Abstract #: 3004 Safety and clinical activity of adenosine A2a receptor (A2aR) antagonist, CPI-444, in anti-PD1/PDL1 treatment-refractory renal cell (RCC) and non-small cell lung cancer (NSCLC) patients

Presenter: Lawrence Fong, M.D.Leader, Cancer Immunotherapy Program Co-Director, Parker Institute of Cancer Immunotherapy @ UCSFUniversity of California, San Francisco

Thispresentationcontainsforward-lookingstatements,includingstatementsrelatedtothepotentialsafetyandefficacyofCPI-444,bothasasingleagentandincombinationwithanti-PD-1andanti-PD-L1,andtheCompany’sabilitytodevelopandadvanceproductcandidatesintoandsuccessfullycompleteclinicaltrials,includingtheCompany’sPhase1/1bclinicaltrialofCPI-444.Allstatementsotherthanstatementsofhistoricalfactcontainedinthispressreleaseareforward-lookingstatements.Thesestatementsoftenincludewordssuchas“believe,”“expect,”“anticipate,”“intend,”“plan,”“estimate,”“seek,”“will,”“may”orsimilarexpressions.Forward-lookingstatementsaresubjecttoanumberofrisksanduncertainties,manyofwhichinvolvefactorsorcircumstancesthatarebeyondtheCompany’scontrol.TheCompany’sactualresultscoulddiffermateriallyfromthosestatedorimpliedinforward-lookingstatementsduetoanumberoffactors,includingbutnotlimitedto,risksdetailedintheCompany’sQuarterlyReportonForm10-QforthethreemonthsendedMarch31,2017,filedwiththeSecuritiesandExchangeCommissiononMay4,2017,aswellasotherdocumentsthatmaybefiledbytheCompanyfromtimetotimewiththeSecuritiesandExchangeCommission.Inparticular,thefollowingfactors,amongothers,couldcauseresultstodiffermateriallyfromthoseexpressedorimpliedbysuchforward-lookingstatements:theCompany’sabilitytodemonstrateevidenceofefficacyandsafetyforCPI-444duringitsPhase1/1b clinicaltrial;theresultsofearlyclinicaltrialsmaynotbepredictiveoffutureresults;theunpredictabilityoftheregulatoryprocess;andregulatorydevelopmentsintheUnitedStatesandforeigncountries.AlthoughtheCompanybelievesthattheexpectationsreflectedintheforward-lookingstatementsarereasonable,itcannotguaranteethattheeventsandcircumstancesreflectedintheforward-lookingstatementswillbeachievedoroccur,andthetimingofeventsandcircumstancesandactualresultscoulddiffermateriallyfromthoseprojectedintheforward-lookingstatements.Accordingly,youshouldnotplaceunduereliance ontheseforward-lookingstatements.Allsuchstatementsspeakonlyasofthedatemade,andtheCompanyundertakesnoobligationtoupdateor revisepubliclyanyforward-lookingstatements,whetherasaresultofnewinformation,futureeventsorotherwise.Additionalinformationmaybeavailableinpressreleasesorotherpublicannouncementsandpublicfilingsmadeafterthedateofthispresentation.

ThispresentationconcernsproductsthathavenotyetbeenapprovedformarketingbytheU.S.FoodandDrugAdministration(“FDA”).Norepresentationismadeastotheirsafetyoreffectivenessforthepurposesofwhichtheyarebeinginvestigated.

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ForwardLookingStatementsForwardLookingStatements

SafetyandclinicalactivityofadenosineA2areceptor(A2aR)antagonist,CPI-444inanti-PD(L)1treatment-refractoryrenalcell(RCC)andnon-smallcelllung

cancer(NSCLC)patientsLawrenceFong,PatrickForde,JohnPowderlyII,JonathanGoldman,JohnNemunaitis,

JasonLuke,MatthewHellmann,ShivaaniKummar,Robert Doebele,DarukaMahadevan,ShirishGadgeel,BrettHughes,BenMarkman,MatthewRiese,JoshuaBrody,

