PICO Confirmation - File/1452-PICO- Confirmation (to guide a new ... research question ... summary of the PICO criteria to address these are provided below. ...

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  • Application1452:

    Pembrolizumab(MK3475)inMismatchRepairDeficientStageIVColorectalCarcinoma

    PICOConfirmation(to guide a new application to MSAC)

    December 2016

    1. SummaryofPICO/PPICOcriteriatodefinethequestion(s)tobeaddressed inanAssessmentReporttotheMedicalServicesAdvisoryCommittee(MSAC)

    Ifdirectevidenceisavailable,directeffectivenessoftheinterventioncanbedeterminedusingthefollowingPICOcriteria.

    Component Description

    Patients Patientsdiagnosedwithcolorectalcancer(CRC;stageIVattimeoftreatmentwithpembrolizumab)

    Priortests Routinehistology,cytologyandimmunohistochemical(IHC)teststoconfirmdiagnosisandstageofCRC

    Intervention a. IHCmismatchrepair(MMR)deficiencytestingusingantibodiesdirectedagainstthefourMMRproteinstodetectadeficiencyforeligibilityfortreatmentwithpembrolizumabonprogressiontostageIVCRC,andstandardofcareinthosewithproficientMMR

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    Component Descriptionb. Currenttestingregimenapluspembrolizumab

    Comparator Currenttestingregimenaplusstandardofcare(chemotherapywithacombinationoftwodrugs)

    Outcomes Safety:harmsfromtesting(includingratesofrebiopsyrequiredfortesting);treatmentassociatedadverseeventsandtolerabilityEffectiveness:Criticaloutcomesb:Overallsurvival,progressionfreesurvival,overallresponserate;Importantoutcomesb:QualityoflifeCosteffectiveness:Cost,costperlifeyeargained,costperqualityadjustedlifeyearordisabilityadjustedlifeyear,incrementalcosteffectivenessratio,costpercaseidentifiedTotalAustralianGovernmenthealthcarecosts

    Directresearchquestion

    What is the safety, effectiveness, and costeffectiveness of IHCMMR deficiencytesting for determining access to pembrolizumab in patients with stage IV CRC,comparedwithnotestingandstandardofcarechemotherapy?What isthesafety,effectiveness,andcosteffectivenessofcurrenttestingregimenplus pembrolizumab, compared to the current testing regimen plus standard ofcare?

    aCurrenttestingregimenmayormaynotincludeMMRtestingforpurposesotherthandeterminingeligibilityforpembrolizumabbOutcomesrankedasrecommendedbyGRADE

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    Ifdirecteffectivenessoftheinterventioncannotbedetermined,alinkedapproachmaybeused.AsummaryofthePICOcriteriatoaddresstheseareprovidedbelow.

    Component DescriptionPatients Patientsdiagnosedwithcolorectalcancer(CRC)

    Priortests Routinehistology,cytologyandimmunohistochemical(IHC)teststoconfirmdiagnosisandstageofCRC

    Intervention IHCmismatchrepair(MMR)deficiencytestingusingantibodiesdirectedagainstthefourMMRproteinstodetectadeficiencyforeligibilityfortreatmentwithpembrolizumabonprogressiontoStageIVCRC

    Referencestandard

    GenomicsequencingofthefourMMRgenes

    Comparator Diagnosticaccuracy:polymerasechainreactionbasedmicrosatelliteinstabilitytestingTherapeuticeffectiveness:currenttestingregimenaplusstandardofcare(chemotherapywithacombinationoftwodrugs)

    Outcomes Diagnosticaccuracy:Sensitivity,specificity,concordance,testretestreliability,positiveandnegativelikelihoodratios,positiveandnegativepredictivevalues.Prognosis:prognosticeffectofbiomarkerChangeinmanagement:%changeinmanagementplan(e.g.changesintreatment)Therapeuticeffectiveness:Criticaloutcomesb:Overallsurvival,progressionfreesurvival,overallresponserate;Importantoutcomesb:QualityoflifePredictivevalidity:treatmenteffectmodification

