1st Asia Pacific Oncology Pharmacy Congress(APOPC)

August 5, 2006 Bangkok, Thailand

Targeted Therapy in Oncology

!Cancer is the most common cause of death! Ineffective and incurable treatment in many cancers!Conventional antineoplastic agents lack specificity

causing normal tissue toxicities!Specific, effective, and safer agents

are needed!Progress in molecular oncology defines

specific anticancer targets!Targeted therapy is clinically available

Targeting the Tumor and Its Microenvironment

Endothelial CellCancer Cell

1. Growth factor signaling2. Microtubule dynamics3. Histone acetylation/deacetylation4. DNA replication, transcription, repair5. Metastasis

1

1

43

2

1

1

4

2

5

Tumor Cell Growth / Replication Angiogenesis

Targets of Cancer Therapy

Cell Growth Motility Survival Proliferation Angiogenesis

PP

PP

PDK1,2Growth Factor

Signaling

Gene Transcription DNA Replication and Repair

1

6 3

5

8

9

1011

2Plasma Membrane

Nuclear Membrane

127

4

7

7 1. Growth factors2. Growth factor

receptors3. Adaptor proteins4. Docking

proteins/binding proteins

5. Guanine nucleotide exchange factors

6. Phosphatases and phospholipases

7. Signaling kinases8. Ribosomes9. Transcription

factors10. Histones11. DNA12. Microtubules

Microtubule Dynamics

RNA Translation

Development of Targeted Therapy in Oncology

Agents

RituximabImatinibTrastuzumabGefitinibBevacizumabThalidomideZevalinErlotinibCetuximabSorafenibSunitinib

FDA ApprovalThailand USA

2001 19972001 20012001 19982004 20032005 20042005 19982005 20022005 1998

- 2004- 2005- 2006

Disease

Non-Hodgkin’s lymphomaCML, GISTAdvanced brest cancerAdvanced NSCLCAdvanced colorectal cancerMultiple myelomaNon-Hodgkin’s lymphomaAdvanced NSCLCColorectal cancerRenal cell carcinomaRenal cell carcinoma, Refractory GIST

Why Epidermal Growth Factor and Receptor are Important Targets ?

!Most cancers are epithelial in origin, so called carcinoma.

!Hallmark of cancer is abnormal/uncontrolled growth.!Cancer growth is controlled by growth factors/receptors.!Major growth factor is epidermal growth factor (EGF).!First discovery by John Mendelsohn

2

Growth Factors and Tumor Growth and Metastasis

Tumor effects– metastasis– proliferation– loss of apoptosis– infinite replication– angiogenesis– invasion

Mutations in– HER family – VEGF– MMPs– ras– p53– COX-2

Primary tumor

Hanahan D, Weinberg RA. Cell. 2000;100:57-70.

Metastasis

Autocrinefactors

Receptors

Paracrinefactors

Normalcells

Tumorcell

Hoststromal

epithelium

Biologic Control of Tumor Growth

Incrine

Acrine

Tumors with HER1/EGFR Dysregulation

Salomon DS, Brandt R, Ciardiello F, et al. Crit Rev Oncol Hematol. 1995;19:183-232.Woodburn JR. Pharmacol Ther. 1999;82:241-250.

BreastEsophagus

GastricPancreaticOvarian

CervicalProstate

Bladder

Colorectal

RenalLung

Glioma

Head and neck

The HER Family of Receptors

HER1/EGFRerbB1

HER2erbB2neu

EGFTGF-α

AmphiregulinBetacellulin

HB-EGFEpiregulin Heregulins

NRG2NRG3

HeregulinsBetacellulin

Cysteine-rich

domains

Tyrosine-kinase

domains

HER3erbB3 HER4

erbB4

Ligands:

Salomon D, Brandt R, Ciardiello F, et al. Crit Rev Oncol Hematol. 1995;19:183-232.Woodburn J. Pharmacol Ther. 1999;82:241-250.

Proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis

Effects of HER1/EGFR Activation

Src PLCγ GAP Grb2 Shc Nck Vav Grb7 Crk

PKC Ras

JNK AblPI3K Akt

Extracellular

Intracellular Transactivation

MAPK

P P

Woodburn J. Pharmacol Ther. 1999;82:241-250; Lynch TJ, Bell DW, Sordella R, et al. New Engl J Med. 2004;350; Knowlden JM, Hutcheson IR, Jones HE, et al. Endocrinology 2003;144:1032-1044; Chakravarti A, Chakladar A, Delaney MA, et al. Cancer Res. 2002;62:4307-4315.

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HER1/EGFR and Proliferation

Harari D, Yarden Y. Oncogene. 2000;19:6102-6114.Quon H, Liu FF, Cummings BJ. Head Neck. 2001;23:147-159.

!HER1/EGFR signaling increases cyclin D level

HER1/EGFRdimer

Cyclin DNucleus

Check-point

Cyclin DChromosomesegregation M S

DNAreplication

Promotes G1→S

G1

G2

Geneactivation

G0

l Cyclin D is a critical G1 checkpoint protein

MitogensGrowth factors

Cell–cell contactdifferentiationP P

HER1/EGFR Dysregulation in Tumors

Ligand overproduction(autocrine loop)

Overexpression

Defectiveinternalization or downregulation

P = phosphate

EGFRvII/III

EGFRvI

Mutationsconferring

constitutiveactivation

P P P P P PP P P P P P

De Miguel P, Royuela, Bethencourt R, et al. Cytokine. 1999;11:722-727; Normanno N, Kim N, WenD, et al. Breast Cancer Res Treat. 1995;35:293-297; Lal A, Glazer CA, Martinson HM, et al. Cancer Res. 2002;62:3335-3339; Lynch TJ, Bell DW, Sordella R, et al. New Engl J Med. 2004;350; Paez JG, Janne PA, Lee JC, et al. Science, 29 April 2004 (10.1126/science.1099314); Yang H, Jiang D, Li W, et al. Oncogene 2000;19:1901-1914.

Common Approaches toTargeting HER1/EGFR

Slamon DJ, Leyland-Jones B, Shak S, et al. N Engl J Med. 2001;344:783-792; Mendelsohn J, Baselga J. Oncogene. 2000;19:6550-6565; Noonberg SB, Benz CC. Drugs. 2000;59:753-767; Raymond E, Faivre S, ArmannJP. Drugs. 2000;60(Suppl 1):15-23; Arteaga C. J Clin Oncol. 2001;19:32s-40s; Pedersen MW, Meltom M, Damstrup L, et al. Ann Oncol. 2001;12:745-760.

Anti-HER1/EGFR-blocking antibodies

Anti-ligand-blocking

antibodies

TKinhibitors

Ligand–toxin

conjugatesAntibody–

toxinconjugates

PP P

P

TK inhibitor

↓ Proliferation

↓ Invasion

↓ Metastasis↓ Angiogenesis

↑ Apoptosis

↓ Adhesion

↑ Sensitivity toradiotherapy

HER1/EGFR Inhibitors: Mode of Antitumor Activity

Etessami A, Bourhis J. Drugs Fut. 2000;25:895-899.Moyer J, Barbacci EG, Iwata KK, et al. Cancer Res. 1997;57:4838-4848.Harari PM, Huang SM. Semin Radiat Oncol. 2002;12(Suppl 2):21-26.

Monoclonal antibody

Therapeutic Needs in NSCLC

! Improved survival

! Improved disease-related symptoms/ quality of life

!Better tolerated regimens

!Effective agents for patients not suitable for chemotherapy

!Longer time to disease progression

Rationale for HER1/EGFR as a target for anticancer drug development

! HER1/EGFR is frequently dysregulated in carcinomas

! HER1/EGFR activation initiates a signal transduction cascade that promotes tumour-cell proliferation and survival

! Overexpression/dysregulation of HER1/EGFR is associated with poor prognosis

! Overexpression of HER1/EGFR can transform cells in a ligand-dependent manner

! HER1/EGFR blockade inhibits tumourigenicity

Arteaga C. Semin Oncol 2003;30(Suppl. 7):3–14

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Treatment Options for Advanced NSCLCTreatment Options for Advanced NSCLC

