KolorektalKolorektal Dışı Gastrointestinal Dışı Gastrointestinal Kanserlerde Hedefe Yönelik Kanserlerde Hedefe Yönelik

TedavilerTedaviler

Dr Serdar TurhalDr Serdar TurhalMarmara ÜniversitesiMarmara ÜniversitesiOnkoloji Bilim DalıOnkoloji Bilim Dalı

Hedefe Yönelik TedavilerHedefe Yönelik Tedaviler

nn EGFR inhibitörleriEGFR inhibitörlerinn Anti EGFR Anti EGFR MoAbMoAbnn EGFR TKIEGFR TKI

nn Hücre Hücre siklüssiklüs inhibitörleriinhibitörlerinn ApoptozApoptoz indükleyicilerindükleyicilernn MMPIMMPInn AnjiogenezAnjiogenez inhibitörleriinhibitörleri

EGFREGFRnn 19621962nn StanleyStanley CohenCohen 1980: 1980:

Fizyoloji ve Tıp Fizyoloji ve Tıp NobeliNobeli!!

nn EGFR: EGFR: ErbBErbBnn GIT’deGIT’de %50%50--8989nn PekçokPekçok kaskattakaskatta

etkili etkili nn PrognozlaPrognozla ilintiliilintili

EGFR İnhibitörleriEGFR İnhibitörleri

nn 1983 John 1983 John MendelsohnMendelsohnMabMab:M225:M225

nn MoAbsMoAbs: TGF: TGF--ααEGFEGF

nn TKIsTKIs: TK: TK--ATPATP

Monoclonal antibodies targeting the epidermal growth factor receptor(EGFR)

I/IIHumanisedMabIgG1York Medical

Bioscience Inc.h-R3

IIHumanisedMabIgG1Merck KGaAEMD72000

II/IIIHumanMabIgG2Amgen/AbgenixABX-EGF

Panitumumab

IIIChimericMabIgG1

MerckKGaA/BMS/Imclon

e

Cetuximab(C225)

FazOriginTipFirmaAntikor

EGFR EGFR MoAbsMoAbs//NonNon--CRCCRC

nn RoyalRoyal MarsdenMarsdennn MatrixMatrixnn Faz IIFaz IInn ECX +/ECX +/-- MatuzumabMatuzumab

nn HerHer--22--neuneu: %12: %12--2020nn PertuzumabPertuzumab

EGFR tirozin kinaz inhibitörleri (TKIs)

Phase INo0.0060.002AEE788Pan-Her and KDR reversible

Phase IYes0.0190.0008CI-1033Pan-Her irreversiblePhases I and IINo0.0090.011GW-2016Pan-Her reversible

Phases I and IIYes1.20.038EKB-569EGFR specific andirreversible

Phase INoPKI-166

Phases II andIIINo3.50.02OSI-774–

erlotinib

Phases II andIIINo3.70.02ZD1839–

GefitinibEGFR specific and

reversible

Her-2 IC50

EGFR

Developmentstage

IrreversibleIC50AgentType of inhibition

GefitinibGefitinib IressaIressa ZD1839ZD1839

1313171780802323GEJGEJAdelsteinAdelsteinUSUS

6.46.41.81.8232310101001003636ÖzofaguÖzofaguss

Van Van GroningenGroningen

AvrupaAvrupa

1.91.92929131370/3070/302727ÖzofaguÖzofaguss

FerryFerryUKUK

3.5 ay3.5 ay1.2 ay1.2 ay17171150/5050/507575MideMideDoiDoiJaponyaJaponya

mOSmOSmTTPmTTPSDSDPRPRKTxKTxnnTmTmYazarYazar

ErlotinibErlotinib TarcevaTarceva OSIOSI--774774

3.5/3.5/6.76.7

NRNR9922++7070GEJGEJDragovichDragovichUSUS

NRNRNRNR55551515++2020EETewTewMSKCCMSKCC

mOSmOSayay

mTTPmTTPSD %SD %PR %PR %KTxKTxnnTmTmYazarYazar

SonuçSonuç

nn TKI E/G/GEJ tümörlerinde biraz etkiliTKI E/G/GEJ tümörlerinde biraz etkilinn Mide kanseri daha dirençliMide kanseri daha dirençlinn Diğerleri Diğerleri nn LapatinibLapatinibnn CICI--10331033

nn Potansiyel kombinasyon ajanlarıPotansiyel kombinasyon ajanlarınn SNSN--3838

nn EGFR ekspresyonun derecesi ne olmalıEGFR ekspresyonun derecesi ne olmalı

ErlotinibErlotinib Plus Plus GemcitabineGemcitabine ComparedCompared to to GemcitabineGemcitabineAlone in Patients With Advanced Pancreatic Cancer Alone in Patients With Advanced Pancreatic Cancer

National Cancer Institute of Canada Clinical Trials Group National Cancer Institute of Canada Clinical Trials Group –– Study PA.3Study PA.3

