CPI-444,anoraladenosineA2Areceptor(A2AR)antagonist,demonstratesclinicalactivityinpatientswith
advancedsolidtumors
LeishaA.Emens1,JohnPowderly2,LawrenceFong3,JoshuaBrody4,PatrickForde1,MatthewHellmann5,BrettHughes6,ShivaaniKummar7,ShereneLoi8 JasonLuke9,Daruka
Mahadevan10,BenMarkman11,IanMcCaffery12,RichardMiller12,andGinnaLaport12
1Johns Hopkins University, Baltimore MD; 2Carolina BioOncology Institute, Charlotte NC; 3University of California, SanFrancisco, San Francisco CA; 4Mount Sinai School of Medicine, New York NY; 5Memorial Sloan Kettering Cancer Center,New York NY; 6Royal Brisbane and Women’s Hospital, Herston, Australia 7Stanford University School of Medicine, PaloAlto CA; 8Peter MacCallum Cancer Center, Melbourne, Australia; 9University of Chicago, Chicago IL; 10University ofArizona, Tucson AZ; 11Monash Health, Victoria, Australia; 12Corvus Pharmaceuticals, Burlingame CA
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Thispresentationcontainsforward-lookingstatements,includingstatementsrelatedtothepotentialsafetyandefficacyofCPI-444,bothasasingleagentandincombinationwithanti-PD-1andanti-PD-L1,theutilityofbiomarkerdatacollectedandthesuitabilityofthedosingregimenselectedfortheCompany’sPhase1/1bclinicaltrialofCPI-444.Allstatementsotherthanstatementsofhistoricalfactcontainedinthispressreleaseareforward-lookingstatements.Thesestatementsoftenincludewordssuchas“believe,”“expect,”“anticipate,”“intend,”“plan,”“estimate,”“seek,”“will,”“may”orsimilarexpressions.Forward-lookingstatementsaresubjecttoanumberofrisksanduncertainties,manyofwhichinvolvefactorsorcircumstancesthatarebeyondtheCompany’scontrol.TheCompany’sactualresultscoulddiffermateriallyfromthosestatedorimpliedinforward-lookingstatementsduetoanumberoffactors,includingbutnot limitedto,risksdetailedintheCompany’sAnnualReportonForm10-KfortheyearendedDecember31,2016,filedwiththeSecuritiesandExchangeCommissiononMarch10,2017,aswellasotherdocumentsthatmaybefiledbytheCompanyfromtimetotimewiththeSecuritiesandExchangeCommission.Inparticular,thefollowingfactors,amongothers,couldcauseresultstodiffermateriallyfromthoseexpressedorimpliedbysuchforward-lookingstatements:theCompany’sabilitytoutilizebiomarkerdata,selectasuitabledosingregimenanddemonstrateevidenceofefficacyandsafetyforCPI-444duringitsPhase1/1b clinicaltrial;theaccuracyoftheCompany’sestimatesrelatingtoitsabilitytoinitiateand/orcompleteclinicaltrials;theresultsofearlyclinicaltrialsmaynotbepredictiveoffutureresults.AlthoughtheCompanybelievesthattheexpectationsreflectedintheforward-lookingstatementsarereasonable,itcannotguaranteethattheeventsandcircumstancesreflectedintheforward-lookingstatementswillbeachievedoroccur,andthetimingofeventsandcircumstancesandactualresultscoulddiffer materiallyfromthoseprojectedintheforward-lookingstatements.Accordingly,youshouldnotplaceunduerelianceontheseforward-lookingstatements.Allsuchstatementsspeakonlyasofthedatemade,andtheCompanyundertakesnoobligationtoupdateorrevisepubliclyanyforward-lookingstatements,whetherasaresultofnewinformation,futureeventsorotherwise.Additionalinformationmaybeavailableinpressreleasesorotherpublicannouncementsandpublicfilingsmadeafterthedateofthispresentation.
ThispresentationconcernsproductsthathavenotyetbeenapprovedformarketingbytheU.S.FoodandDrugAdministration(“FDA”).Norepresentationismadeastotheirsafetyoreffectivenessforthepurposesofwhichtheyarebeinginvestigated.
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ForwardLookingStatements
DisclosureInformation
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Ihavethefollowingfinancialrelationshipstodisclose:Consultantfor:Vaccinex,Celgene,BristolMeyersSquibb,AstraZeneca,Amgen,Syndax,Molecuvax,eTHeRNA,Peregrine, BayerGrant/Researchsupportfrom:Genentech/Roche,EMDSerono,Maxcyte,Merck,AstraZeneca,Aduro,Corvus
Iwilldiscussthefollowingoff-labeluseand/orinvestigationaluse:CPI-444aloneandcombinedwithatezolizumabforadvancedsolidcancers.
