LUNG CANCER MOLECULAR THERAPY Prof. Dr. Can ÖZTÜRK

LUNG CANCER MOLECULAR THERAPY

Prof. Dr. Can ÖZTÜRK

Gazi University School of Medicine Department of Pulmonology

Crude Rate* ASR (World)

LungLung 37.337.3 47.747.7

StomachStomach 9.69.6 12.212.2

BladderBladder 8.68.6 11.011.0

ColorectalColorectal 7.4 7.4

9.1 9.1

LarinxLarinx 6.46.4 8.08.0

ProstateProstate 6.16.1 8.08.0

LeukemiaLeukemia 5.15.1 5.85.8

Brain,CNS Brain,CNS

3.93.9 4.54.5

NHLNHL 3.33.3 3.8 3.8

Oral cavityOral cavity 2.62.6 3.23.2

Total(exceTotal(except skin)pt skin)

110.3110.3 137.3137.3

Turkey - Male (All ages)

*per 100.000

Crude Rate* ASR (World)

BreastBreast 19.919.9 22.022.0

Colorectal Colorectal

7.67.6 8.58.5

StomachStomach 5.75.7 6.46.4

OvariumOvarium 4.84.8 5.45.4

LungLung 4.64.6 5.35.3

LeukemiaLeukemia 4.44.4 4.74.7

Corpus-Corpus-UterusUterus

4.14.1 4.84.8

Cervix- Cervix- UterusUterus

4.04.0 4.54.5

Brain, CNS Brain, CNS 3.53.5 3.83.8

Non-Non-Hodgkin Hodgkin lenfoma lenfoma

2.92.9 3.13.1

Total(excepTotal(except skin) t skin)

82.082.0 91.291.2

Turkey - Female (All Ages)

*per 100.000

UNTREATED NSCLC- PROGNOSISUNTREATED NSCLC- PROGNOSIS

STAGESTAGE MS(Mts)MS(Mts) 1yr. Sur.(%)1yr. Sur.(%) 2yr. Sur.(%) 2yr. Sur.(%)

c I, IIc I, II 1313 5656 88

c IIIc III 4-94-9 16-3016-30 0-40-4

c IVc IV 33 -- --

UNTREATED SCLC- PROGNOSISUNTREATED SCLC- PROGNOSIS

STAGESTAGE MEDIAN SUR.MEDIAN SUR. 1 YR. SURVIVAL1 YR. SURVIVAL

LIMITEDLIMITED

++

Supportive CareSupportive Care

12 weeks12 weeks

18 weeks18 weeks % 7% 7

EXTENSIVEEXTENSIVE

++

Supportive CareSupportive Care

5 weeks5 weeks

8 weeks8 weeks

TreatmentTreatment- Prognosis- Prognosis

Status of treatment is dismalStatus of treatment is dismal

Five year survival Five year survival approx.approx. 15% 15%– 61% for Colon61% for Colon– 86% for Breast86% for Breast– 96% for Prostate96% for Prostate

NSCLC – Survival based on stagesNSCLC – Survival based on stages

Greene et al, eds. AJCC Cancer Staging Manual. 6th ed. 2002.

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5

Years following diagnosis

% S

urv

ival

Stage IStage IIStage IIIStage IV

5 year survival - TARGETS5 year survival - TARGETS

NSCLC CURRENT TARGETNSCLC CURRENT TARGET

STAGE STAGE % % % %

IAIA 70-85 85-95 70-85 85-95

IBIB 60-70 70-85 60-70 70-85

IIAIIA 35-45 45-60 35-45 45-60

IIB 25-35 35-45IIB 25-35 35-45

IIIA 5-20 20-30IIIA 5-20 20-30

IIIB 3-7 10-20IIIB 3-7 10-20

IV <1 2-5IV <1 2-5

SCLC CURRENT TARGETSCLC CURRENT TARGET

STAGE STAGE % % % %

LTD 15-25 25-30LTD 15-25 25-30

EXT <1 2-5EXT <1 2-5

Langer CJ, Fox Chase Cancer Center-2006

NSCLC- Systemic TherapyNSCLC- Systemic Therapy

Uptodate standart therapiesUptodate standart therapiesEpidermal Epidermal GrowthGrowth Fa Faccttoor Rer Recceptor (EGFR) eptor (EGFR) InhibitorsInhibitors– Gefitinib (Iressa)Gefitinib (Iressa)– Erlotinib (Tarceva)Erlotinib (Tarceva)

Anti-Anti-EGFR MonoEGFR Monocclonal antilonal antibodiesbodies– Cetuximab (Erbitux)Cetuximab (Erbitux)

Anti-Anti-VasVascucullaar Endotr Endothheleliial al GrowthGrowth Fa Faccttoor (VEGF) r (VEGF) MonoMonocclonal antilonal antibodybody– Bevacizumab (Avastin-Altuzan)Bevacizumab (Avastin-Altuzan)

2-drug platinum-based combinations2-drug platinum-based combinations

Schiller JH. NEJM 2002; 346:92-98

Systemic TherapySystemic Therapy – – First LineFirst Line

2 drug platinum based regimens

Results- First LineResults- First Line

Medan survival8 months

Survival

TTP

Schiller JH. NEJM 2002; 346:92-98

MedianTTP3.7 months

Response rate%19

Second Line TherapiesSecond Line Therapies

Docetaxel Docetaxel is superior than best supportive is superior than best supportive carecare

Response rateResponse rate % % 77 MedMedian survivalian survival 7.0 vs 4.6 7.0 vs 4.6 monthsmonths* * MedMediian TTP 10.6 vs. 6.7 an TTP 10.6 vs. 6.7 weeksweeks**

