Post on 07-Aug-2020
PKandPKPDconsiderationsfordoseselectioninthe
developmentofpembrolizumabDineshdeAlwis,PhD
QuantitativePharmacologyandPharmacometrics.MSD
.
2
Disclosure Information
Dinesh de Alwis, Ph.D.
I have the following financial relationships to disclose:
• I am an Employee and Stockholder of MSD
Outline• Dosefindinginoncology– A“historical”perspective
– WhywehopefocusonMTDishistorical?
• Keytruda
MTD:MaximumToleratedDose
AllfocusonfindingMTD!3+3,CRM,mCRM,TITE-CRM,accelerated
titration,…
4
Traditional Dose Finding in Oncology
MTD/MAD MTD/MAD
Whataboutefficaciousdose?Deservesmoreattention
Ph1:Doseescalation
Perceivedbenefit:Fasttoregistration
MTD:MaximumToleratedDoseMAD:MaximumAdministeredDose
Historically oncology has performed relatively poorly in identifying “optimal” doses in the pre-market setting
FDAcanissuepost-marketingcommitments/requirementstostudyoptimaldoseconsideringsafetyandefficacy
Clin CancerRes,focusissue,2016
MTD/MAD ≠ Optimal dose/regimenOncologyEarlyPhaseDoseSelectionneedsSignificantImprovement
Roughly2/3rd (48/77)ofthecompoundsareapprovedatdoseslowerthanMTDRoughly1/3rd (25/77)areapprovedatlessthanMTD/2
JR.Sachs,KMayawala,SGadamsetty,SPKang,DP.deAlwis.OptimalDosingforTargetedTherapiesinOncology:DrugDevelopmentCasesLeadingbyExample.Clin CancerRes2016;22:1318-1324
ForTargetedTherapies, DosesReachingMTDIncreaseToxicityWithoutNecessarily ImprovingResponseinPhaseI
Clin CancerRes2010;16:1289-1297
DosesapproachingMTDledtomorepatientsofftrialdue
totoxicity
MTDdoesnotnecessarilyimproveresponse
24trialstreating683patientsbetweenOct,2004- Jun,2008,atMDAndersonCancerCenter
Normalizationtocombinedatafromdifferenttrials:low-dose:≤25%MTDofthetrialHigh-dose:≥75%MTDofthetrialMedium-dose:25-75%
AllfocusonfindingMTD!3+3,CRM,mCRM,TITE-CRM,accelerated
titration,…
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Proper Dose Finding in Oncology – MTD/MAD and BED
MTD/MAD MTD/MAD
BiologicallyEffectiveDose(BED)
Whataboutefficaciousdose?Deservesmoreattention
Ph1:Doseescalation
KEYTRUDA®
(MK-3475,pembrolizumab)CaseStudy
.
InitiationofKEYTRUDA® ClinicalProgram
• PreclinicaldatasuggestedthatKEYTRUDA® wouldhaveanti-tumoractivityinmultiplecancers
• USINDwasopenedonJan7,2011– APhaseIStudyofSingleAgentMK-3475inPatientswithProgressive
LocallyAdvancedorMetastaticCarcinomasandMelanoma(Protocol001)
• InitialintentwastodefineDLT,characterizePK,andestablishPOC
PartA:FIHDoseEscalationandPK/PDEvaluation
• PartA-1doseescalationstudy– Objectives:
• TodefineDLT,MTD(MaximumAdministeredDose),andcharacterizePK
– Design:• Openlabel,nonrandomizedtraditional3+3doseescalationfollowedbyasmallexpansioncohortn~32
– 1mg/kgQ2Wà3mg/kgQ2Wà10mg/kgQ2W
– Results• NoDLTattesteddoses• Objectiveresponsein2outof3firstmelanomapatients
– Firstresponseat3mg/kgQ2Winmelanoma• Basedonastrongactivitysignal,amendmentwasissuedtoexpandmelanoma
cohort– 10mg/kgQ2W(MAD)selectedasthefirstdose
PKprofilesupportforQ3Wdosing• PharmacokineticprofileistypicalforatherapeuticmAb with
