EGFR抑制剂.ppt

Epidermal Growth Factor Receptor(EGFR)InhibitorsDr.M.Jayanthi1.Introduction2.Cellular Signalling PathwaysVital for cell cycle progression,growth,differentiation&death.Growth Factors The key stoneA delicate balance between activating and inhibitory signals needs to be maintained normallyAlteration in this balance-Dysregulated cellular proliferation&survival of abnormal cells.3.Gene TranscriptionG0G1PrimingSG2MCell Cell CycleGrowth Factors+Growth Factors&Cell CycleReceptors4.Epidermal Growth Factor Receptor(EGFR)5.Breast 14%-91%Colon 25%-77%Lung Cancer 40%-80%(Non small cell)Ovarian 35%-70%Pancreatic 30%-50%Head&Neck 80%-95%EGFR Expression RateTumour6.Some Landmarks in EGFR SignallingStanley Cohen v Human EGF(1970s)v Isolation and cloning of EGFR(1980s).Link between EGFR and malignant transformation of cells demonstratedv EGF in mice(1960s)Mendelsohn et al.,vBlocking EGFR signalling to treat cancer v Murine monoclonal antibodies targeting EGFR-TK Human:murine chimeric version More than 20 anti-EGFR agents in development 7.TKTKTKerbB1HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4No specific ligands-often acts as dimer partnerHeregulinsNRG2NRG3Heregulins-cellulinEGF,TGFa,b CellulinAmphiregulin,HB-EGFHuman Epidermal Growth Factor Receptor Family 8.TKIntracellular DomainTransmembrane Domain Extracellular DomainEGFR Structure9.TKTKTKTKerbB1HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4EGFR Homo DimerisationEGFR Stimulation&dimerisation10.TKTKTKerbB1HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4Hetero DimerisationRisk for cancerEGFR stimulation cont11.TKEGFR Function in Normal CellTKATPATPCell ProliferationAntiapoptosisAngiogenesisGene TranscriptionCell Cycle Progression+12.TKTKEGFR signal transduction in tumour cellsSurvival(anti-apoptosis)PI3-KSTAT3AKTPTENMEKGene transcriptionMAPKProliferation/maturationChemotherapy/radiotherapyresistanceAngiogenesisMetastasispYpYRASRAFSOSGRB2pYG1SMG213.MMPPyk2SrcRasMAPKCa+PPerbB Ligand Gene Transcription+HB-EGFSteroidhormoneSteroid hormone receptorG proteinOther mechanisms of EGFR stimulation14.EGFR-Variant IIIEGFR Wild TypeNo extracellular domainPresentLigand cannot bindCan bindTK constitutively activeTK activated by ligand bindingCannot dimeriseCan dimeriseNot found in normal cellsFound normallyMore propensity for cancerUp regulation leads to cancerHow EGFR variant differs from the wild type15.TKGene transcriptionCell Cycle ProgressionCell ProliferationMetastasisAnti ApoptosisCancerATPEGFR variant16.Normal CellCancerous CellUp RegulationMutationConsequence of proliferation of EGFR receptors17.EGFR A good target for lung cancer(non small cell)vHigh level of receptor expression compared with healthy tissue.vEGFR-Key role in tumour cell growth&function.vEGFR inhibition can inhibit downstream activity.vEGFR inhibitors have no severe toxicity.18.Rationale for EGFR Inhibitors in Head&Neck cancervEGFR expressed in 90%of head&neck cancers.vEGFR over expression associated with decreased survival.vIncreased EGFR expression is an early event in carcinogenesis&even present in premalignant lesions.vInhibition of EGFR TK slows the growth of xenograft tumour models of head&neck.19.TKTKTKTKStrategies to inhibit EGFR signaling-EGFR tyrosine kinase inhibitorsAnti-EGFR mAbsAnti-ligand mAbsBispecificAbsImmune effector cellATP20.Drugs AvailablevGefitinibvErlotinibHighly selective,potent&reversible EGFR Tyrosine Kinase Inhibitor vCetuximab Monoclonal Anti EGFR antibodyvH 447vMDX 210Bispecific Anti EGFR antibody linked to Anti CD 6421.Indications Monotherapy in advanced stage of NSCLC Gefitinib&Erlotinib:Gefitinib 250 mg O.D.oral Erlotinib 150 mg O.D.oral Cetuximab 400 mg/m2 i.v.200 mg/m2 i.v.wklyCetuximabMetastatic colorectal cancer with/without IrinotecanDose22.Side EffectsvSkin rash vDiarrhoea(EGFR TKI s)vFever(EGFR mAb)vInterstitial lung disease 1%(only for Gefitinib)Discontinuation rates due to adverse effects are very low unlike chemotherapy.23.Drug InteractionsvEGFR TK Inhibitors metabolised by CYP3A4.vInhibitors/inducers of CYP3A4 can alter drug levels.vWarfarin interactions have occurred in clinical trials of Gefitinib.vConcomitant administration with warfarin requires monitoring of PT,INR.24.Advantages of EGFR InhibitorsvOrally effectivevBetter quality of life.vCan be used as monotherapy.vNo need for premedication or dose monitoring.vNo hematological toxicity.vPotential for long term treatment.vReduced resistance to radiation or hormone therapy25.Current StatusGefitinibvvFDA Approved on May,2003 for Lung cancer-NSC FDA Approved on May,2003 for Lung cancer-NSC(Accelerated Approval Programme)(Accelerated Approval Programme)ErlotinibvFDA Approved on Nov,2004 for Lung cancer Non Small Cell (AAP)CetuximabvvFDA