• cisplatin + paclitaxel• cisplatin + gemcitabine• cisplatin + docetaxel• carboplatin + paclitaxel• cisplatin + vinorelbine

1st line

Standard platinum based regimens

2nd line

3+ line ErlotinibGefitinib

Docetaxel

Pemetrexate (Alimta)

Erlotinib

Erlotinib (TarcevaTM)

! Erlotinib is the first and only HER1/EGFR TKI proven to significantly prolong survival in second and third line NSCLC patients

! Erlotinib is for the treatment of patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) after failure of at least one prior chemotherapy regimen

! Erlotinib is not chemotherapy

Erlotinib Structure

O

O

H3C

H3CO

O

NH

N

N

IC50 = 2nM1 Erlotinib binding

Basic Pharmacokinetics of Erlotinib

! Bioavailability of 150mg tablet: 60%! Tmax: 4 hours! Steady-state: 7-8 days! Half-life: 36.2 hours! Plasma protein binding: 92% to 95% ! Metabolization: liver CYP3A4

– Ketoconazole– Enzyme-inducing anti-epileptic drugs

! Excretion: 83% feces

Erlotinib: Simple Once-Daily Dosing! Recommended dose: 150 mg O.D.! 2 dosages of Oral forms (film-coated tablet), 100 and 150 mg! Take 1 tablet one hour before or two hours after meal! Dose modifications

- reduce to 100 mg in case of intolerable skin reactions or diarrhea

! Dose interruption- Erlotinib should be discontinued if ILD is diagnosed

Safety Profiles of Erlotinib

!Rash and diarrhea; mild and moderate grade

! ILD occurred in 0.8% of patients equal to placebo

!Asymptomatic increases in liver transaminases

! Infrequent cases of conjunctivitis, keratitis and

corneal ulceration

Drug Interactions with Erlotinib

!Co-treatment with CYP3A4 inhibitors increases

Erlotinib exposure such as

– ketoconazole, itraconazole, clarithromycin,

indinavir, nelfinavir, nefazodone

!Pre-treatment with CYP3A4 inducers decreases

Erlotinib exposure such as

– rifampicin, phenytoin, carbamazepine

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Phase III Randomized Study of Erlotinib versus Placebo in Advanced NSCLC Failure to Chemotherapy

RANDOM I Z E

Erlotinib* 150 mg daily

Placebo “150 mg” daily

*2:1 Randomization

Stratified by:CentrePS, 0/1 vs 2/3Response to prior Rx(CR/PR:SD:PD)

Prior regimens, (1 vs 2)

Prior platinum, (Yes vs no)

Primary Endpoint – SurvivalSecondary Endpoint – PFS, Response, Safety, QoL

Phase III Study of Erlotinib vs Placebo in Advanced NSCLC Failure to Chemotherapy

Response Rate (N=638)

N/A15%57%27%N/AN/A

Placebo(N=211)

7.9 mo (95% CI 5.7-10.6)

Response duration18%Inevaluable / Not assessed38%Progression35%Stable disease8%Partial response1%Complete response

Erlotinib(N=427)

Patient characteristics predictive of response to Erlotinib (Study BR.21)

13.0Unknown (23)24.73.87.5

18.94.1

13.96.1

14.4

Erlotinibpatients (%)

(n=427)

No (93)Yes (311)Other (374)Asian (53)Other (218)Adenocarcinoma (209)Male (281)Female (146)

p value*

<0.001Ever smoked**

0.02Ethnicity

<0.001Histology

0.006Gender

*Significance between subgroups**Data collected retrospectivelyIn multiple logistic-regression analyses, only never having smoked (p<0.001) and adenocarcinoma histology (p=0.01) were associated with response

Shepherd F, et al. N Engl J Med 2005;353:123–32

Detection of EGFR Gene Amplification by Fluorescence in situ Hybridization (FISH Scoring)