Pemetrexed (Alimta) Pemetrexed (Alimta) is effective as is effective as docetaxeldocetaxel, , but less toxicity profilebut less toxicity profile

Shepherd et al. JCO 2000;18:2095-2103Hanna et al. JCO 2004; 22:1589-97

Targeted Therapies in Lung CancerTargeted Therapies in Lung Cancer

GeneGeneralral SpesifiSpesificc

AngiogenesisAngiogenesis VEGFVEGFVEGFRVEGFRFGFFGFIntegrinIntegrin

EGFR EGFR familyfamily EGFREGFRHER2HER2

SiSignalgnal RasRasRaf kinazRaf kinazMEKMEKmTORmTORPKCPKC

GeneGeneralral SpesifiSpesificc

Cell CycleCell Cycle cdkscdks

ApoptoApoptosissis Bcl-2Bcl-2SurvivinSurvivinXIAPXIAPP53P53clusterinclusterin

OthersOthers DNA MTaseDNA MTaseHDACHDACproteproteoosomsom

ExtracellularExtracellular MMPMMP

ReReceptors/ceptors/kinaseskinases

C-kitC-kitPDGFRPDGFRablabl

Targeted TherapiesTargeted Therapies

EGFR EGFR IInhibitornhibitorss– Gefitinib (Iressa)Gefitinib (Iressa)– Erlotinib (Tarceva)Erlotinib (Tarceva)

Anti-Anti-EGFR MonoEGFR Monocclonal antilonal antibodybody– Cetuximab (Erbitux)Cetuximab (Erbitux)

Anti-Anti-VEGF MonoVEGF Monocclonal antilonal antibodybody– Bevacizumab (Avastin-Altuzan)Bevacizumab (Avastin-Altuzan)

Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor (EGFR) (EGFR) && Human Cancer Human Cancer

EGFR critically regulates tumor cell division,EGFR critically regulates tumor cell division, proliferation, proliferation, repair repair

EGFR may play a critical role in EGFR may play a critical role in metastasismetastasis, angiogenesis, , angiogenesis, invasioninvasion

Binding of specific ligands to EGFR (eg, EGF, TGF-Binding of specific ligands to EGFR (eg, EGF, TGF-) activates ) activates the receptor and triggers signal transduction cascades that the receptor and triggers signal transduction cascades that affect cell proliferationaffect cell proliferation

EGFR is expressed in a significant percentage of human tumors EGFR is expressed in a significant percentage of human tumors and is correlated with poor prognosis, decreased survival, and is correlated with poor prognosis, decreased survival, and/or increased metastasisand/or increased metastasis

Inhibition of EGFR on tumor cells may inhibit the growth or Inhibition of EGFR on tumor cells may inhibit the growth or progression of EGFR-expressing tumorsprogression of EGFR-expressing tumors

TK Intracellular area

Transmembranous area

Extracellular area

EGFR structure

Tumors showing high EGFR expression

High expression generallyassociated with

EGFR expression in human tumorsEGFR expression in human tumors

NSCLCNSCLC 40-80%40-80%

ProstateProstate 40-80%40-80%

GastricGastric 33-74%33-74%

BreastBreast 14-91%14-91%

ColorectalColorectal 25-77%25-77%

PancreaticPancreatic 30-50%30-50%

OvarianOvarian 35-70%35-70%

InvasionInvasion

Metastasis Metastasis

Late-stage diseaseLate-stage disease

Chemotherapy resistanceChemotherapy resistance

Hormone-therapy resistanceHormone-therapy resistance

Poor outcomePoor outcome

NSCLC-NSCLC- EGFR & HER2 EGFR & HER2

86

35

25

85

30

60

10

66

0

10

20

30

40

50

60

70

80

90

100

Sq (n=36) Ad (n=73) LC (n=16) BAC (n=10)

Histology

Frequency (

%)

EGFR HER2

F. Hirsch et al. Semin Oncol, 2002F. Hirsch et al. Semin Oncol, 2002

Lung Cancer-EGFR expression

NSCLC-NSCLC- EGFR & HER2 EGFR & HER2SurvivalSurvival

Relationship of HER1 & HER2 to Survival in NSCLC

J. Brabender et al. Clin Cancer Res, 2001J. Brabender et al. Clin Cancer Res, 2001

EGFR Targeted TherapiesEGFR Targeted Therapies

Inhibition of EGFR signalling with either the monoclonal Inhibition of EGFR signalling with either the monoclonal Ab or the tyrosine kinase inhibitors(TKI) reduces Ab or the tyrosine kinase inhibitors(TKI) reduces proliferation in a variety of epithelial tumor cells and blocks proliferation in a variety of epithelial tumor cells and blocks cell cycle progression in the G1 phasecell cycle progression in the G1 phase

Inhibition of cell cycle progression is an effective Inhibition of cell cycle progression is an effective mechanism for modulating the growth of tumorsmechanism for modulating the growth of tumors

EGFR inhibition, using TKI; induce apoptosis (in human EGFR inhibition, using TKI; induce apoptosis (in human tumor cells and vascular endothelial cells)tumor cells and vascular endothelial cells)

Ongoing trials are evaluating the clinical utility of EGFR Ongoing trials are evaluating the clinical utility of EGFR inhibitors for the treatment of EGFR-expressing cancersinhibitors for the treatment of EGFR-expressing cancers

Acquired spesifications of Cancer CellsAcquired spesifications of Cancer Cells

SpesificationsSpesifications

Autocrine growth signalAutocrine growth signal YesYes Yes Yes

Insensitivity to anti-growth signalsInsensitivity to anti-growth signals Yes Yes Yes YesAwareness of cell deathAwareness of cell death Yes Yes Yes YesUncontrolled proliferationUncontrolled proliferation Yes Yes Yes YesContinious angiogenesisContinious angiogenesis Yes Yes Yes YesTissue invasion and MetastasisTissue invasion and Metastasis YesYes Yes Yes