    Linkedevidenceresearchquestions

    What is thediagnosticaccuracyof IHCMMRdeficiencytestingcomparedwith thereferencestandardfordeterminingaccesstopembrolizumabinpatientswithstageIVCRC?WilltheextrainformationgeneratedasaresultofIHCMMRdeficiencytestingbeofadditionalprognosticvalueinpatientswithCRC?Is there a change in management in patients in whom an MMR deficiency isdiagnosed?Does treatmentwith pembrolizumab lead to better health outcomes in patientswithMMRdeficientCRCcomparedwithstandardofcarechemotherapy?IsMMRstatusatreatmenteffectmodifier?

    aCurrenttestingregimenmayormaynotincludeMMRtestingforpurposesotherthandeterminingeligibilityforpembrolizumab;bOutcomesrankedasrecommendedbyGRADE

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    2. PICOrationale

    2.1 Population

    Theproposedpopulationarethosepatientsdiagnosedwithcolorectalcancer(CRC).Patientswouldreceiveimmunohistochemical(IHC)DNAmismatchrepair(MMR)deficiencytestingusingantibodiesdirectedagainstthefourmismatchrepairproteinstodetectadeficiencyforeligibilityfortreatmentwithpembrolizumabonprogressiontoStageIVdisease.

    CRCcanoccur inanypartofthe largebowel(colonorrectum)and ifuntreated,canspreadtothelymphnodes(glands)andeventuallymetastasize.StageIVCRCisdefinedascancerthathasspreadtodistantorgansortissues.

    In2016,itisestimatedthattheagestandardisedincidenceratewillbe62casesper100,000persons(74 formalesand51 for females)andCRCwillbe thesecondmostcommoncauseofdeath fromcancer in Australiawith an estimated agestandardisedmortality rate of 14 deaths per 100,000persons(16formalesand12forfemales)1.Thistranslatesintoanestimated17,520AustraliancasesofCRC,10%ofwhomwillbediagnosedwithstageIVdisease,anda1in52(1in45formalesand1in62forfemales)chanceofanindividualdyingfrombowelcancerbytheir85thbirthday.

    TheMMRsystem ismainlycomposedoffourproteins(MLH1,MSH2,MSH6andPMS2) interactingtogether to recognizeDNAmismatches thatmayoccurduringDNA replicationandexcising them(Buecher et al. 2013). Microsatellites are short tandem DNA repeat sequences of 16 basesdistributedthroughoutthecodingandnoncodingregionsofthegenomeandareespeciallypronetoreplicationerrorsthatarenormallyrepairedbytheMMRsystem.AnMMRdeficiencyresultsinacancer with a 10 to 100fold increase in themutation rate and leads to the accumulation offrameshiftmutations inmicrosatellites,which results inagenetic instability (Buecheretal.2013;Dudleyetal.2016).Microsatellite Instability (MSI)alsoarises fromeitheragermline (hereditary)mutationinonecopyofanyofthegenesthatencodetheMMRproteins(Lynchsyndrome)orfromsporadic somatic hypermethylation of theMLH1 promoter (Dudley et al. 2016).Homozygous orcompound heterozygousmutation in these genes leads to childhood cancer syndromes such asconstitutionalmismatchrepairdeficiencysyndromeandTurcotsyndrome.

    MMRdeficientCRCsaccountfor1217%ofCRCs,ofwhichonly23%arehereditary(Ashktorabetal. 2016; Dunne et al. 2016). MMR deficiency is more frequent in stage II CRC (almost 20%)comparedtostageIII(12%)andisrelativelyuncommonamongmetastatictumours(4%)(Kawakami,Zaanan & Sinicrope 2015). The reduced level ofMMR deficiency among stage IV CRC probablyreflectstheimprovedprognosisofMMRdeficientstageIICRC(i.e.thesepatientsdonotprogresstostage IVdisease).Data tosupport theprevalenceofMMRdeficientCRCshouldbeprovided in thereport.

    Biologicalplausibility

    MMRdeficientCRCtumourscommonlyhaveincreasednumbersoftumourinfiltratinglymphocytes,and patients have a greater inflammatory state as evidenced by higher Creactive protein,neutrophil, andplatelet counts thanMMRproficientCRCpatients (Buecher et al. 2013;Quiroga,

    1AvailablefromURL,Accessed24August2016.

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    Lyerly &Morse 2016). This ismost likely due to the increasedmutation rate resulting in neoepitopes recognisedas foreignby the immunesystem (Llosaetal.2015).MMRdeficient tumoursare associatedwith a good prognosis, and the presence of this immune responsemay partiallyexplaintheirbetterclinicaloutcome(Buecheretal.2013).