LeishaEmens,IanMcCaffery,RichardMillerandGinnaLaport

UniversityofCalifornia,SanFrancisco,SanFrancisco,CA;JohnsHopkinsKimmelCancerCenterandBloomberg- KimmelInstituteforCancerImmunotherapy,Baltimore,MD;CarolinaBioOncologyInstitute,Huntersville,NC;DavidGeffenSchoolofMedicineatUCLA,LosAngeles,CA;MaryCrowleyCancerResearchCenters,Dallas,TX;UniversityofChicago,Chicago,IL;MemorialSloanKetteringCancer

Center,NewYork,NY;StanfordUniversitySchoolofMedicine,Stanford,CA;UniversityofColoradoAnschutzMedicalCampus,Aurora,CO;TheUniversityofArizona,Phoenix,AZ;KarmanosCancerInstitute/WayneStateUniversity,Detroit,MI;RoyalBrisbaneHospital,ChapelHill,Australia;MonashHealthandMonashUniversity,Melbourne,Australia;MedCollofWisconsin,Milwaukee,WI;IcahnSchoolofMedicineatMountSinai,NewYork,NY;TheJohnsHopkinsUniversity,Baltimore,MD;CorvusPharmaceuticals,Burlingame,CA

PhICPI-444Trial22

Background

• Anti-PD-(L)1antibodiesareapprovedfortreatmentofRCCandNSCLCbutasmallproportionofpatientsbenefit.

• Noapprovedagentsovercomeresistancetoanti-PD-(L)1withfewreporting benefitinPD-1resistant/refractorysetting.

• ConvertingtumorsdevoidofTcellinfiltration(“coldtumors”)intoTcellinflamedtumors(“hottumors”)couldimproveresponsetoimmunotherapies.

• Adenosineisamediatorofimmunosuppressionwithinthetumormicroenvironment.

• CPI-444isanoralsmallmoleculeantagonistoftheadenosineA2Areceptor(A2AR)(Emens,AACR2017).

PhICPI-444Trial44

cells, and (3) direct anti-proliferative and pro-apoptotic effectson tumor cells (Platanias, 2005). But continuous interferon-gamma exposure can lead to immunoediting of cancer cells, re-sulting in immune escape (Benci et al., 2016; Shankaran et al.,2001). One mechanism by which cancer cells could escape theeffects of interferon gamma is by downregulating or mutatingmolecules involved in the interferon gamma signaling pathway,which goes through the interferon gamma receptor chainsJAK1 and/or JAK2 and the signal transducer and activators oftranscription (STATs) (Darnell et al., 1994). In cell line and animalmodels, mutations or epigenetic silencing of molecules in theinterferon receptor signaling pathway results in loss of the anti-tumor effects of interferon gamma (Dunn et al., 2005; Kaplanet al., 1998). Analysis of tumors in patients who did not respondto therapy with the anti-CTLA-4 antibody ipilimumab revealed anenriched frequency of mutations in the interferon gammapathway genes interferon gamma receptor 1 and 2 (IFNGR1and IFNGR2), JAK2, and interferon regulatory factor 1 (IRF1)(Gao et al., 2016). Any of these mutations would preventsignaling in response to interferon gamma and give an advan-tage to the tumor cells escaping from T cells, thereby resultingin primary resistance to anti-CTLA-4 therapy. Mutations in thispathway would additionally result in lack of PD-L1 expressionupon interferon gamma exposure, thereby resulting in cancercells that would be genetically negative for inducible PD-L1expression. In such a scenario, blocking PD-L1 or PD-1 withtherapeutic antibodies would not be useful, and these wouldbe patients who are primary resistant to anti-PD-1 therapy(Shin and Ribas, 2015; Shin et al., 2016).An additional cancer-cell-intrinsic mechanism of primary

resistance to immunotherapy is expression of a certain set ofgenes that were found to be enriched in tumors from patients

