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,…

8

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.

21

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

23

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