MJ Moore, D Goldstein, J Hamm, A MJ Moore, D Goldstein, J Hamm, A FigerFiger, JR Hecht, , JR Hecht, S S GallingerGallinger, HJ Au, K Ding, HJ Au, K Ding, , M M PtaszynskiPtaszynski,, WR WR ParulekarParulekar

Patient Population§ Adenocarcinoma of

pancreas§ No prior

chemotherapy§ Measurable or non-

measurable disease§ EGFR status not an

eligibility criterion

Stratification§ Center§ PS (0/1 vs 2)§ Stage of disease

RANDOM I ZE

Gemcitabine+

Erlotinib

Gemcitabine+

Placebo

Primary Primary nnOverall survivalOverall survival

SecondarySecondarynn Progression free survivalProgression free survivalnnQuality of life (selected countries)Quality of life (selected countries)nn Response rateResponse ratenn ToxicityToxicitynn Correlate tissue EGFR expression with outcomeCorrelate tissue EGFR expression with outcome

PA.3 Study EndpointsPA.3 Study Endpoints

Overall Survival for All PatientsOverall Survival for All Patients

* Adjusted for PS, pain and disease extent at randomization

Perc

enta

ge

0

20

40

60

80

100

Time (Months)0 6 12 18 24

HR = 0.81*95% CI (0.67, 0.97)P = 0.025

Gemcitabine + ErlotinibMedian = 6.37 months1 Year Survival = 24%

Gemcitabine + PlaceboMedian = 5.91 months1 Year Survival = 17%

Hazard ratios for survival by Hazard ratios for survival by pretreatmentpretreatment characteristicscharacteristics

HR 95% CI n

Erlotinib : placebo

Performance status 0–1Performance status 2

Locally advancedDistant metastasis

Pain Score ≤20Pain Score >20

MaleFemale

Age <65Age ≥65

HER1/EGFR positiveHER1/EGFR negativeSample not available

Favors Erlotinib 1 Favors Placebo

0.81 0.69–0.99 569

0.87 0.71–1.06 4630.56 0.37–0.85 106

0.95 0.65–1.41 1380.77 0.63–0.95 431

0.70 0.53–0.92 2580.98 0.77–1.25 296

0.74 0.57–0.94 2980.96 0.74–1.25 271

0.74 0.58–0.96 3010.93 0.72–1.21 268

0.74 0.46–1.17 860.82 0.51–1.34 760.85 0.69–1.05 407

Fact

ors

ProgressionProgression--Free SurvivalFree Survival

* Adjusted for PS, pain and disease extent at randomization

Perc

enta

ge

0

20

40

60

80

100

Time (Months)0 5 10 15

HR = 0.76*95% CI (0.63, 0.91)P = 0.003

Gemcitabine + ErlotinibMedian = 3.75 monthsN=285

Gemcitabine + PlaceboMedian = 3.55 monthsN=284

49.249.257.557.5CR + PR + SDCR + PR + SD41.241.248.948.9SDSD

26.326.322.422.4PDPD24.424.420.120.1Not Not evaluableevaluable

6.96.91.11.1

Placebo %Placebo %(N = 262)(N = 262)

8.28.2PRPR0.40.4CRCR

ErlotinibErlotinib %%(N = 268) (N = 268)

ResponseResponse

PA.3 Tumour ResponsePA.3 Tumour Response

1616343417174343Infection Infection

1515868615158989FatigueFatigue5510103388DehydrationDehydration

<1<1112222PneumonitisPneumonitis001414<1<12323StomatitisStomatitis

6666

Grade Grade 3,43,4

56567272

AnyAny

ErlotinibErlotinib (%)(%)N = 282N = 282

2211

Grade Grade 3,43,4

Placebo (%)Placebo (%)N = 280N = 280

4141DiarrheaDiarrhea2929RashRash

AnyAnyEventsEvents

PA.3 Adverse EventsPA.3 Adverse Events

PA.3 EGFR AnalysisPA.3 EGFR Analysisnn Archival tissue collectedArchival tissue collectednn EGFR analyzed by EGFR analyzed by immunohistochemistryimmunohistochemistry using using

DakoDako EGFR EGFR PharmPharm DxDxTMTM kitskitsnn 184 samples submitted184 samples submittednn 162 adequate for analysis162 adequate for analysisnn Positive defined as Positive defined as >> 10% of tumor cells 10% of tumor cells

demonstrating membranous stainingdemonstrating membranous stainingnn 86 (53%) EGFR Positive86 (53%) EGFR Positivenn 76 (47%) EGFR Negative76 (47%) EGFR Negative

Survival by EGFR statusSurvival by EGFR statusPe

rcen

tage

0

20

40

60

80

100

Time (Months)0 5 10 15 20

Perc

enta

ge

0

20

40

60

80

100

Time (Months)0 5 10 15 20

EGFR Positive (N=86)