lowclearance(0.22L/h),limitedvolumeofdistribution(3.7L)andlowvariability(28%CVonCL)
• 26dayhalflife(95%CI24-28days)
AStrongData,fromCohortB1,AcceleratedtheDevelopmentProgram
ObjectiveResponse
(N,95% CI)
CompleteResponse
(N,95% CI)
Durationof Response
(days)Median(Range)
All MELN=8540%
(34‡; 29% - 51%)
3.5%
(3;0.7%- 10%)Not reached(28-240+)
IPINaïve
N=58
43.1%
(25;30% - 57%)
3.4%
(2;0.4%- 11.9%)Not reached(30-240+)
IPITreated
N=27
33.3%
(9‡;16%- 54%)
3.7%
(1;0.1%- 19%)Not reached(28-169+)
Allpatients doseat10 mg/kg.Includesall patientswhoreceivedthe first doseasofApril 25, 2012.Centrallyavailable response information as ofDec. 3, 2012.† Confirmed objectiveresponseisdefined asacompleteresponseorpartialresponsethat isevident ontwoconsecutiveCTscans obtainedatleast 4weeksapart.
ObjectiveResponseRatesandDurationofResponse basedonIndependentRadiologyReviewusingRECIST1.1Criteria
Protocol001FirstinHumantoRegistrationFromasmallPhase1-thestudyexpandedtoa 655-melanomapatientmulti-partstudy• 5amendments,betweenDec-2011toSep-2013,toansweremergingquestions• 4“phase2study-like”partsincluding3randomizeddosecomparisonsub-studies
Kang, S.P., Gergich, K., Lubiniecki, G.M., de Alwis, D.P., Chen, C., Tice, M.A. and Rubin, E.H., 2017. PembrolizumabKEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion diagnostic. Annals of Oncology, 28(6), pp.1388-1398.
DefiningadoserangeforthepivotalB2cohort
• PartA-2doseexpansionstudy– Objectives:
• ToevaluatePK/PDofQ3Wdosingschedule• Intra-patientdoseescalationtoexplorePKPDofKEYTRUDA® in0.005to10mg/kgQ3W
– BasisfortranslationalPK/PDtodefinetheefficaciousdoseof2mg/kgQ3W
– Patientswereescalatedin3steps(atdays1,8and22)fromlow(0.005to0.06mg/kg)tohighdoses(2and10mg/kg)
– Ex vivo IL-2 assay developed» No IL-2 release from lymphocytes with activated PD-1
pathway» SEB causes release, further enhanced by
pembrolizumab effect on PD-1
Ex-vivoIL2assay:PeripheralPK-PDintheClinictoinformefficaciousdose
• 95-%saturationlevelreachedat~1mg/kgQ3W
• Simulations show, > 95% of the effect of Keytruda on the ex vivoIL-2 release is achieved at Ctroughreached with a dose regimen of ~1mg/kgQ3W
• Therefore,1mg/kgQ3Wislowerboundaryforclinicalefficacy
Keytruda ExposureisAssociatedwithCompleteFunctionalBlockadeofPD-1intheexvivo IL-2ReleaseAssayatDosesof1 mg/kgQ3WorHigher
JElassaiss-Schaap,SRossenu,ALindauer,SPKang,RdeGreef,JRSachsandDPdeAlwisCPT:PSP,Jan2017
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PK-PD simulations to select BED
l PK-PD model was developed for simulations considering PK and PD variability
l At 1 mg/kg Q3W, the probability of achieving full target engagement is 64%. ≥ 2 mg/kg the probability is ≥ 90%.
– Dose of 2 mg/kg falls likely near the plateau of the underlying exposure-response
l Proposed BED: 2 mg/kg Q3W
J Elassaiss-Schaap, S Rossenu, A Lindauer, SP Kang, R de Greef, JR Sachs and DP de Alwis CPT:PSP,Jan2017
CanTranslationalPK-PDfurtherinformourchoice?