    Llosaetal.(2015)foundthatMMRdeficienttumourshadsignificantgeneupregulationof immunecheckpointproteins,includingPDL1,enablingthemtosurvivetheimmuneresponse.Rosenbaumetal. (2016)wasable todetectPDL1expressionby IHC (using theantiPDL1monoclonalantibodyE1L3N)in12/54(22%)MMRdeficientCRCtumours(primaryandmetastatic),andfoundthatPDL1positivitywasassociatedwitha lowersurvivalwithinthisMMRdeficientCRCpatientcohort.Thus,immune checkpoint inhibitors, such as the PD1 inhibitor pembrolizumab,may provide a clinicalbenefitintreatingMMRdeficientCRC.

    Amoredetailedanalysisof thebiologicalplausibility for theuseof IHCMMRdeficiency testing toidentify CRC tumours susceptible to immune checkpoint inhibitors, such as the PD1 inhibitorpembrolizumab,shouldbeprovidedinthereport.Furthermore,evidenceofMMRdeficiencybeinganeffectmodifierfortreatmentwithpembrolizumab,aboveandbeyonditsprognosticeffectshouldbeprovided.

    Rationale

    ThreetrialsthatarelistedinthesummaryofevidenceincludepatientpopulationsthatarebroaderthanstageIVCRCindicatedfortreatmentinthisapplication.WhileallthreetrialsenrolledpatientswithmetastaticCRC,theKEYNOTE164singlearmphase IIpembrolizumabtrialandthesinglearmphaseIItrialtoevaluatetheefficacyofMEDI4736(durvalumab)alsoenrolledpatientswithlocallyadvanceddiseasewhereasthethirdCheckMate142singlearmphaseIInivolumabtrialalsoenrolledpatientswithrecurrentCRC.ThisapproachwillincreasethenumberofpatientswithMMRdeficientCRCeligiblefortheMEDI4736trial,andtheproportionofpatientswithMMRdeficientdiseaseintheKEYNOTE164andCheckMate142trialsasagreaterproportionofpatientswithstageIIICRCwillbeMMRdeficient(12%)thanthosewithstageIVdisease(4%).ThiswillhavelittleimpactonIHCMMRdeficiencytestingasmostpatientsaretestedatdiagnosis,regardlessofdiseasestage.However,asMMRdeficiency isa strongprognosticmarker inearlier stagesofdisease, its roleasa treatmenteffectmodifiermustbeclearlydemonstratedinthesepatients.

    2.2 Priortest

    Routinehistology,cytologyandIHCteststoconfirmdiagnosisandstageofCRC.

    2.3 Intervention

    TheinterventiontobeassessedisIHCMMRdeficiencytestingpluspembrolizumabinthosewhoareMMRdeficient,andstandardofcare(chemotherapywithacombinationoftwodrugs)inthosewhoareMMRproficient.

    An alternative intervention would be the current IHC MMR deficiency testing regimen pluspembrolizumab administered to all patients. Thismay be of use in clarifying the benefit of thetestingcomponent.

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    IHCMMR deficiency testing uses antibodies directed against eachMMR protein (MLH1,MSH2,MSH6andPMS2)andIHCstainingtodetecttheexpressionoftheseproteinsinthetumourcellstodetermine eligibility for treatment with pembrolizumab. The test uses formalinfixed paraffinembedded (FFPE) tumour tissue from either a surgical resection or a biopsy (if unresectable).EvidenceofthestabilityoftheseproteinsinFFPEtissueblocksshouldbeprovidedifarchivaltissueislikelytoberetrievedfortesting.

    Theproteins formheterodimers (eitherMLH1/PMS2orMSH2/MSH6), as the lossofoneproteinusuallyaffects theexpressionof itspartner,mostMMRdeficientCRCsshow lossofexpressionofbothproteinsintheaffectedheterodimer.Lossofproteinexpressionshouldbecomplete,withtheabsence of nuclear staining of all cancer cells and unequivocal positive staining of the nuclei ofsurroundingnoncancercellsand intratumoral lymphocytes.The lossofexpressionofMSH2/MSH6ishighlysuggestiveofaMSH2germlinemutation,andlossofexpressionofMLH1/PMS2mayresulteither fromaMLH1germlinemutationor fromacquired somatichypermethylationof theMLH1genepromoter.PatientswhosetumoursshowedalackofexpressionofanyoftheseproteinswouldbeclassedasMMRdeficientandwouldbeeligiblefortreatmentwithpembrolizumabatdiagnosisoforprogressiontostageIVdisease.