Decrease by EGFR Inhibition

Hanahan ve Weinberg, Cell, 2000Hanahan ve Weinberg, Cell, 2000

Increase by EGFR activation

TKI

Proliferation

Invasion

MetastasisAngiogenesis

Apoptosis

Adhesion

Sensitivity to chemotherapy

TKI-Small moleculesTKI-Small molecules: mechanism of : mechanism of actionaction

Etessami A, et al. Drugs Fut 2000;25:895–9Moyer J, et al. Cancer Res 1997;57:4838–48

Harari PM, et al. Semin Radiat Oncol 2002;12(Suppl. 2):21–6

Gene Transcription

G0G1

Priming

S

G2

M

Cell CycleCell Cycle

Growth Factor

++

Growth Factors & Cell Cycle

Receptors

Untreated advanced NSCLC*

Stratification:Weight loss in last 6

months(%5 vs >%5)

PS: 0 - 1 vs 2

*Evre IIIB/IV KHDAK†INTACT = IRESSA NSCLC Trial Assessing Combination Therapy; INTACT 1 (N=1093) gemcitabin (1250 mg/m2)/cisplatin (80 mg/m2); INTACT 2 (N=1037) paclitaxel (225 mg/m2)/carboplatin (AUC=6).

Chemo† x 6 cycles + 250 mg gefitinib

Chemo† x 6 cycles + 500 mg gefitinib

Chemoi† x 6 cycles + Placebo

Gefitinib / Placebo until progression

Randomise

Gefitinib-Gefitinib- with Chemotherapy with ChemotherapyFirst Line-Phase IIIFirst Line-Phase III

INTACT 1 & 2

Gefitinib-Gefitinib- with Chemotherapy with ChemotherapyFirst Line-Phase IIIFirst Line-Phase III

Med. survival

~10 months

~10 months

Gefitinib – Gefitinib – Second & Third LineSecond & Third Line--Phase II Phase II

Patient no. Response Rate (%)Median

survival (Mts)

IDEAL-1Japan, Europe, Australia, S. Africa

208% 18.4 (total)% 27.5 (Japan)% 10.4 (Non-Japan)

7.6

IDEAL-2United States 216 12 % 7

250mg ve 500mg doses- no difference in efficacyAdverse effects- acceptable (rash and diarrhea) – more frequent in 500 mg group

IDEAL-1: M. Fukuoka et al. JCO 2003; 21:2237-2246

IDEAL-2: MG Kris et al. JAMA 2003; 2149-2158

(250mg vs. 500mg)

Inclusion Criteria• Stage IIIB veya IV NSCLC• Treated with platinum

based CT( 1 or 2 times)• PS 0-3

Gefitinib – Gefitinib – Second & Third LineSecond & Third Line--Phase III Phase III ISEL: Iressa Survival Evaluation in Lung CancerISEL: Iressa Survival Evaluation in Lung Cancer

Gefitinib 250 mg/gün

Placebo

RANDOMİZE

N=1692

Thatcher et al. Lancet 2005

Thatcher et al. Lancet 2005

Gefitinib – Gefitinib – Second & Third LineSecond & Third Line--Phase III Phase III ISEL - SISEL - Survivalurvival

1.0

0.6

0.8

0.2

0.0

0.4

0 162 144 10 1286

Pro

bab

ility

Months

(n=1129)Placebo(n=563)

Median survival (mts)

1-year survival (%)

5.6 5.1

27

HR=0.89 (95% CI, 0.78-1.03)* P<0.11*

22

Gefitinib

Gefitinib

Placebo

Erlotinib-Erlotinib-With ChemotherapyWith Chemotherapy--First Line - Phase IIIFirst Line - Phase III

TALENT TALENT studystudy - Cisplatin/gemcitabin - Cisplatin/gemcitabinee + + (tarceva (tarceva oror pla placcebo) ebo)

1172 1172 ptspts, , chchemo-naiveemo-naive

TarcevaTarceva PlaPlacceboebo

Med. sMed. survivalurvival ((daysdays))

301301 309309

TTP (TTP (daysdays)) 167167 179179

Gatzemeier U. ASCO 2004 Abstract

Erlotinib-Erlotinib-with chemotherapywith chemotherapy--First Line-Phase IIIFirst Line-Phase III

TRIBUTE TRIBUTE studystudy - - CCarboplatin/paclitaxel + arboplatin/paclitaxel + (tarceva (tarceva or placeboor placebo))

1059 1059 ptspts, , chchemo-naiveemo-naive

TarcevaTarceva PlaceboPlacebo

Med. Med. survivalsurvival ((mtsmts))

10.810.8 10.610.6

RR (%)RR (%) 21.521.5 19.319.3

TTP (TTP (mtsmts)) 5.15.1 4.94.9

Herbst R. J Clin Oncol 2005

Erlotinib-Erlotinib-with chemotherapywith chemotherapy--First Line-Phase IIIFirst Line-Phase III

TRIBUTE TRIBUTE studystudy – – Subgroup analysisSubgroup analysis::

NonsmokersNonsmokers

tarceva vs platarceva vs placcebo:ebo:

MedMediian san survivalurvival = 23 = 23 mtsmts v vs.s. 10 10 mtsmts

Miller VA et al. ASCO 2004 Abstract

Why are TALENT and TRIBUTE negative Why are TALENT and TRIBUTE negative

studies? Possible explanationsstudies? Possible explanations

Concurrent use may be antagonisticConcurrent use may be antagonistic

– in vitro evidence of antagonism with combination chemotherapy in vitro evidence of antagonism with combination chemotherapy regimensregimens

Remarkable benefit in the non-smoker subset:Remarkable benefit in the non-smoker subset:

– smoking potentially reduces exposure to Tarceva via induction of smoking potentially reduces exposure to Tarceva via induction of metabolising enzymesmetabolising enzymes11

Triplets are redundant doublets; Tarceva kills the same Triplets are redundant doublets; Tarceva kills the same tumour cell population?tumour cell population?

