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ClinicalAc)vityofAdenosineA2AReceptor(A2aR)InhibitorCPI-444isAssociatedwithTumorExpressionofAdenosine
PathwayGenesandTumorImmuneModula)on
2 2
Drew Hotson1, John Powderly2, Leisha Emens3, Patrick Forde3, Matthew Hellmann4, Lawrence Fong5, Ben Markman6, Brett Hughes7, Jonathan Goldman8, Mario Sznol9, Daruka Mahadevan10, Shivaani Kummar11, Joshua Brody12, Philip Bonomi13, Jason Luke14, Matthew Riese15, Taofeek
Owonikoko16, Sherene Loi17, Amy Wiese18, Robert Doebele19, James Lee20, Chunyan Gu1, Stephen Willingham1, Ginna Laport1, Richard Miller1 and Ian McCaffery1
1Corvus Pharmaceuticals, Burlingame, CA; 2Carolina BioOncology Institute, Huntersville, NC; 3Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD; 4Memorial Sloan Kettering Cancer Center, New York City, NY; 5University of California, San
Francisco, San Francisco, CA; 6Monash Medical Centre, Clayton, Australia; 7Royal Brisbane and Women’s Hospital, Herston, Australia; 8University of California, Los Angeles, Los Angeles, CA; 9Yale University School of Medicine, New Haven, CT; 10University of Arizona Cancer Center, Tucson, AZ; 11Stanford University School of Medicine, Stanford, CA; 12Icahn School of Medicine at Mount Sinai, New York City, NY;
13Rush University Medical Center, Chicago, IL; 14University of Chicago Medical Center, Chicago, IL; 15Medical College of Wisconsin, Milwaukee, WI; 16Emory University Hospital, Atlanta, GA; 17Peter MacCallum Cancer Centre, Melbourne, Australia; 18Karmanos Cancer Institute/Wayne
State University, Detroit, MI; 19University of Colorado Anschutz Medical Campus, Aurora, CO; 20University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA.
Capitalized title A2aR Disclosures
2
Consultancy 7 Hills, Actym, Amgen, Array, AstraZeneca, BeneVir, Bristol-Myers Squibb, Castle, CheckMate, EMD Serono, Gilead, Janssen, Novartis, Merck
Clinical Trial Support to Institution
AbbVie, Boston Biomedical, Bristol-Myers Squibb, Celldex, Corvus, Delcath, Five Prime, Genentech, Immunocore, Incyte, Intensity, MedImmune, Macrogenics, Novartis, Pharmacyclics, Merck, Tesaro
Funding for CPI-444 clinical trial provided by Corvus
Background
• An2-PD-(L)1an2bodiesareapprovedfortreatmentofseveralcancersbutasmallpropor2onofpa2entsbenefit
• Mechanismsofan2-PD-(L)1resistancearenotwellunderstoodandnoagentsareapprovedtoovercomeresistance
• Adenosinepathwaymediatestumorimmunosuppression;maybearesistancemechanismtoan2-PD-(L)1therapy
• CPI-444isanoral,smallmoleculeinhibitorofA2ARthathasshownan2-tumorac2vityinan2-PD-(L)1resistant/refractory,andPDL-1nega2vepa2ents1
1Fong,ASCO2017; 2Beavisetal.,CanImmunRes2015;3Sharmaetal.,Cell2017
Adenosineinthetumormicroenvironment2,3
Adenosine
A2ARATPAMP
CD73
Tumor
TCell
CD39
TCell
