kolorektal dışı gastrointestinal kanserlerde hedefe...
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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