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

BR.21 Phase III

Erlotinib – Erlotinib – Second or Third LineSecond or Third Line

Erlotinib – Erlotinib – Second or Third LineSecond or Third LineBR.21 Phase III

Stratification

• Center

• PS: 0-1 vs. 2-3

• Previous response: PR vs. SD vs. PD

• Previous CT: 1 vs. 2

• Previous cisplatin: Yes or No

RANDOMISE

Erlotinib: 150 mg/day

Placebo: “150 mg”/day

2

1

Erlotinib – Erlotinib – Second or Third LineSecond or Third LineBR.21 Phase III

TarcevaTarceva

(n=488)(n=488)

PlaPlacceboebo

(n=243)(n=243)

RR (%)RR (%) 8.98.9 <1<1

MedMedianian ssurvivalurvival 6.7 6.7 mtsmts** 4.7 4.7 mtsmts

PFSPFS 2.2 2.2 mtsmts** 1.8 1.8 mtsmts

Shepherd FA et al. NEJM 2005

En sık yan etki: kızarıklık, diyare

BR.21 Study-Survival

HR=0.73, P<0.001*

MedianSurvival (mts)

1-yearSurvival (%)

6.7 31.2

4.7 21.5

Months

% S

urv

iva

l

Erlotinib

Placebo

100

0 5 10 15 20 25 30

80

40

20

0

60

BR.21: BR.21: ToxicityToxicityPatientsPatients % %

ErlotinibErlotinib(n=485)(n=485)

PlaPlacceboebo(n=242)(n=242)

TotalTotal Grade 3Grade 3 Grade 4Grade 4 TotalTotal Grade 3Grade 3 Grade 4Grade 4

RashRash 7575 88 <1<1 1717 00 00

DiDiarrheaarrhea 5454 66 <1<1 1818 <1<1 00

AnoreksiAnoreksiaa 5252 88 11 3838 55 <1<1

FatigueFatigue 5252 1414 44 4545 1616 44

DDyspneyspne 4141 1717 1111 3535 1515 1111

CoughCough 3333 44 00 2929 22 00

EmesisEmesis 3333 33 00 2424 22 00

InfectionInfection 2424 44 00 1515 22 00

VomittingVomitting 2323 22 <1<1 1919 22 00

Tarceva (erlotinib) PI.

BR.21 BR.21 SummarySummary

Erlotinib Erlotinib has confered a survival advantage in previously treated and relapsed NSCLC has confered a survival advantage in previously treated and relapsed NSCLC

patientspatients

Erlotinib is effective in both subgroupsErlotinib is effective in both subgroups

Therapy is well toleratedTherapy is well tolerated

– Most frequent toxicity is rash and diarrheaMost frequent toxicity is rash and diarrhea

– Pulmonary toxicity is rare, but 30% fetalPulmonary toxicity is rare, but 30% fetal

BR.21BR.21 ISELISEL

No. of patientsNo. of patients 731731 16921692

Response rateResponse rate

Overall survivalOverall survival

1 1 year survivalyear survival

HRHR

P P valuevalue

%8.9%8.9

Tarceva = 6.7 Tarceva = 6.7 mtsmts

Plasebo = 4.7 Plasebo = 4.7 mtsmts

%31 vs. %21%31 vs. %21

0.730.73

<0.001<0.001

%8%8

Iressa = 5.6 Iressa = 5.6 mtsmts

Plasebo = 5.1 Plasebo = 5.1 mtsmts

%27 vs. %22%27 vs. %22

0.890.89

0.11 0.11

Response to TKI- Important factorsResponse to TKI- Important factors

GrGroupoup Response rateResponse rate (%)(%) pp

Male vs. FemaleMale vs. Female 19 v19 vs.s. 3 3 0.0010.001

AAsian vs. Non-sian vs. Non-AsianAsian 27.5 v27.5 vs.s. 10.4 10.4 0.00230.0023

AdAdeno. vs. otherseno. vs. others 13 v13 vs.s. 4 4 0.0460.046

BAC vBAC vs.s. adeno adeno 38 v38 vss 14 14 <0.001<0.001

Nonsmoker vs. Nonsmoker vs. smokersmoker 36 v36 vs.s. 8 8 <0.001<0.001

Fukuoka JCO 2003;21:2237-46. Kris JAMA 2003;290:2149-58. Miller JCO 2004;22:1103-09.