Disomy

High polysomy

Trisomy

Gene amplificationCappuzzo F, et al. J Natl Cancer InstI 2005;97:643–55

Known HER1/EGFR activating mutations underlyingNSCLC sensitivity to Erlotinib or Gefitinib

Pao W, et al. Proc Natl Acad Sci USA 2004;101:13306–11

Sensitive to GefitinibSensitive to ErlotinibNever treated with TKI

Phase III Study of Erlotinib vs Placebo in Advanced NSCLC Failure to Chemotherapy (Study BR.21)

Overall survival & Progression Free Survival

*HR and p-value adjusted for stratification factors at randomisation + HER1/EGFR status

42.5% improvement in median survival

Surv

ival

dis

trib

utio

n fu

nctio

n

Survival time (months)

ErlotinibTM

Placebo

HR* = 0.73, p<0.001

ErlotinibTM (n=488)

Placebo (n=243)

Median survival (months) 6.7 4.7

1-year survival (%) 31 21

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30

* *Adjusted for stratification factors (except centre) and EGFR status

Perc

enta

ge

0

20

40

60

80

100

0.0488

5.0153

10.052

15.08

___ Erlotinib, _____ Placebo

2.2 mos 1.8 mos*HR 0.61, p <0.0001

Months

Overall Survival Progression Free Survival

6

Phase III Study of Erlotinib vs Placebo in Advanced NSCLC Failure to Chemotherapy (Study BR.21)

Adverse Events (%)

538952Anorexia4

118<1

2369

Grade 3, 4

24

27521723335475

Any

ErlotinibTM

(n=485)

03Stomatitis2045Fatigue<19Ocular (all)

2

22

<10

Grade 3, 4

Placebo(n=242)

15Infection

19Vomiting24Nausea18Diarrhoea17Rash

Any

Skin Rash is a Predictor of Response to Erlotinib

Surv

ival

dis

trib

utio

n fu

nctio

n

0.00

0.25

0.50

0.75

1.00

Months0 5 10 15 20 25 30

Grade 2/3 (n=17)

Grade 1 (n=26)

None (n=14)

Grade Median survival (95% CI) No rash 1.5 (1−2.2) Grade 1 8.5 (4.8−14.8) p<0.0001* Grade 2/3 19.6 (10.8−+) p<0.0001* *vs no rash

Perez-Soler R, et al. Am Soc Clin Oncol Mol Ther Symp. 2002

Safety of Erlotinib

! Erlotinib at 150mg/day (the maximum tolerated dose) was well tolerated

! Rash and diarrhoea were the most common adverse events and were generally mild or moderate in severity

! 10% of Erlotinib-treated patients had dose reductions due to rash and 7% had dose interruptions >7 days

! Although incidence of pulmonary infection was higher in the Erlotinib group, the incidence of pulmonary infections per patient week was the same as for the placebo group

! Only 5% of patients discontinued Erlotinib due to related adverse events (2% in the placebo arm)

Summary of BR.21 Study

!This is the first placebo controlled randomized trial to confirm that an oral tyrosine kinase inhibitor of EGFR can prolong survival

!Treatment with erlotinib was associated with significantly– longer overall survival– longer progression free survival– improved lung cancer-related symptoms– improved QoL

Comparison of Erlotinib versus Chemotherapy in Relapsed NSCLC: Efficacy

8.35.7–7.96.7Median survival (months)

9.459.159.42Median survival in PS 0/1 patients with 1 prior regimen (months)

3030–37311-year survival rate (%)

4.65.3–9.17.9Median duration of response (months)

9.17.1–8.88.9Response rate (%)

Pemetrexed(500mg/m2)

Docetaxel (75mg/m2)

Erlotinib (150mg/day)Outcome

1Shepherd F, et al. N Engl J Med 2005;353:123–32; 2OSI and Roche data on file; 3Shepherd F, et al. J Clin Oncol 2000;18:2095–103; 4Fossella F, et al. J Clin Oncol 2000;18:2354–62; 5Hanna N, et al. J Clin Oncol 2004;22:1589–97