StudyfundingprovidedbyCorvusPharmaceuticals.RocheGenentechprovidedatezolizumabandsupportforbiomarkeranalyses
AACR Annual Meeting 2017: Leisha A. Emens
AdenosineSignalingSuppressesImmunityintheTumorMicroenvironment
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• PD-1/PD-L1antibodiesareeffectiveimmunotherapieswithresponserates~20-30%
• Novelagentsthatenhanceresponseorovercomeresistancetoimmunotherapyareahighpriority
• Theadenosinepathwayisapotentialnewimmunotherapytarget
CPI-444:ANovelInhibitoroftheA2ARPathway
• PharmaceuticalProperties– Molecularweight=407Da– A2ARKi=3.5nM– >55-foldselectiveoverA1R,>400-foldA2BRandA3R– Oralbioavailability>50%– Plasmahalflife:~10-14hours
• Singleagentactivityinmultiplepreclinicalmodels*– Synergywithanti-PD-(L)1andanti-CTLA-4antibodiesandothercheckpoint
inhibitors• Well-toleratedinearlytrialswithhealthyvolunteersandADHDpatients
• ThisisthefirstevaluationofsafetyandclinicalactivityofanA2ARantagonistinpatientswithcancer
CPI-444
*SeeAbstract#55985
APhase1/1b,Open-Label,Multicenter,Repeat-Dose,Dose-SelectionStudyofCPI-444asaSingleAgentandinCombinationwithAtezolizumab(atezo)inPatientswithSelectedIncurableCancers
PrimaryObjectives– EvaluatethesafetyofCPI-444aloneandwithatezo– IdentifyarecommendeddoseandscheduleforCPI-444alone
andwithatezo• Safety,PKandPDdata*
– MeasuretheclinicalactivityofCPI-444aloneandwithatezo• ORR,CBRandDOR*
6*PK– pharmacokinetics;PD=pharmacodynamics;ORR=overallresponserate;CBR- clinicalbenefitrate;DOR=durationofresponse
TrialDesign:Step1DoseSelection(Accrualcompleted)
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SelectSingleAgentDose
SelectCombination
Dose**
100mgCPI-444BIDdays1-14/28days*
100mgCPI-444BID28dayscontinuous*
200mgCPI-444dailydays1-14/28days*
50mgCPI-444BIDd1-14/28dayswith840mgatezo every2weeks*
100mgCPI-444BID14or28dayswith840mgatezo every2weeks*
DLTevaluation
DLTevaluation
Eligibility• Selectedincurablecancers:NSCLC,Melanoma,RCC,TNBC,Others
(UBC,CRPC,CRC-MSI+,SCCHN)• 1to5linesofpriortherapy• Stable,treatedbrainmetastasesallowed• Resistant/refractory(R/R)topriorantiPD-1/PDL-1allowed• PD-L1,CD73,A2aRexpressionnotrequiredforenrollment
*1cycle=28days
**SeeAbstract#5593
TrialDesign:Step2CohortExpansionbyDisease(Accrualongoing)
8*Others:CRPC,CRC-MSI,UBC,SCCHN
Randomize
SingleAgentArmExpansion CombinationArmExpansion
NSCLCN=14
MELN=14
RCCN=14
TNBCN=14
Others*N=14
NSCLCN=14
MELN=14
RCCN=14
TNBCN=14
Others*N=14
Potentialexpansionto26and48patients
PatientDemographics/DiseaseCharacteristics*Medianage,years(range) 64(36– 85)
Gender,n(%)FemaleMale
58(51%)55(49%)
ECOGperformancestatus01
47(42%)66(58%)
TNBCNSCLCMELRCCOthers
32 (28%)28(25%)14(12%)14(12%)25 (23%)
Median#ofpriorregimens 2(1–5)
PriorChemotherapyPrioranti-PD1/PD-L1exposure
NaïveResistant/Refractory
VisceralmetastasesLiverBrain
90(80%)
50 (44%)63(56%)102(90%)42(37%)10(9%)
• Enrollment(n=113)• Step1:n=47(33singleagent)• Step2:n=66(26singleagent)
• Heavilypre-treatedwithextensivedisease
• Overhalfwithdiseaseresistant/refractorytoPD-1/PD-L1antibodies
*Datacutoff:Mar20179
Treatment-RelatedAdverseEvents(AE)
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• Mediandurationoftreatment:9weeks(range:upto40+)
• 56%ofpatientsexperiencedatreatment-relatedAE(anygrade)
• Nograde3/4AEswithsingleagentCPI-444
• Immune-relatedAEsseenonlywithcombinationofCPI-444andatezo (n=1foreach):-Pancreatitis(Gr2)-Autoimmunehemolyticanemia(Gr3)-Meningoencephalitis/thrombocytopenia(Gr4)
Adverse Events> 5%Frequency(Gr1/2)SingleAgent Combo
Nausea 14% 13%
Pruritus 10% 9%
Fatigue 5% 7%
AbdominalPain 5% ---
Rash 5% ---
Diarrhea 5% ---
Pyrexia 5% 7%
DecreasedAppetite 5% 7%
Chills 5% ---
OverallPatientOutcomesDiseaseControlRate(CR,PR,SD)inEvaluablePatients
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CPI-444(n=52)