Erlotinib - Faz II Erlotinib - Faz II Survival & Grade of RashSurvival & Grade of Rash

Su

rviv

al

0.00

0.25

0.50

0.75

1.00

Months

0 5 10 15 20 25 30

Grade 2/3 (n=17)

Grade 1 (n=26)

Yok (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

NSCLC & EGFR Mutations

Gefitinib-EGFR mutaGefitinib-EGFR mutation andtion and amplifiamplificationcation

EGFREGFR EGFREGFR amplifi amplificationcation muta mutationtion

+ - + - + - + -

%%3333 %67 %67 %%17 %8317 %83

Obj. Obj. responseresponse(%)(%) 3636 3 (<.001)3 (<.001) 53 53 5 5 (<.001)(<.001)

Med. SMed. Survivalurvival (ay) (ay) 18.7 7.0 (.03) 18.7 7.0 (.03) 20.820.8 8.4 (.09)8.4 (.09)

1 y1 year survivalear survival (%)(%) 57 33 (.03) 57 33 (.03) 5757 38 38 (.22)(.22)

Cappuzzo JNCI 97:643,2005

Single agent Cetuximab

Phase II studyPhase II study

(n=60, ≥1 (n=60, ≥1 chemochemo):):

Response rateResponse rate: % 3.3: % 3.3

MedMediian TTPan TTP: 2.3 : 2.3 ayay

MedMediian an survivalsurvival: 8.1 mo.: 8.1 mo.

Well toleratedWell tolerated ((Most frequent adverse effectMost frequent adverse effect: : rashrash))

Lilenbaum ASCO 2005

Cetuximab-with chemotherapyCetuximab-with chemotherapy

Docetaxel 75 mg/m2

Every 3 weeksCetuximab400 mg/m2 every week then,250 mg/m2 every week

Kim ES. 2005 ASCO

Patients (no.=47)Stage IIIB/IV 1 previous CT Median KPS 80Faz II study

RR: % 28,SD %17TTP: ~3 mtsWell tolerated(rash, neutropenia)

Cetuximab- With chemotherapyCetuximab- With chemotherapy

RANDOMISATION

Cisplatin 80 mg/m2 Day 1Vinorelbin 25 mg/m2

Day 1,8. Every 3 weeksCetuximab 400 mg/m2

week 1, then 200 mg/m2

week 2 and 3

Cisplatin 80 mg/m2 Day 1Vinorelbin 25 mg/m2

Day 1,8 Every 3 weeks

Rosell 2004 ASCO

Patients (No.=86)Stage IV (%92)Chemo-naiveMedian KPS 90Faz II study

Cetuximab- With chemotherapyCetuximab- With chemotherapy

RR (%)RR (%)

((GAGA))

MedMediian an survivalsurvival

((mts)mts)

MedMediian an TTP (TTP (mtsmts))

Cisplatin/Vinor.Cisplatin/Vinor.2020

(7.6-32.4)(7.6-32.4)7.07.0 4.24.2

Cisplatin/Vinor.Cisplatin/Vinor.

++CetuximabCetuximab

3232

(17.5-46.0)(17.5-46.0)8.38.3 4.74.7

Rosell 2004 ASCO

What is VEGF?What is VEGF?

Key Key driverdriver of angiogenesis of angiogenesisStimulates angiogenic remodelling and Stimulates angiogenic remodelling and sproutingsproutingStimulates growth of endothelial cellsStimulates growth of endothelial cells, , promotes endothelial cell survival (i.e promotes endothelial cell survival (i.e prevents endothelial cell apoptosis and prevents endothelial cell apoptosis and vessel regression)vessel regression)Also known as VEGF-AAlso known as VEGF-ARelated molecules are VEGF-B, C and D, Related molecules are VEGF-B, C and D, placental growth factor (PlGF)placental growth factor (PlGF)When angiogenesis is stimulated , a When angiogenesis is stimulated , a region of the mature vessel becomes region of the mature vessel becomes destabilized and undergoes angiogenic destabilized and undergoes angiogenic sprouting if VEGF is presentsprouting if VEGF is presentBinds VEGF receptor-2 Binds VEGF receptor-2

VEGF ReceptorsVEGF Receptors

The biological effects of VEGF appear to be The biological effects of VEGF appear to be exerted through binding to VEGF receptor-2, exerted through binding to VEGF receptor-2, which is expressed predominantly on vascular which is expressed predominantly on vascular endothelial cellsendothelial cells

VEGF-2 receptor consists of 7 extracellular Ig VEGF-2 receptor consists of 7 extracellular Ig like domains, a transmembrane region and an like domains, a transmembrane region and an intracellular domain having tyrosine kinase intracellular domain having tyrosine kinase activityactivity

VEGFVEGF

This binding to trans-membrane receptors This binding to trans-membrane receptors activatesactivates;;

Proliferation of vascular endothelial cellsProliferation of vascular endothelial cells

Migration of vascular endothelial cellsMigration of vascular endothelial cells

Survival of immature endothelial cellsSurvival of immature endothelial cells

Increased vascular permeabilityIncreased vascular permeability

AngiogenesisAngiogenesis

The primary factor controlling vessel formation is The primary factor controlling vessel formation is lack of oxygenlack of oxygen

This triggers the secretion of pro-angiogenic This triggers the secretion of pro-angiogenic factors, principally vacular endothelial growth factors, principally vacular endothelial growth factor (VEGF) factor (VEGF)

TGF alfa/beta, fibroblast growth factor(FGF) are TGF alfa/beta, fibroblast growth factor(FGF) are other two pro-angiogenic growth factorsother two pro-angiogenic growth factors

AngiogenesisAngiogenesis

Tumor angiogenesis can be considered to Tumor angiogenesis can be considered to involve two phases ;involve two phases ;

Avascular phaseAvascular phase: lesions remain dormant and are not : lesions remain dormant and are not more than 1-2 mm diameter, proliferation and apoptosis more than 1-2 mm diameter, proliferation and apoptosis are balancedare balanced

Vascularization phaseVascularization phase: new vessels continue to form as : new vessels continue to form as long the tumor growslong the tumor grows

Why inhibit angiogenesis in NSCLC?Why inhibit angiogenesis in NSCLC?