Approved on Feb,2004 for advanced FDA Approved on Feb,2004 for advanced colorectal cancercolorectal cancer26.Clinical Trials27.ParameterIDEAL IIDEAL IIDesign Randomized double blind Parallel Group,multicenter Randomized double blind parallel group,multicenterProtocolMonotherapyMonotherapyN of patients209216Cancer Advanced NSCLC;1-2 prior Chemotherapy cyclesAdvanced NSCLC;2 prior Chemotherapy cycles Dose/regimen250 or 500 mg/day250 or 500 mg/day Adverse effects GI,RashGI,RashActivityCR/PR 18%&19%,CR/PR/SD 54%&51 OS 7.6&7.9 mnths at 250&500 mg/dCR/PR 12%&9%,CR/PR/SD 42%&36%;OS 6.5&5.9 mnths at 250&500 mg/dGefitinib Phase II Trials28.ParameterINTACT IINTACT IIDesign Randomized double blind Placebo cont.,multicenter Randomized double blind placebo cont.,multicenterProtocolCombination gemcitabine&cisplatinCombination-Carboplatin&PaclitaxelN of patients10931037CancerAdv.NSCLC Chemotherapy nave stage III/IVAdv.NSCLC;Chemotherapy nave stage III/IV Dose/regimenStd.chemo plus 250 or 500 mg/dayStd.chemo plus 250 or 500 mg/day Adverse effectsDiarrhoea,RashDiarrhoea,RashActivityNo difference in overall surv.,Prog.Free surv.,or time to worsening symptomsNo difference in overall surv.,Prog.Free surv.,or time to worsening symptomsGefitinib Phase III Trials29.ParameterIProtocolMonotherapyMonotherapyN of patients12457Cancer Head&neck Ca refractory to chemo-/radiotherapyAdvanced NSCL refractory to platinum based therapy Dose/regimen 150 mg/day150 mg/day Adverse effectsDiarrhoea,RashDiarrhoea,RashActivity PR 6%;PR/SD 46%CR/PR 12%,CR/PR/SD 51%;OS 8.4 mnths Design Open label Open labelIIErlotinib Phase II Trials30.Outcomes with Targeted TherapyvProgression-free survivalvQuality of lifevResponse to treatment vSafetyvOverall Survival31.Unanswered QuestionsvPatient selectionv How long patients should be treatedv Timing and sequencing of combination therapyvUse in various stages of diseasevAppropriate markers for responsevManaging unique adverse events ILD Liver toxicity vBest use in other solid tumours32.Ongoing TrialsvDifferent treatment schedules for use in combination chemotherapyvIn other malignancies Breast,Prostate,Head&Neck,Colon as single/combination therapyStrategiesvCombining EGFRI with Radiotherapy/Surgery or other novel targeted agents like trastuzumabvIdentify subset of people who will benefit from TKI Skin rashes,Mutation in TK,KRAS33.Conclusion34.ConclusionEGFR inhibitors-a definite role in treatment of cancerCombination chemotherapy Further studies neededImproves QOL with minimal adverse effectsCan be administered at optimal biological dose Potential for use in multiple tumors 35.Role in early stage of cancer needs to be assertained Survival not significantly prolonged Costly Conclusion36.Reference37.Review Articles1.Soler R.P.HER1/EGFR Targeting:Refining the strategy.Oncologist 2004;9:58 67.2.Herbst R.S,Fukuoka M,Baselga J.Gefitinib a novel targeted approach to treating canver.Nature rev cancer 2004;4:956 65.3.Strausberg R.L,Simpson A.J.G,Old L.J,Riggins G.J.Oncogenomics and the development of new cancer therapies.Nature 2004;429:469 74.4.Noble M.E.M,Endicott J.A,Johnson L.N.Protein kinase inhibitors:Insights into drug design from structure.Science 2004;303:1800 05.5.Glover K.Y,Soler R.P,Papadimitradopoulou V.A.A review of small molecule Epidermal Growth Factor Receptor specific tyrosine kinase inhibitors in development for non small cell lung cancer.Sem.Oncol.2004;31 suppl:83 92.6.Janmaat M.L,Giaccone G.Small molecule Epidermal Growth Factor Receptor tyrosine kinase inhibitors.Oncologist 2003;8:576 86.38.Review Articles cont 7.Yano S,Nishioka Y,Goto H,Sone S.Molecular mechanism of angiogenesis in non small cell lung cancer and therapeutics trageting related molecules.Cancer sci.2003;94:479 85.8.Vlahovic G,Crawford J.Activation of tyrosine kinases in cancer.Oncologist 2003;8:531 8.9.Spiro S.G,Porter J.C.Lung cancer where are we today?Current advances in staging and non surgical treatment.Am J Respir Crit Care Med 2002;166:1166 96.10.Arteaga C.L,Epidermal Growth Factor Receptor dependence in human tumors:more than just expression?Oncologist 2002;7 suppl 4:31 9.11.Raymond E,Faivre S,Armand J.P.Epidermal growth factor receptor tyrosine kinaase as a target for anticancer therapy.Drugs 2000;60 suppl 1:15 23.39.Mini Review1.Levin E.R.Bidirectional signalling between the estrogen receptor and the epidermal growth factor receptor.Mol.Endocrinol.2003;17:309 17.Original Articles1.Kelly K,Averbuch S.Gefitinib:Phase II and III results in advanced non small cell lung cancer.Sem.Oncol.2004;31 suppl1:93 9.2.Pao W,Wang T,Riley G.J,Miller V.A,Pan Q,Varmus H.E et al.KRAS mutations and primary resistance of lung adenocarcinoma to Gefitinib or Erlotinib.PLOS Medicine 2005;2:e17.40.41.