PD-1PD-L1
An2-PD-1
CPI-444
Phase1/1bClinicalStudywithOralDrugCPI-444
DoseSelec@on
CohortExpansion100mgBID28days
DoseSelec@on
CohortExpansion100mgBID28days+840mgatezolizumab
Q2W
• Prioran2-PD-(L)1allowed• Resistant:SDorbeZer>3monthsof
treatment• Refractory:progressionwithin3months
• Musthaveprogressivediseaseonpriortherapy
• Noselec2onforPD-L1expression
Eligibility
CPI-444Monotherapy
CPI-444withatezolizumab(an@-PD-L1)
RCCNSCLCMelanomaTNBCOthers
Naive
Refra
ctory
Resis
tant
10
100
1000
CD
39 E
xpre
ssio
n
Naive
Refra
ctory
Resis
tant
10
100
1000
10000
CD
73 E
xpre
ssio
n
Naive
Refra
ctory
Resis
tant
10
100
1000
A2A
R E
xpre
ssio
n
PriorAn2-PD-(L)1TreatmentIncreasesA2AR,CD73andCD39Adenosinepathwayisapoten)almechanismofresistance
p=0.002
n=36 n=26 n=35
p=0.1
n=36 n=26
5
n=35 n=36 n=26 n=35
p=0.01
p=0.002
p=0.003
p=0.002
A2AR CD73 CD39 Exposuretoan2-PD-(L)1therapy(>3months)increasesA2AR,CD73,andCD39expression
RCC
NSCL
COt
her
10
100
1000
CD
39 E
xpre
ssio
n
RCC
NSCL
COt
her
10
100
1000
10000
CD
73 E
xpre
ssio
n
RCC
NSCL
COt
her
10
100
1000
A2A
R E
xpre
ssio
nAdenosinePathwayExpressionisHigherinRCCandNSCLCPre-TreatmentBiopsies
A2AR CD73
6 Other = bladder, colorectal, triple-negative breast, melanoma, prostate
p < 0.0001
p = 0.05
p = 0.03
p < 0.0001
CD39 p < 0.0001
p = 0.0002
n=19 n=33 n=49 n=19 n=33 n=49 n=19 n=33 n=49
RenalCellCohortsExpandedPa)entcharacteris)cs
RenalCellCancer(N=51)Prioran@-PD-(L)1exposureNaïveResistant/Refractory
16(31%)35(69%)
PD-L1Nega@ve(archival)* 91%
Median@mesinceIOagent,months(range) 1.6(1–71)
Histology 50(98%)Clearcell1(2%)Papillary
Medianage,years(range)No.ofpa@ents:singleagent/combina@onMediannumberpriortherapies(range)
64(44-70)25/263(1-5)
AdversePrognos@cFactors(%)VisceralmetastasesHepa@cmetastasesAnemiaElevatedLDH
88%20%45%21%
7 * PD-L1 status determined using FDA-approved assay (SP142, cutoff = 5%) Data cutoff 10/26/17
CPI-444An2-TumorAc2vityinRenalCellCancerResponseswithsingleagentandcombina)on
8
Single agent CPI-444 (atezolizumab-refractory)
Combination CPI-444 + atezolizumab
Partial Responses in RCC
ResistanttopriorIORefractorytopriorIONaïvetopriorIO
Single Agent Combination
Data cutoff 10/26/17
RenalCellCancerResponserateanddiseasecontrolrateinevaluablepa)ents
Treatment Objec@veResponseRate
DiseaseControlRate
CPI-444CPI-444+atezolizumab
2*/14(14%)2/16(13%)
4/14(29%)11/16(69%)
9 Drug Treatment (months)
CPI-444 + atezolizumab
% c
hang
e fro
m b
asel
ine
*1 unconfirmed
% c
hang
e fro
m b
asel
ine
CPI-444
Drug Treatment (months) Data cutoff 10/26/17
Treatment-RelatedAdverseEvents
10
AdverseEvents(Gr1/2)>5%Frequency(n=210)
CPI-444(%) CPI-444/Atezo(%)
Fa@gue 21 29
Nausea 12 14
Pruritus 11 10
Pyrexia 5 9
Decreasedappe@te 6 7
Diarrhea 7 5
Anemia 6 4
Vomi@ng 3 6
Rash 3 6