Angiogenesis plays a role at several stages in the growth Angiogenesis plays a role at several stages in the growth and progression of all types of solid tumourand progression of all types of solid tumour

– tumours are incapable of growth beyond 1–2mm in the absence tumours are incapable of growth beyond 1–2mm in the absence of vasculatureof vasculature11

Expression of high levels of VEGF, the key mediator of Expression of high levels of VEGF, the key mediator of angiogenesis, is associated with poor prognosis in angiogenesis, is associated with poor prognosis in NSCLCNSCLC2–42–4

Novel combinations of existing chemotherapy agents are Novel combinations of existing chemotherapy agents are not predicted to provide increased survival benefit in not predicted to provide increased survival benefit in advanced NSCLC, suggesting that new therapeutic advanced NSCLC, suggesting that new therapeutic strategies are requiredstrategies are required55

1Folkman J. J Natl Cancer Inst 1990;82:4–6; 2Volm M, et al. Int J Cancer 1997;74:64–8 3O’Byrne KJ, et al. Br J Cancer 2000;82:1427–32; 4Fontanini G, et al. Br J Cancer 2002;86:558–63

5Socinski MA. Respir Care Clin N Am 2003;9:207–36

Why inhibit angiogenesis in NSCLC?Why inhibit angiogenesis in NSCLC?

Inhibition of angiogenesis, using antiangiogenic Inhibition of angiogenesis, using antiangiogenic agents has shown to be effective in preventing agents has shown to be effective in preventing tumor growthtumor growth

In some cases tumor regression has also been In some cases tumor regression has also been shownshown

Many antiangiogenic agents are currently in Many antiangiogenic agents are currently in devolopment, targeting various factors and devolopment, targeting various factors and stages in the regulation of angiogenesisstages in the regulation of angiogenesis

Anti-angiogenic agents in clinical Anti-angiogenic agents in clinical development for NSCLCdevelopment for NSCLC

DrugDrugMechanism Mechanism of actionof action Molecular target(s)Molecular target(s)

Stage of Stage of developmentdevelopment

BevacizumabBevacizumab Anti-VEGF Anti-VEGF antibodyantibody

VEGFVEGF Phase IIIPhase III

Sorafenib Sorafenib (BAY43-9006)(BAY43-9006)

TKITKI Raf-1, VEGFR-2, -3, PDGFR-Raf-1, VEGFR-2, -3, PDGFR-, Flt-3, c-, Flt-3, c-KitKit

Phase IIIPhase III

Sunitinib Sunitinib (SU11248)(SU11248)

TKITKI VEGFR-1, -2, -3, Flt-3, PDGFR-VEGFR-1, -2, -3, Flt-3, PDGFR-, -, -, c-, c-KitKit

Phase IIPhase II

Vatalanib Vatalanib (PTK787)(PTK787)

TKITKI VEGFR-1, -2, -3, PDGFR-VEGFR-1, -2, -3, PDGFR-, c-Kit, c-, c-Kit, c-FmsFms

Phase IIPhase II

CP-547,632CP-547,632 TKITKI VEGFR-2VEGFR-2 Phase IIPhase II

ZD6474ZD6474 TKITKI VEGFR-2, -3, EGFRVEGFR-2, -3, EGFR Phase IIPhase II

AG-013736AG-013736 TKITKI VEGFR-1, -2, -3VEGFR-1, -2, -3 Phase IIPhase II

Monoclonal antibodies against VEGFMonoclonal antibodies against VEGF Inhibitors of VEGF receptor tyrosine Inhibitors of VEGF receptor tyrosine kinaseskinases

Directly block interaction between Directly block interaction between VEGF and its receptorsVEGF and its receptors

Block signalling by activated VEGF Block signalling by activated VEGF receptorsreceptors

Prevent activation of downstream Prevent activation of downstream signalssignals

Down-regulate signalling pathways Down-regulate signalling pathways which are already activatedwhich are already activated

Bind specifically to VEGFBind specifically to VEGF Interact with other receptor tyrosine Interact with other receptor tyrosine kinases; effects are not all specific to kinases; effects are not all specific to angiogenesis inhibitionangiogenesis inhibition

Specific action on VEGF; minimal Specific action on VEGF; minimal effects on normal physiologyeffects on normal physiology

Non-specific action could produce Non-specific action could produce unexpected side effectsunexpected side effects

Inhibit all functions of VEGFInhibit all functions of VEGF May not inhibit all functions of VEGFMay not inhibit all functions of VEGF

Different mechanisms of anti-angiogenesis: VEGF Different mechanisms of anti-angiogenesis: VEGF versus VEGF receptorversus VEGF receptor

Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25

Angiogenesis is involved throughout tumour Angiogenesis is involved throughout tumour formation, growth and metastasisformation, 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)

Effects of VEGF inhibition:Effects of VEGF inhibition:regression of microvasculatureregression of microvasculature

Inai T, et al. Am J Pathol 2004;165:35–52

Reduction in tumour blood flow after 1 day of Reduction in tumour blood flow after 1 day of anti-VEGF therapyanti-VEGF therapy

Effects of VEGF inhibition:Effects of VEGF inhibition:normalisation of existing vasculaturenormalisation of existing vasculature

Abnormal vasculature is ‘normalised’ following VEGF inhibitionAbnormal vasculature is ‘normalised’ following VEGF inhibition

Inai T, et al. Am J Pathol 2004;165:35–52

Summary: mechanism Summary: mechanism of action of anti-VEGF therapyof action of anti-VEGF therapy

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

EARLY BENEFIT CONTINUED BENEFIT

Regressionof existing microvasculature

Normalisationof surviving microvasculature

Inhibitionof vessel regrowth and neovascularisation

BevacizumabBevacizumab

VEGFR-2VEGFR-1P

PPPP

PPP

Endothel

VEGF

Anti-VEGF antibody

(Bevacizumab)

Presta et al. Cancer Res. 1997;57:4593.