*Results cannot be compared directly because of different patient populations

! Erlotinib and chemotherapy have similar efficacy in the second-line setting

Adverse Events of Erlotinib vs Chemotherapy

Shepherd F, et al. N Engl J Med 2005;353:123–32Hanna N, et al. J Clin Oncol 2004;22:1589–97

Serious haematological toxicities may require hospitalisation and blood transfusions

Patients (%)

Adverse event (grade 3/4)

Erlotinib (150mg/day)

Docetaxel (75mg/m2)

Pemetrexed (500mg/m2)

Neutropenia <1 40.2 5.3

Febrile neutropenia <1 12.7 1.9

Anaemia <1 4.3 4.2

Thrombocytopenia <1 0.4 1.9

! No haematological toxicities reported with Erlotinib! Main reported toxicities were rash and diarrhoea

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An expanded access clinical program of Erlotinib in patients with advanced stage IIIB/ IV non-small

cell lung cancer in Thailand

TRUST : Erlotinib LUng Cancer Survival Treatment

Narin Voravud M.D. Vichien Srimuninnimit M.D. Pornchai Jonglertham M.D.

Protocol: Objectives! Primary

– To provide Erlotinib to patients with advanced stage IIIB /IV Non Small Cell Lung Cancer

! Secondary

– Response Rate

– Time to Progression

– Safety (SAEs and Adverse Events leading to premature withdrawal, unexpected erlotinib-related AEs and erlotinib-related rash)

– Survival

– Correlation of EGFR expression rate (HER1) and other markers potentially predictive for response

Tumour Response

13%4Progressive disease

17%5*Not done

53%16Stable disease

17%5Partial response

0%0Complete response

N = 30Best response

• 3 cases has not reached the evaluation

• 2 cases were SAE (pulmonary emboli, sudden death)

Before Erlotinib

2 months after Erlotinib

Median Time to Disease Progression & Overall Survival

Median TTP 315 days

Erlotinib - Related Rash

Grade 1•Macular or papulareruption or erythema•No symptom

Grade 2•Macular or papulareruption or erythema•Pruritis or other symptoms

2A-Symtomatic but tolerable2B-Symptomatic, interfere

daily life

Grade 3•Severe, generalisedErythroderma or macular,papular,vesicular eruption

Grade 4•Generalised exfoliative, Ulcerative,bullous dermatitis

Grade 1,2 = 93% (28/30) Grade 3,4 = 3% (1/30)

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Management of Erlotinib-Related Rash

Primary rashTreatment! Topical corticosteroids! Analgesia

Secondary infected rashPrevention! Intranasal mupirocin (apply O.D.)

Treatment! Topical antibiotics (clindamycin)! Oral antibiotics (minocycline)! Topical mupirocin for S.aureus

Recommendations•Emollient cream•Sunscreen•Evaluate 1-2 wks•Prohibit topical retinoids and benzoyl peroxide•Unresponsive -> Dose reduction or interruption

Management of Erlotinib-Related Diarrhoea

! 4 mg Loperamide at onset of symptom! 2 mg Loperamide every 2-4 hrs

Unresponsive to loperamide!Dose reduction or interruption

Phase III studies of Gefitinib (ISEL): Survival

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Month: 0 2 4 6 8 10 12 14At risk: 1692 1348 876 484 252 103 31

Patie

nts

surv

ivin

g (%

)

1 yr survival

Median (mo)

HR = 0.89 (0.78, 1.03), P = .11N = 1692, deaths = 969Cox analysis, P = .042

22%27%

5.15.6PlaceboGefitinib1.0

0.90.80.70.60.50.40.30.20.10.0

—— Gefitinib------ Placebo

*HR and p-value adjusted for stratification factors at randomisation + HER1/EGFR status

Study BR.21 Overall survival of Erlotinib VS Placebo

42.5% improvement in median survival

Surv

ival

dis

trib

utio

n fu

nctio

n

Survival time (months)

ErlotinibTM

Placebo

HR* = 0.73, p<0.001

TarcevaTM (n=488)

Placebo (n=243)