Hazard ratio = 0.74p= 0.19

EGFR Negative (N=76)

Hazard ratio = 0.83p= 0.44

Erlotinib

Erlotinib

Placebo

Placebo

PA.3 Rash PA.3 Rash vsvs SurvivalSurvivalPe

rcen

tage

0

20

40

60

80

100

Time (Months)0 5 10 15 20

Grade 2

Grade 0

HR [Rash]= 0.71

p<0.0001

Grade 1

43%43%11%11%16%16%1 year Survival1 year Survival10.5110.515.755.755.295.29Median SurvivalMedian Survival

Grade Grade >>22N= 103N= 103

Grade 1Grade 1N= 108N= 108

Grade 0Grade 0N= 79N= 79

nn This is the first randomized trial to demonstrate that This is the first randomized trial to demonstrate that anyany drug added to drug added to gemcitabinegemcitabine prolongs survival in prolongs survival in advanced pancreatic canceradvanced pancreatic cancernn Improvement in overall survival: HR 0.81; p=0.025Improvement in overall survival: HR 0.81; p=0.025

nn Improvement in PFS: HR 0.76 ; p=0.003Improvement in PFS: HR 0.76 ; p=0.003

nn Modest increases in toxicity associated with Modest increases in toxicity associated with erlotiniberlotinib

nn First demonstration of a benefit of EGFR TK First demonstration of a benefit of EGFR TK inhibitors in combination with chemotherapyinhibitors in combination with chemotherapy

PA.3 ConclusionsPA.3 Conclusions

Hücre Döngüsü İnhibitörleriHücre Döngüsü İnhibitörleri

nn CDK inhibitörleriCDK inhibitörlerinn FlavopiridolFlavopiridol panpan--inhibitörinhibitörnn Ktx ilintili Ktx ilintili apoptozuapoptozu arttırırarttırırnn İrinotekanİrinotekan, , cisplatincisplatin, , paclitaxelpaclitaxel , , docetaxeldocetaxelnn 2. seri 2. seri nn Faz I/IIFaz I/II

ApoptotikApoptotik MoleküllerMoleküller

nn Nükleer Faktör Nükleer Faktör ККBBnn BortezomibBortezomib VelcadeVelcade PS341PS341nn ProteasomeProteasome inhibitörüinhibitörünn Faz I tek başına ve Faz I tek başına ve IrinotekanlaIrinotekanla birliktebirliktenn Gen profiliGen profili

MMPIMMPI

nn Çinko ilintili Çinko ilintili proteolitikproteolitik enzimlerenzimlernn GC: MMPGC: MMP22--77--99--1414nn MarimastatMarimastat BB2516 oralBB2516 oralnn XenograftXenograft--InIn vivovivonn 369 GC/GEJC hastası (123 daha önce 5FU)369 GC/GEJC hastası (123 daha önce 5FU)nn mOSmOS 5.2 vs 4.5 ay p:0.075.2 vs 4.5 ay p:0.07nn 2 yıllık GS: %9 vs %3 p:=0.0242 yıllık GS: %9 vs %3 p:=0.024nn Post Post ktxktx: : mOSmOS: 8.4 vs 5.8 ay p:0.045: 8.4 vs 5.8 ay p:0.045

Bramhall ve ark Br J Cancer 86 (2002) 1864–1870

AnjiogenezAnjiogenez İnhibitörleriİnhibitörleri

BevacizumabBevacizumab

nn Faz II GC/GEJCFaz II GC/GEJCnn n 23n 23nn CisplatinCisplatin//IrinotekanIrinotekan + B+ Bnn PR %61, 1yıl PFS %55 ve PR %61, 1yıl PFS %55 ve mTTPmTTP NR!NR!nn 2 2 perforasyonperforasyon 11 11 vaskülervasküler olayolay

nn MAGIC II: MAGIC II: nn RezektablRezektabl GC’deGC’de NeoadjuvanNeoadjuvan Ktx + BKtx + B

Shah Proc Am Soc Clin Oncol 24 (2005), p. 314s (A4025)

VEGFR inhibitörü TKIVEGFR inhibitörü TKI

nn ValatinibValatinib PTK787PTK787nn SU5416SU5416nn ZD6474ZD6474nn AEE 788AEE 788nn SU11248SU11248

nn XenograftXenograft çalışmalarıçalışmaları

Hedef Yönelik Tedavilerde Hedef Yönelik Tedavilerde ToksisiteToksisite!!

nn HipertansiyonHipertansiyonnn DöküntüDöküntünn DiareDiarenn PeriorbitalPeriorbital ödemödemnn PerforasyonPerforasyonnn Uyku HaliUyku Hali

nn Kötü yara iyileşmesiKötü yara iyileşmesinn ProteinüriProteinürinn MakulerMakuler dejenerasyondejenerasyonnn AnasarkaAnasarkann KanamaKanamann DiabetDiabet