Figure 3. Known Extrinsic Mechanisms ofResistance to ImmunotherapyThis includes CTLA-4, PD1, and other immunecheckpoints, T cell exhaustion and phenotypechange, immune suppressive cell populations(Tregs, MDSC, type II macrophages), and cytokineand metabolite release in the tumor microenvi-ronment (CSF-1, tryptophan metabolites, TGF-b,adenosine). Abbreviations are as follows:APC, antigen-presenting cells; MHC, major his-tocompatibility complex; TCR, T cell receptor;Treg, regulatory T cell; MDSC, myeloid-derivedsuppressor cell; Mɸ II, type II macrophage.

who did not respond to anti-PD-1 ther-apy, termed innate anti-PD-1 resistancesignature, or IPRES (Hugo et al., 2016).These genes that lead to lack of responseare related to mesenchymal transforma-tion, stemness, and wound healing andare preferentially expressed by cancersthat seldom respond to PD-1 blockadetherapy, such as pancreatic cancer.Epigenetic modification of the DNA

in cancer cells may lead to changesin gene expression of immune-relatedgenes, which can impact antigen pro-

cessing, presentation, and immune evasion (Karpf and Jones,2002; Kim and Bae, 2011). Therefore, demethylating agentsmay enable re-expression of immune related genes, with poten-tial for therapeutic impact, especially in the setting of combina-tion treatment with immunotherapy. (Heninger et al., 2015). His-tone deacetylase inhibitors led to increased expression of MHCand tumor-associated antigens, which synergized with ACTtherapy to improve anti-tumor responses in a murine melanomamodel (Vo et al., 2009). Similarly, in a lymphomamodel, hypome-thylating agents were found to increase CD80 expression on tu-mor cells, with aconcomitant increase in tumor-infiltrating CD8+

T cells (Wang et al., 2013). These pre-clinical data indicate thepotential to reverse the epigenetic changes in cancer cells,which may enable enhanced immune recognition and responseto immunotherapy.

Tumor-Cell-Extrinsic Factors for Primary and AdaptiveResistanceTumor-cell-extrinsic mechanisms that lead to primary and/oradaptive resistance involve components other than tumor cellswithin the tumor microenvironment, including Tregs, myeloidderived suppressor cells (MDSCs), M2 macrophages, and otherinhibitory immune checkpoints, which may all contribute to inhi-bition of anti-tumor immune responses.Tregs, which can be identified by expression of the FoxP3

transcription factor, have a central role in maintaining self-tolerance (Rudensky, 2011). The existence of suppressorT cells that could downregulate immune responses of anti-gen-specific T cells was first identified nearly four decadesago in thymectomized, lethally irradiated, bone-marrow-recon-stituted mice (Gershon and Kondo, 1970). Tregs are known tosuppress effector T cell (Teff) responses by secretion of certain

Cell 168, February 9, 2017 711

(Sharma et al. Cell, 2017)

2

AdenosineSuppressesImmunityandisaPotentialMechanismofResistancetoPD-(L)1Therapy

CD73expressioninbaselinetumorbiopsiesfromtheCPI-444phase1trial

Adenosineinthetumormicroenvironment

Tumorscangenerateadenosineinresponsetoanti-PD-(L)1

(Beavisetal,CanImmunolRes2015)

Adenosine

A2ARATP

AMP

CD73

Tumor

TCell

CD39

TCell

PD1PDL-1

Anti-PD-(L)1 N=1710

CD73

Expression(m

RNA)

p=0.001

Anti-PD-1Naive

100

1,000

10,000

Anti-PD-1Resist/Refract

N=19

PhICPI-444Trial55

T cell inhibition

3

Phase1/1bClinicalStudywithOralDrugCPI-444Expansioncohorts:renalcellandnon-smallcelllungcancer

CPI-444Monotherapy

DoseSelection100mgBIDor200mgQD,

14or28days

CohortExpansion100mgBID28days

CPI-444withatezolizumab

(anti-PD-L1)