Phase II trial of bevacizumab in Phase II trial of bevacizumab in NSCLC: summaryNSCLC: summary

Addition of bevacizumab to carboplatin and paclitaxel Addition of bevacizumab to carboplatin and paclitaxel improved response rate, time to progression and overall improved response rate, time to progression and overall survival in patients with advanced NSCLCsurvival in patients with advanced NSCLC

Patients with non-squamous cell histology appear to be a Patients with non-squamous cell histology appear to be a subpopulation with improved outcome and acceptable subpopulation with improved outcome and acceptable safety riskssafety risks

Recommended dose of bevacizumab for further Recommended dose of bevacizumab for further evaluation is 15mg/kg every 3 weeksevaluation is 15mg/kg every 3 weeks

The promising benefit of bevacizumab with chemotherapy The promising benefit of bevacizumab with chemotherapy in this trial warrants further investigationin this trial warrants further investigation

Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): study design(ECOG 4599): study design

Primary objective: to assess overall survival in patients with Primary objective: to assess overall survival in patients with advanced non-squamous NSCLC treated with CPadvanced non-squamous NSCLC treated with CP (carboplatin/paclitaxel)(carboplatin/paclitaxel) versus CP + bevacizumab versus CP + bevacizumab

Secondary objective: to assess response rates, time to Secondary objective: to assess response rates, time to progression and toxicityprogression and toxicity

Previously untreated stage

IIIB/IV non-squamous

NSCLC(n=878)

CP 6 (n=444)

Bevacizumab (15mg/kg)

every 3 weeks + CP 6 (n=434)

PD*

PD

*No cross over will be permitted

Bevacizumab every

3 weeks until progression

Sandler A, et al. J Clin Oncol 2005;23(Suppl 16 Pt I):2s (Abs. 4)

Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): k(ECOG 4599): key eligibility criteriaey eligibility criteria

Chemotherapy-naChemotherapy-naïïve stage IIIB (pleural or pericardial ve stage IIIB (pleural or pericardial effusion only) or stage IV effusion only) or stage IV non-squamousnon-squamous NSCLC NSCLCMeasurable or non-measurable diseaseMeasurable or non-measurable diseaseECOG PS 0–1ECOG PS 0–1INR <1.5 and a PTT no greater than upper limits of INR <1.5 and a PTT no greater than upper limits of normal within 1 week prior to randomisation normal within 1 week prior to randomisation No history of thrombotic or haemorrhagic disordersNo history of thrombotic or haemorrhagic disordersNo gross haemoptysis (defined as bright red blood of a No gross haemoptysis (defined as bright red blood of a 1/2 teaspoon or more) 1/2 teaspoon or more) Brain metastases were not allowedBrain metastases were not allowed

Sandler A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):2s (Abs. LBA4)

Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): patient population(ECOG 4599): patient population

90909191CaucasianCaucasian

50505858MaleMale

40403838ECOG PS 0ECOG PS 0

43434444Age Age 65 years65 years

28282828Prior weight loss Prior weight loss 5%5%

91919191Measurable diseaseMeasurable disease

13131414Stage IIIB Stage IIIB

CP + bevacizumab CP + bevacizumab n=424 (%)n=424 (%)

CPCPn=431 (%)n=431 (%)


Phase III trial of bevacizumab Phase III trial of bevacizumab in NSCLC (E4599): efficacyin NSCLC (E4599): efficacy

CPCPCP + CP +

bevacizumabbevacizumab

p valuep value

(HR)(HR)

Complete response, n (%)Complete response, n (%) 0 (0)0 (0) 5 (1.4)5 (1.4)

Partial response, n (%)Partial response, n (%) 35 (10)35 (10) 92 (25.8)92 (25.8)

Overall response rate, n (%)Overall response rate, n (%) 35 (10)35 (10) 97 (27.2)97 (27.2) <0.0001<0.0001

Median OS (months)Median OS (months) 10.210.2 12.5 12.5 0.0070.007

(0.77)(0.77)

Median PFS (months)Median PFS (months) 4.54.5 6.46.4<0.0001<0.0001

(0.62)(0.62)

Sandler A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):2s (Abs. 4)

ECOG 4599 ECOG 4599 - - SSurvivalurvival

Sandler et al. ASCO 2005; 23:LBA4.

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

363630302424181812126600

% 16.9% 16.9% 43.7% 43.7

% 22.1% 22.1% 51.9 % 51.9

24 ay24 ay12 ay12 ay

AyAy

Pro

babi

lity

Medyan: 10.2, 12.5Medyan: 10.2, 12.5

PCBPCB

PCPC

HR: 0.77 (0.65, 0.93)HR: 0.77 (0.65, 0.93)

P = 0.007P = 0.007

ECOG 4599 ECOG 4599 - - PPFSFS

363630302424181812126600

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

MtsMts

Pro

babi

lity

% 6.4% 6.4% 32.6% 32.6

% 14.6% 14.6% 55.0% 55.0

12 12 mtsmts6 6 mtsmts

MedMediian: 4.5, 6.4an: 4.5, 6.4

PCBPCB

PCPC

HR: 0.62 (0.53, 0.72)HR: 0.62 (0.53, 0.72)

Sandler et al. ASCO 2005; 23:LBA4.