    The applicant indicated that IHCMMRdeficiency testing for access topembrolizumab shouldberequestedbythetreatingclinician.Patientsareexpectedtoreceiveonetestthroughoutthecourseoftheirdisease.ThetestisaClassIIinvitrodiagnostictestandmustbeperformedinanaccreditedlaboratorybyacertifiedpathologist.ItshouldbenotedthatmostlaboratoriesalreadyperformtheIHCMMRdeficiencytest,eitherroutinelyorbasedoneitherclinicianrequestorredflagcriteria.Iffound to be MMR deficient, treatment with pembrolizumab would be managed by medicaloncologists.

    The IHCMMR test is a simple, fast and inexpensive andmostpatients already receive IHCMMRdeficiencytestingaspartoftheir initialdiagnosticworkupat initialdiagnosis.Asurveyfoundthatcurrently, 54% of pathology laboratories conduct routine IHC MMR deficiency testing and anadditional40%conductIHCMMRdeficiencytestingoneitherclinicianrequestorredflagcriteriaforLynchsyndrome.Redflagcriteriainclude:aged

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    Table 1 Current MBS item number for IHC MMR deficiency testing Category 6 Pathology Services

    Group: P5 - TISSUE PATHOLOGY 72847 Immunohistochemical examination of biopsy material by immunofluorescence, immunoperoxidase or other labelled antibody techniques with multiple antigenic specificities per specimen - 4-6 antibodies (Item is subject to rule 13)

    Fee: $89.40 Benefit: 75% = $67.05 85% = $76.00

    Rationale

    TheRCPA4currentlyrecommendsthatIHCtestsshouldbeperformedtotestMMRdeficiencystatusand the results recorded in the pathology report. It recommends that for the purposes ofdiagnosingLynchsyndrome,ataminimumallcasesofCRCarisinginindividualslessthan50yearsofage shouldbe tested. In addition, all casesmeeting the revisedBethesda guidelines (Umaret al.2004),whichconsiderage,familyhistoryandhistologyofCRC,forbeingatriskofhavinghereditarynonpolyposisCRCshouldbetested.TheRCPAalsonotesthattheprognosisofmucinouscarcinomasis dependent on theirMMR deficiency status.Whereas theMMR deficient phenotype confers afavourable prognosis, mucinous CRCs that areMMR proficient tend to have an overall poorerprognosis.

    Additionally,IHCMMRdeficiencytestingisusedtopredictofefficacyoffluorouracilbasedadjuvantchemotherapy. This is especially useful for stage II CRC; in these patients MMR deficiency isassociatedwithanexcellentprognosisanda lackofbenefitfromfluorouracilbasedchemotherapyin sporadicMMR deficiency CRC cases (Buecher et al. 2013). The test is not currently used todetermine eligibility for treatmentwith immune checkpoint inhibitors, such aspembrolizumab inAustralia.

    If pembrolizumab is listed by the PBS, IHCMMR deficiency testingwould also be used to directtreatmenttopembrolizumab;patientswithMMRdeficientstage IVCRCreceivingtheirfirst lineoftherapywouldbeeligible.

    Asmostpatientsalreadyhave IHCMMRdeficiencytesting,thechangestocurrentpracticewillbeminimal.Theapplicantsuggeststhatthetestwouldonlyneedtobeperformedonce,regardlessofstageofdiseasewhentested.Datatosupportthestabilityofthebiomarkeroverthecourseofthedisease should be included in the report.Additionally, the heterogeneity ofMMR deficiency bothwithinthetumourandbetweentheprimarytumourandmetastasesshouldalsobeexplored.

    2.4 Comparator

    The suggested comparator for direct evidence of effectiveness, safety and costeffectiveness ofMMR testing and targeted pembrolizumab is the current testing regimen plus standard of care(chemotherapywithacombinationoftwodrugs).

    4ColorectalCancerStructuredReportingProtocol(3rdEdition2016).AvailablefromURLaccessed22...