DoseSelection50mgBIDor100mgBID+

840mgatezo Q2W

CohortExpansion100mgBID28days+840mgatezo Q2W

• Tumortypes:RCC,NSCLC,Melanoma,TNBC,Others• PriorantiPD-(L)1allowed

• Resistant:SDorbetter>3monthsoftreatment• Refractory:progressionwithin3months

• Musthaveprogressivediseaseonpriortherapy• NoselectionforPD-L1expression

Eligibility

664

CPI-444BlocksA2AReceptorSignaling

50mgBID 100mgBID 200mgQD

pCREBcAMP

A2AR

Adenosine

CPI-444

CD4+Tcell

PhICPI-444Trial

0 5000 10000 150000

50

100

150

CPI-444 (ng/mL)

A2A

R P

athw

ay A

ctiv

ity

(% R

elat

ive

to B

asel

ine)

AnalysisofpCREB byflowcytometry

Adenosine(NECA)stimulationexvivo

77

CPI-444

Plasma CPI-444 (ng/ml)

5

PatientCharacteristicsNon-Small CellLungCancer

(N=45)Renal CellCancer

(N=30)

Prioranti-PD-(L)1exposureNaïveResistant/Refractory

8(18%)37 (82%)

8(27%)22 (73%)

PD-L1Negative* 54% 95%

Median timesinceIOagent,months(range) 2.8(0.6– 24) 1.7(1– 71)

Histology 28(62%)Nonsquamous17(38%) Squamous

28 (93%)Clearcell2(7%)Papillary

Medianage,years(range)

No.ofpatientssingle agent/No.ofpatientscombination

Median numberpriortherapies

70(41-85)

22/23

2 (1-5)

65(44-76)

14/16

3(1-5)

*Archive samples data available on 19 RCC and 28 NSCLC patients based on FDA-approved test

886

Treatment-RelatedAdverseEvents

Grade>3AEs:• Singleagent:none

• CombinationCPI-444+atezolizumab• OnepatientwithGr3immune

relatedhepatitis,pneumonitis,mucositisanddermatitis

Adverse Events(Gr1/2)> 5%Frequency(n=75)

SingleAgent(%) Combination(%)

Fatigue 11 15

Nausea 6 8

Pruritus 8 5

Constipation 6 ---

Dizziness 6 ---

Hypertension 6 ---

Pyrexia 6 ---

Rash --- 5

ASTincreased --- 5

ALTincreased --- 5

997

Phase1/1bTrialwithCPI-444:DiseaseControlinNSCLCPartialresponsescanbeseeninanti-PD-1progressors

10

(%)C

hangefro

mBaseline

Patie

nts

CPI-444Combination (CPI-444+atezolizumab)

DiseaseControlDuration

Treatment(Months)Resistant/refractorytopriorIONaïvetopriorIOPD-L1Positive/Negative-+

- + - - + - - - + + + - + - + + -

8

Phase1/1bTrialwithCPI-444:DiseaseControlinRenalCellCancerPartialresponsescanbeseeninananti-PD-1progressingandnaïvepatients

Resistant/refractorytopriorIONaïvetopriorIO Treatment(Months)

- - - - - - - - - - - - - -

PD-L1Positive/Negative+ -

CPI-444Combination (CPI-444+atezolizumab)

(%)C

hangefro

mBaseline

Patie

nts

DiseaseControlDuration

9

TumorGrowthKineticsin“Stable”RCCPatients

Days1212

-100 100 200 300

-80

-60

-40

-20

20

101001 SLD

Rela

tive

Targ

et L

esio

n(s)

Siz

e

Days

-400 -200200

400

-30

-20

-10

10

20

103101 SLDRe

lativ

e Ta

rget

Les

ion(

s) S

ize

Days

-600 -400 -200 200

-30

-20

-10

10

20

100410 SLD

Rela

tive

Targ

et L

esio

n(s)

Siz

e

Days

-100 100 200

-30

-20

-10

10

20

103210 SLD

Rela

tive

Targ

et L

esio

n(s)

Siz

e

Days

-100

100

200 300 400

-30

-20

-10

10

20

101501 SLD

Rela

tive

Targ

et L

esio

n(s)

Siz

e

Days

CPI-444 Single Agent CPI-444 in Combination with AtezolizumabAnti-PD-1 Naïve Nivolumab Refractory