Model fittumordatafrommouse
Dose of 2mg/kgevery 3weeks ormoreshowsmaximalresponse.Dose rangeof2- 10Q3Wdetermined for clinical trials
Semi-mechanistictPKPD model
Step1:DevelopmousemodelrelatingPKà Targetbindingà tumorgrowthinhibition
Step2:TranslationtohumanbyadjustingPKandtumorgrowthparameters
ALindauer,CRValiathan,KMehta,VSriram,RdeGreef,JElassaiss-Schaap andDPdeAlwis;CPTPSP.2017
PK-PDmodelingguidesacriticaldecisiononKEYTRUDA®
• Teamdiscussiononwhatdosestotakeforwardbasedonresultsfromnon-randomizedstudies (B1)– ORRipi treated10Q2:56%>10Q3:27%– ORRipi naïve2Q3:45%,10Q3:37%,10Q2:46%
BasedontheTranslationalmodeling,ex-VivoIL-2dataandobservedclinicaldata,whatdoseordoseswouldyoutakeforwardintoB2pivotalcohort?
PK-PDmodelingguidesacriticaldecisiononKEYTRUDA® dose
• Exposure-response analysis:flatexposure-responsebetween2Q3,10Q3,10Q.– Keypoint:Tumorsizechangewasusedformodelingasresponseinsteadof
conventionalRECISTcriterion– ChangeinTumorsizevs Exposure:nodifferencebetween2Q3,10Q3,10Q2
Theblacklineshowsthe(log)linearregressionofchangefrombaselinevs.AUC.Dashedreferencelinesindicate+20%,0and-30%change.
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TumorResponsemodelCharacterizesGrowthPatternsandOverallPredictionswithDose
Observed Predicted
Relativelyflatexposure-responserelationshipsinefficacy[tumorsizereduction]resultinginoptimallyefficaciousdoseof2mg/kgQ3W
MS Chatterjee, J Elassaiss-Schaap, A Lindauer, DC Turner, A Sostelly, T Freshwater, K Mayawala, M Ahamadi, JA Stone, R de Greef, AG Kondic and DP de Alwis ; CPT:PSP, 2017
Flatexposure-AErelationshipresultinginsupportingoptimallyefficaciousdoseof2mg/kgQ3W
Solidlinesrepresentmodelestimatedprobabilityandshadedareasrepresentthe95%confidenceintervals.P-valuesrepresentsignificanceleveloftheexposure-responsetermwhenforcedintothemodel.
AEs (AEOSI;AEsofspecialinterest)
AUCover6wks atSteadyState
Prob
ability
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PFS from randomized studies confirmed 2 mg/kg as an optimal dose
Ribas et al, Lancet 2015
PK/PDFindingssupportedDevelopmentandApproval
• Exposure-Responseanalysiswaskeytoidentifyingoptimaldose.
• Awidetherapeuticrangewasestablished,basedonExposure-Response,Exposure-Safetyanalyses
• ApprovalofKEYTRUDA®baseduponpositiverisk/benefit– EfficacybasedoncohortB2173IPI-refractorypatients,with80
patientsatthe2mg/kgrecommendeddose• ReceivedAcceleratedApprovalonSept4,2014
l Productsapprovedundertheacceleratedapprovalregulations,21CFR601.41,requirefurtheradequateandwell-controlledstudies/clinicaltrialstoverifyanddescribeclinicalbenefit.
l Twoconfirmatorytrials(P002(IPI-treated)andP006(IPI-naïve))wereconductedtoconfirmthesafetyandefficacyofKEYTRUDA
Acknowledgements• Rik deGreef• ScottEbbinghaus• Jeroen Elassaiss-Schaap• PeterKang• AndreasLindauer• Kapil Mayawala• Khamir Mehta• Alise Reicin• EricRubin• JeffSachs• VSriram• MelissaTice• Chandni Valiathan