Median survival (months) 6.7 4.7

1-year survival (%) 31 21

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30

Phase III studies of Erlotinib and Gefitinib: Results

Subset analysis

Overall survival

No survival benefit in adenocarcinoma (HR=0.84,

p=0.089)Suggestion of survival benefit in never-smokers and patients

of Asian origin

Evidence of survival benefit in most subgroups tested,including adenocarcinoma

(HR=0.7, p=0.008)

HR=0.89 (p=0.087)Gefitinib: 5.6 monthsPlacebo: 5.1 months

HR=0.73 (p<0.001)Erlotinib: 6.7 monthsPlacebo: 4.7 months

Gefitinib(n=1692)

Erlotinib(n=731)

1Shepherd FA, et al. N Engl J Med 2005;353:123–322Thatcher N, et al. Lancet 2005;366:1527–37

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Targeted Therapy in Lung CancerThailand! Erlotinib has approved in 2nd and 3rd line NSCLC treatment.! Gefitinib has approved only in 3rd line NSCLC treatment.

USA! Erlotinib has approved in 2nd and 3rd line NSCLC treatment.! Gefitinib is no longer for new patients.

EMEA! Erlotinib has approved in 2nd and 3rd line NSCLC treatment.! Gefitinib has not approved.

Chromatin Remodeling: Histone Modifications

Targeting Histone Modifying Enzymesin Cancer Treatment

HAT / HDAC and Gene Expression

Growth Factors and the mTOR Pathway

Protein Production

Akt/PKB

4E-BP1

PI3-K

PTEN

S6

S6K1

elF-4E

Growth FactorsIGF-1, EGF, TGFα, VEGF,

etc

Cell Growthand Proliferation

Angiogenesis

mTOR

Oxygen, energy, and nutrients

Ras/RafAbl

ER

!mTOR

– Intracellular protein

– Central controller ofcell growth andproliferation

!mTOR signaling is often deregulated in cancer

!Downstream inhibition of mTOR has potential for

– Antiproliferative effects on tumor cells

– Angiogenesis inhibition

– Enhancement of the effects of chemotherapy

TSC2 TSC1

Ras/Rafpathway kinases

Human Epidermal Growth Factor Receptor-2 (HER-2) Positive Breast Cancer

! 20% of Breast Cancer!Aggressive disease with short survival!Resistance to several chemotherapy!Response to anti HER-2 antibody (Trastuzumab)

Median survival

HER2 positive 3 years

HER2 negative 6–7 years

Slamon DJ et al. Science 1987;235:177–82

!Targets HER2 protein!High affinity (Kd = 0.1 nM) and specificity!95% human, 5% murine

– Decreases potential for immunogenicity

– Increases potential for recruiting immune effectormechanisms

HER2 epitopes recognized by hypervariable murine

antibody fragment

Human IgG-1

Trastuzumab (Herceptin®):Humanized Anti-HER2 Antibody

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Trastuzumab plus Chemotherapy in Advanced Breast Cancer Improves Survival

Smith IE. Anticancer Drugs.2001;12:S3–10

1.0

0.8

0.6

0.4

0.2

0

Time (months)

0 5 10 15 20 25 30 35 40 45 50

17.9 24.8

Prob

abili

ty o

f sur

viva

l

↑ 40%

Trastuzumab + paclitaxelPaclitaxel

Extra et al. Eur J Cancer. 2004;2:125. Abstract 239.

1.0

36Month

sIntent-to-treat population, 12-month cut-offDocumented crossover = 48%

P = 0.0062

8.4 months

22.1 30.5

Trastuzumab + docetaxelDocetaxel

0.8

0.6

0.4

0.2

0.0 33302724211815129630

Trastuzumab + Paclitaxel Trastuzumab + Docetaxel

Trastuzumab plus a Taxane inHER-2 Positive Metastatic Breast Cancer

1Slamon DJ, et al. N Engl J Med 2001;344:783–922Baselga J. Oncology 2001;61(Suppl. 2):14–21

3Marty M, et al. J Clin Oncol 2004. In Press

Slamon1,2 Marty3

Outcome

H + P (n=68)