Grade > 3 Serious Adverse Events CPI-444 (n=1) • Gr 3 nausea/vomiting/diarrhea CPI-444/Atezolizumab (n=5) • Gr 3 immune related hepatitis, dermatitis,
mucositis, pneumonitis • Gr 3 autoimmune hemolytic anemia • Gr 3 increased ALT/AST • Gr 3 thrombocytopenia/ Gr 4 encephalitis • Gr 3 pneumonitis
Data cutoff 10/26/17
ScreeningA2ARandCD73AssociatedwithResponseDoubleposi)veA2AR,CD73maybepredic)ve
11
Pro
gres
sion
R
egre
ssio
n
A2AR
low
A2AR
high
-100
-50
0
50
100
150T
um
or
Resonse (
Best %
Change)
A2AR
Neg Pos
Tum
or R
espo
nse
(Bes
t % C
hang
e) p=0.01
n = 35 n = 32
Partial Responses✝
✝Tissue not available for all PRs
CRC (MSI-H) NSCLC RCC RCC
CD73
low
CD73
high
-100
-50
0
50
100
150
Tum
or
Resonse (
Best %
Change)
CD73
p=0.09
n = 16 n = 51
Neg Pos Neg Double Positive
A2AR+/CD73+
p=0.0006
n = 49 n = 24
ScreeningA2AR,CD73AssociatedwithDiseaseControlRateDoubleposi)veA2AR,CD73maybepredic)ve
Nega@ve Posi@ve
A2AR 4/39(10%) 10/34(29%)
CD73 2/22(9%) 12/51(24%)
A2AR+CD73(DoublePosi@ve) 4/49(8%) 10/24(42%)*
*p=0.0007
DiseaseControlRate(allindica@ons;biomarkerassessable)
CD73Q1/Q2to4
Q1 Q2toQ4
0.0 0.5 1.0
JITTER
0.0 0.5 1.0
JITTER
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
log2FOLD
CD8infiltrationIHC
single-agentfoldCD73Q1vs
Q2to4
CD73Q1/Q2to4
Q1 Q2toQ4
0.0 0.5 1.0
JITTER
0.0 0.5 1.0
JITTER
-3
-2
-1
0
1
2
3
4
5
6
Delta
PD-L1IHCsingle-agent
deltaCD73Q1vsQ2to
4Gene/CD73Q1/Q2to4
CXCL9
Q1 Q2toQ4
CXCL10
Q1 Q2toQ4
GZMA
Q1 Q2toQ4
GZMB
Q1 Q2toQ4
IDO1
Q1 Q2toQ4
LAG3
Q1 Q2toQ4
0.0 1.0 0.0 1.0 0.0 1.0 0.0 1.0 0.0 1.0 0.0 1.0 0.0 1.0 0.0 1.0 0.0 1.0 0.0 1.0 0.0 1.0 0.0 1.0
-3
-2
-1
0
1
2
log2FOLD
Sheet3
InCD73+Tumors,SingleAgentCPI-444InducesExpressionofTcellAc2va2onMarkersinPost-DoseBiopsies
Infiltration IFNγ Induction Effector Checkpoints
Neg Pos Neg Pos Neg Pos Neg Pos Neg Pos Neg Pos Neg Pos Neg Pos
z
CXCL9 p=0.02
CXCL10 p=0.07
GZMA p=0.07
GZMB p=0.04
IDO1 p=0.01
LAG3 p=0.16
CD73 Expression (in Screening Biopsies)
Log 2
Fol
d C
hang
e (P
ost/P
re B
x)
Gen
e E
xpre
ssio
n
CD
8 Lo
g 2 F
old
Cha
nge
(Pos
t/Pre
Bx)
CD73 Expression (in Screening Biopsies)
Inflammation
PD
-L1
Cha
nge
(Pos
t-Pre
Bx)
CD8 (IHC) p = 0.005
PD-L1 (IHC) p = 0.15
Summary
16 16 14
• TumorexpressionofA2AR,CD73andCD39areincreasedinpa2entsthatareresistanttopriortreatmentwithan2-PD-(L)1
• RCCandNSCLChavehightumorexpressionofadenosinepathwaygenesA2AR,CD73andCD39
• CPI-444hasan2-tumorac2vityinRCC– Reponsesseeninan2-PD-(L)1resistant/refractorypa2ents– A2ARandCD73expressioninscreeningbiopsiesisassociatedwithresponseto
therapy
• CPI-444increasesCD8+infiltra2onintumorsandinducesexpressionofIFNγ-dependentgenesandTh1ac2va2on
• Thisstudycon2nuestoenrollpa2entswithRCCandNSCLCinexpansioncohorts
Acknowledgements
Patients and their Families Clinical Investigators and their staff Colleagues at Corvus