Pembrolizumab Resistant Nivolumab Refractory

Anti-PD-1 Naïve

Anti-PD-1 Naïve

Prior to CPI-444 On CPI-444

Perc

ent C

hang

e in

Tar

get L

esio

n(s)

-150 -100 -50 50 100 150

-40

-20

20

10

TumorRegressioninNivolumabRefractoryRenalCancerSingleAgentCPI-444

Pre-treatment 3monthsoftreatment

FivepriorregimensincludingTKIs,mTORinhibitor,andnivolumab

Pre-treatment PostDose(8w)

14% >70%

H&E

CD8IHC

PhICPI-444Trial131311

CPI-444InducesCD8TCellInfiltrationandTh1GeneExpressioninTumorTissues

1414

Log Fold Change Gene ExpressionPost vs pre biopsies (N=14)

ImmuneGeneExpression(pairedbiopsies)CD8TCellChange(IHC)

NSCLCRCC

Median95%CI

Pre-dose

NSCLC

Post-dose

RCC

Post-dosePre-dose

CD8

0.1

1

10

CD

8 R

ati

o (

Po

st/

Pre

bio

psy) SD

PR

-2 -1 0 1 2

1

2

3

4

5

Log Fold Change Gene Expression

-log

P va

lue

CXCL10GZMB

PD-L1

OPGCXCL11CXCL16GZMACCL17TEFF_SIG

PD-L2

ICAM1NFATC4 IL2RAEOTAXIN

CCL13CD44IL7R CXCL9

CD8A

12

CPI-444ExpandsNewTCellClonesinBloodandTumor

Treatment induces expansion of identical T cell clones in blood and tumor

Posttreatm

ent

Pre-treatment

Blood TumorBiopsy

0.01 0.1 1 100.01

0.1

1

10

Screen Biopsy

Pos

t dos

e B

iops

y

1515

• RCC patient with PR on single-agent CPI-444

• T cell receptor (TCR) sequencing of blood and tumor biopsies pre-and post-treatment

• T cell clonotypes can be matched between blood and tumor

Pre-treatment

Posttreatm

ent

13

Phase1/1bTrialwithCPI-444:Summary

• CPI-444iswell-toleratedasamonotherapyandincombinationwithatezolizumab

• CPI-444hasclinicalactivityaloneandincombinationwithatezolizumab

• Anti-tumoractivityseenin:

– Patientswhohaveprogressedonprioranti-PD-(L)1

– PatientswithPD-L1negativetumors

• CPI-444caninduceCD8TcellinfiltrationandexpressionofTcellactivationgeneswithinthetumormicroenvironment

• CPI-444inducesnewTcellclonotypesintheblood,whicharecapableofmigratingtotumors

• AccrualofpatientsintotheexpansioncohortsforNSCLCandRCCisongoing

161614

Acknowledgements• Thepatientsandtheirfamilies

• ParticipatingCenters:BritishColumbiaCancerAgency,CarolinaBioOncologyInstitute,ClevelandClinic,ColumbiaUniversityMedicalCenter,CrossCancerInstitute,EmoryUniversity,GeorgetownUniversity,IndianaUniversity,JohnsHopkinsUniversity,JuravinskiCancerCentre,KarmanosCancerCenter,MaryCrowleyCancerResearchCenters,MassachusettsGeneralHospital,MedicalCollegeofWisconsin,MemorialSloanKetteringCancerCenter,MonashHealth,MountSinaiSchoolofMedicine,OhioStateUniversity,OttawaHospitalCancerCentre,PeterMcCallumCancerCenter,RoyalBrisbaneandWomen’sHospital,RushUniversity,StanfordUniversity,UniversityofCaliforniaatLosAngelesMedicalCenter,UniversityofCaliforniaatSanFranciscoMedicalCenter,UniversityofArizonaMedicalCenter,UniversityofChicagoMedicalCenter,UniversityofColoradoCancerCenter,UniversityofNebraska,UniversityofPittsburgh,UniversityofWashington,UTSouthwestern,WashingtonUniversityatSaintLouis,YaleUniversity

• ColleaguesatCorvus• ColleaguesatRocheGenentech

PhICPI-444Trial1715