P < 0.0001P < 0.0001

Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): h(ECOG 4599): haematological toxicityaematological toxicity

*Includes one death on each arm due to neutropenic fever

CPCP(n=427)(n=427)Grade 4Grade 4

CP + CP + bevacizumabbevacizumab

(n=420)(n=420)Grade 4Grade 4 p valuep value

Neutropenia Neutropenia (%)(%) 16.416.4 2424 0.0060.006

Thrombocytopenia (%)Thrombocytopenia (%) 00 1.41.4 0.010.01

Anaemia (%)Anaemia (%) 0.70.7 00 NSNS

Febrile Febrile neutropenia (%)neutropenia (%) 1.9*1.9* 3.3*3.3* NSNS


Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): n(ECOG 4599): non-haematological toxicityon-haematological toxicity

CP n (%)

>Grade 3

CP + bevacizumab n (%)

>Grade 3 p value

Haemorrhage Haemoptysis CNS GI Other

3 (0.7)1 (0.2)02 (0.5)1 (0.2)

19 (4.5)8 (1.9)4 (1.0)5 (1.2)4 (1.0)

<0.00 10.040.03

NS NS

Hypertension 3 (0.7) 25 (6.0) <0.001

Venous thrombosis 13 (3.0) 16 (3.8) NS

Arterial thrombosis 4 (1.0) 8 (1.9) NS


Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): (ECOG 4599): treatment-related deathstreatment-related deaths

CP (n=427)

CP + bevacizumab (n=420)

Haemorrhage

Haemoptysis

GI bleed

0

1

5

2

Neutropenic fever 1 1

Total 2 8


Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): c(ECOG 4599): conclusionsonclusions

The addition of bevacizumab (15mg/kg every 3 The addition of bevacizumab (15mg/kg every 3 weeks) to CP improves OS, RR and PFS in weeks) to CP improves OS, RR and PFS in patients with NSCLCpatients with NSCLC

In certain patients, bevacizumab plus CP is In certain patients, bevacizumab plus CP is associated with life-threatening and fatal associated with life-threatening and fatal haemorrhagehaemorrhage

– event is associated with squamous cell histologyevent is associated with squamous cell histology

– patients with squamous cell NSCLC excluded patients with squamous cell NSCLC excluded from ongoing trialsfrom ongoing trials

Bevacizumab in first-line advanced Bevacizumab in first-line advanced NSCLCNSCLC

Bevacizumab is the first novel agent combined Bevacizumab is the first novel agent combined with standard chemotherapy to significantly with standard chemotherapy to significantly improve overall survival in unselected patients improve overall survival in unselected patients with advanced NSCLC in the first-line settingwith advanced NSCLC in the first-line setting

Bevacizumab plus CP is now the ECOG Bevacizumab plus CP is now the ECOG reference standard for the first-line treatment of reference standard for the first-line treatment of advanced non-squamous NSCLCadvanced non-squamous NSCLC

Bevacizumab + ErlotinibPhase II study

Erlotinib 150 mg/dayBevacizumab 15mg/kgevery 3 weeks

Herbst RS. JCO 2005; 23:2544-55.

Patients (No.=40)Stage IIIB/IV Nonsquamous typePreviously treated with chemoMedian KPS 80

RR: % 20Med. survival 12.6 mtsTTP: 6.2 mtsWell tolerated

ReRecurrent NSCLCcurrent NSCLC Erlotinib Erlotinib Bevacizumab Bevacizumab

ResultsResults

Gefitinib does not prolong survivalGefitinib does not prolong survival

Erlotinib prolongs survivalErlotinib prolongs survival– There is no advantage when added to standard There is no advantage when added to standard

chemochemo– Efficacy is better in nonsmokers, asians, Efficacy is better in nonsmokers, asians,

adenocarcinomas, femalesadenocarcinomas, females– Response rates are higher in patients who have EResponse rates are higher in patients who have Exon xon

19 19 - - 21 21 mutationsmutations andand gen genee amplifi amplificationcation – If there isIf there is K-rasK-ras mutation response rates are lowermutation response rates are lower

ResultsResults

There is no advantage to add cetuximab to There is no advantage to add cetuximab to standard chemostandard chemo

Bevacizumab + chemotherapy Bevacizumab + chemotherapy combination is an effective optioncombination is an effective option

Bevacizumab + Erlotinib Bevacizumab + Erlotinib combination may combination may have sinergic effecthave sinergic effect

FutureFuture

Molecular biology of lung cancer has many unknown aspectsMolecular biology of lung cancer has many unknown aspects

New agents acting on different signal transduction pathwaysNew agents acting on different signal transduction pathways

Important and significant predictive factors must be definedImportant and significant predictive factors must be defined

Chemotherapy + Targeted therapiesChemotherapy + Targeted therapies

To understand which patients will benefit the most from targeted To understand which patients will benefit the most from targeted

therapiestherapies

Targeted therapies in the early stages of the diseseTargeted therapies in the early stages of the disese

Future plans for bevacizumab and Future plans for bevacizumab and ErlotinibErlotinib in NSCLC in NSCLC

Planned and ongoing trials of bevacizumab in Planned and ongoing trials of bevacizumab in NSCLC include:NSCLC include:– combination with chemotherapy and radiotherapycombination with chemotherapy and radiotherapy– combination with other novel agents combination with other novel agents – neo-adjuvant and adjuvant settings neo-adjuvant and adjuvant settings – SAiL (Safety of bevacizumab in Lung) in 2006SAiL (Safety of bevacizumab in Lung) in 2006

Planned and ongoing trials of Planned and ongoing trials of erlotiniberlotinib in NSCLC in NSCLC include:include:– sequencing with chemotherapysequencing with chemotherapy– monotherapy trialsmonotherapy trials

LUNG CANCER MOLECULAR THERAPY Prof. Dr. Can ÖZTÜRK

Documents

Transcript of LUNG CANCER MOLECULAR THERAPY Prof. Dr. Can ÖZTÜRK