P (n=77)

H + D (n=92)

D (n=94)

ORR (%) 49.0 17.0 61.0 34.0

TTP (months) 7.1 3.0 10.6 5.7

OS (months) 24.8 17.9 30.5 22.1

ORR = objective response rateTTP = time to disease progression OS = overall survivalH = HerceptinP = paclitaxelD = docetaxel

Adjuvant Trastuzumab Efficacy in Early Breast Cancer: Disease Free Survival

0 1 2

HERA 1 year

Combined analysis 2 years

Median follow-up

FavoursHerceptin

Favours noHerceptin

HR

BCIRG 006 DCarboH 2 years

2 yearsBCIRG 006 AC DH

FinHER VH / DH CEF 3 years

Piccart-Gebhart et al 2005; Romond et al 2005;Slamon et al 2005; Joensuu et al 2005 Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25

Angiogenesis is involved throughout tumour formation, growth and metastasis

Stages at which angiogenesis plays a role in tumour progression

Premalignantstage

Malignanttumour

Tumourgrowth

Vascularinvasion

Dormantmicrometastasis

Overtmetastasis

(Avasculartumour)

(Angiogenicswitch)

(Vascularisedtumour)

(Tumour cellintravasation)

(Seeding indistant organs)

(Secondaryangiogenesis)

Tumour characteristics and environment promote VEGF expression

EGF

Hypoxia PDGF

IL-8

bFGF

COX-2Nitric oxideOncogenes

VEGF releaseBinding and activation

of VEGF receptor

IGF-1

ProliferationSurvival Migration

ANGIOGENESISPermeability

Increased expression(MMP, tPA, uPA, uPAr,

eNOS, etc.)

– P– P

P–P–

Agents inhibiting angiogenesis through the VEGF pathway

VEGFVEGF

receptor-2

Cation channel

↑ Permeability

Antibodies inhibiting VEGF(e.g. bevacizumab)

Antibodies inhibiting VEGF receptors Soluble VEGF receptors

(VEGF-TRAP)

Small-molecules inhibiting VEGF receptors

(TKIs)(e.g. PTK-787)

Ribozymes(Angiozyme)

– P– PP–

P–

– P– P

P–P–

– P– P

P–P–

Migration, permeability, DNA synthesis, survival

LymphangiogenesisAngiogenesis

11

Summary: mechanism of action of anti-VEGF therapy

! Inhibition of VEGF may act against tumours in three ways– regression of existing microvasculature– normalisation of mature vasculature – inhibition of production of new vasculature

EARLY BENEFIT CONTINUED BENEFIT

Regressionof existing microvasculature

Normalisationof surviving microvasculature

Inhibitionof vessel regrowth and neovascularisation

Phase III trial of IFL ± Bevacizumabin metastatic Colorectal Cancer : survival

Median survival (months)IFL + placebo: 15.6 (95% CI: 14.3–17.0) vsIFL + Bevacizumab: 20.3 (95% CI: 18.5–24.2)HR=0.66 (95% CI: 0.54–0.81)p<0.001

CI = confidence intervalHR = hazard ratio

Pro

babi

lity

of s

urvi

val

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Survival (months)

IFL + BevacizumabIFL + placebo

15.6 20.3

Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Targeted Therapy in Colorectal Cancer Bevacizumab

Approved Indication! First-line treatment in combination with 5FU-based chemotherapy for

advanced colorectal cancer

Adverse events! Hypertension! Proteinuria! GT perforation, bleeding

Future Perspectives of Targeted Therapy

Narin Voravud, M.D.Medical Oncology Unit, Department of Medicine,

Faculty of Medicine, Thai Red Cross Society and King Chulalongkorn Memorial Hospital, Chulalongkorn University

Bangkok, Thailand

The 1st Asia Pacific Oncology Pharmacy Congress(APOPC)

August 5, 2006 Bangkok, Thailand

Published Randomized Trials of Targeted Therapy in Non-Small Cell Lung Cancer

1Hamilton M, et al. Proc Am Assoc Cancer Res 2005;43 (Abs. 6165)