CPI-444/Atezolizumab(n=44)
AllSubjects(n=96)
Allsubjects 20(38%) 17(39%) 37 (38%)
PriorPD-1/PD-L1ExperienceNaïveResistant/Refractory
13/29(45%)7/23(30%)
5/18(28%)12/26(46%)
18/47(38%)19/49(39%)
Disease Histology- NSCLC- MEL- RCC- TNBC- Others
4/14(29%)2/5 (40%)3/5(60%)7/17(41%)4/11(36%)
5/10 (50%)2/6(33%)5/5(100%)3/14(21%)2/9(22%)
9/24(38%)4/11(36%)8/10(80%)10/31(32%)6/20(30%)
• MedianfollowuptimeforDCR:16weeks(range,4-44weeks)• 23/37ofPRandSDpatientsremainonstudy
ClinicalActivity:OverallPatientPopulation*
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• SDsandPRsobservedwithCPI-444aloneandincombinationwithatezo
%Changefro
mBaseline
*PatientswithdiseaseevaluablebyCT,n=70Treatment:SingleAgentCombination
ClinicalActivity:ByDiseaseType
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• TumorregressionobservedinRCC,NSCLC,TNBC,SCCHNandCRC
%Changefro
mBaseline
OTHERTNBCMELNSCLCRCC
ClinicalActivity byPriorPD-(L)1Experience
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• CPI-444hasactivityinpatientsresistant/refractorytoPD-1blockade
• 2PRsand7minorregressionsinPD-1resistant/refractorypatients
• 1PRand4minorregressionsinPD-1naïvepatients
%Changefro
mBaseline
Resistant/RefractoryNaive
DurationofTreatment
15OTHERTNBCMELNSCLCRCC
SingleAgentCPI-444 CPI-444CombinedwithAtezo
TumorRegressioninNivolumab RefractoryLungCancerSingleAgentCPI-444
Pre-treatment 2monthsoftreatment16
• 2priorchemotherapyregimens• Refractorytonivolumab• StartedsingleagentCPI-444
RegressioninNivolumab ResistantLungCancerCombinationCPI-444/Atezolizumab
Pre-treatment 2monthsontreatment17
• 1priorchemotherapy• Respondedtonivolumab,
thenprogressed• StartedCPI-444+atezo
TumorRegressioninNivolumab RefractoryRenalCancerSingleAgentCPI-444
Pre-treatment 3 monthsoftreatment18
• FivepriorregimensincludingTKIsandmTOR inhibitor
• Tumorprogressiononnivolumab
• StartedCPI-444
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SerialBiopsiesofLiverMetastasisfromPD-1RefractoryRCCPatientTreatedwithSingleAgentCPI-444
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Pre-treatment Posttreatment(2months)
InflammatoryInfiltrateinTumor=1%
InflammatoryInfiltrateinTissue=20%
CD8+ intumor=14%
CD8+ intissue>70%;notumorcellsdetectable
InflammationandCD8+ TCellInfiltrationAfterProgressiononPD-1TherapyIncreasedwithSingleAgentCPI-444Therapy
H&E H&E
IHCIHC
SeeAbstract#5593
Conclusions• CPI-444iswelltoleratedasasingleagentandincombinationwithatezo– MostcommonGrade1/2toxicities:nausea,fatigue,pruritus– irAEs ofhemolyticanemia(Gr3),meningoencephalitis(Gr4),andpancreatitis(Gr2)
seenwithcombinationtherapy
• SelecteddoseofCPI-444is100mgbidcontinuous
• Observedclinicalactivity:– Assingleagentandincombinationwithatezo inmultipletumortypesinadvanced
cancerpatients– Inpatientsrefractory/resistanttoPD-1/PD-L1blockade– 23/37patientswithPR/SDremainonstudymedian16weeks
• IncreasedinflammationandCD8+ TcellsinbiopsyobservedinanantiPD(L)-1-experiencedpatientsrespondingtosingleagentCPI-444
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Acknowledgements
• Thepatientsandtheirfamilies• ParticipatingCenters:CarolinaBioOncology Institute,ColumbiaUniversityMedicalCenter,CrossCancerInstitute,EmoryUniversity,IndianaUniversity,JohnsHopkinsUniversity,Juravinski CancerCentre,Karmanos CancerCenter,MaryCrowleyCancerResearchCenters,MedicalCollegeofWisconsin,MemorialSloanKetteringCancerCenter,MonashHealth,MountSinai,RoyalBrisbaneandWomen’sHospital,START,UniversityofCaliforniaatSanFranciscoMedicalCenter,UniversityofArizonaMedicalCenter,UniversityofChicagoMedicalCenter,UniversityofColoradoCancerCenter,UniversityofPittsburgh,UniversityofWashington,WashingtonUniversityatSaintLouis
• ColleaguesatCorvus• ColleaguesatRocheGenentech
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