No benefitPaclitaxel+CarboplatinLonafinibFarnesyltransferase

No benefitPaclitaxel+CarboplatinBMS 275291No benefitPaclitaxel+CarboplatinAG 3340Metalloproteinase

(Ras oncogene)

Benefit in non -

smoker

Paclitaxel+CarboplatinErlotinib(TRIBUTE)

EGFRNo benefitGemcitabine+CisplatinGefitinib

No benefitGemcitabine+CisplatinErlotinib (TALENT)

No benefitPaclitaxel+CarboplatinGefitinibEGFR

OutcomeChemotherapyTargeted AgentTarget

Published Randomized Trials of Targeted Therapy in Non-Small Cell Lung Cancer

1Hamilton M, et al. Proc Am Assoc Cancer Res 2005;43 (Abs. 6165)

↑Survival

↑Response Rate

Paclitaxel+CarboplatinBevacizumabVascular Endothelial

No benefitPaclitaxel+CarboplatinBexaroteneRetinoid X Receptor

↑PFSGrowth Factor

No benefitPaclitaxel+CarboplatinISIS 3521Protein kinase C

OutcomeChemotherapyTargeted AgentTarget

12

Ongoing Randomized Trial of Erlotinib inNon – Small Cell Lung Cancer

Advanced NSCLLTITAN

after platinum-based x 4(N=854)

after platinum-based chemotherapy(N=648)

Advanced NSCLLSATURN

(EGFR+)first-line

Advanced NSCLLOSI-774-203

Adjuvant treatment(N=945)

NSCLC (EGFR+)RADIANT

Second-line(N=650)

Advanced NSCLLBETA

after chemotherapy(N=1150)

Advanced NSCLLATAS

Study

RErlotinib+bevacizumab

Placebo+bevacizumab

RErlotinib+bevacizumab

Erlotinib+Placebo

RErlotinibPlacebo

RErlotinib

Erlotinib

Pemetrexed

R

Docetaxel

chemotherapy x 4+ Erlotinib

RErlotinibPlacebo

First-line phase III trial of Erlotinib sequencing with chemotherapy

! Primary endpoint: survival! Secondary endpoints: QoL, PFS, molecular

assessment! Enrolment planned to start Q1 2006

Gemcitabine + cisplatinsix cycles

Erlotinib150mg/day

Chemotherapy-naïve stage

IIIB/IV NSCLC (n>900)

Gemcitabine + cisplatinsix cycles

Erlotinib150mg/day

PD

PD

Erlotinib/bevacizumab phase I/II combination trial: rationale

Tumour

Inhibitor Erlotinib bevacizumabMechanism Inhibits tumour cell growth

and blocks synthesis of angiogenic proteins (e.g. bFGF, VEGF, TGF-α) by tumour cells

Binds to the angiogenic protein VEGF, and inhibits all of its functions

bFGFVEGFTGF-α

Endothelial cells

Sandler AB, et al. Proc ASCO 2004;23:127 (Abs. 2000)Herbst RS, et al. J Clin Oncol 2005;23:2544–55

Phase III trial of bevacizumab plus Erlotinib in NSCLC

bevacizumab15mg/kg +

Placebo

Chemotherapy naïve stage IIIB/IV non-squamous

NSCLC (n≈1,100) Erlotinib

150mg/day

Non-PD

*Specified regimens: carboplatin/paclitaxel, carboplatin/gemcitabine, carboplatin/docetaxel

Off study

bevacizumab15mg/kg +Erlotinib

150mg/day

PD

Off study

(n≈800)

PD

1:1Bevacizumab 15mg/kg plus

chemotherapy*

PD or significant

toxicity

Conclusions

!Progress in molecular oncology has Identified potential targets for cancer treatment.

!Targeted therapy becomes new standard treatment in oncology.

!Survival benefits are achievable with Erlotinib,Trustuzumab, and Bevacizumab.

!Combinded chemotargeted therapy or new targeted therapy to different or many targets are under active investigation.

Thank you for your attention