l’immunothérapie en onco-urologie...durvalumab. 100-100 0) time ... dreicer asco 2016 petrylak...

L’immunothérapieenonco-urologie

VACCINE

APCinfusion

TCARcells

Bispecific antibodies

Strategy 1:eliciting tumor-targetingcytolytic lymphocytes

TosupplyoraugmentthefrequencyofTcellsinapatientspecificforoneormoretumor-associatedantigens

cytokines

Strategy 2:disrupting immuneregulation

AntiCTLA4mAb

AntiPD1/PDL1mAb

Strategy 3:altering thetumor microenvironment

MDSC

TregCellsIL10IDO

Cancerdelaprostate:canceridéalpourl’immunothérapie

• Maladieengénérallentementévolutive• Nombreuxantigènescibles• Tissuciblenonessentiel• Marqueurantitumoral àpeuprèsfiable:PSA• Maladiefréquente• Secondecausededécèsparcancerchezl’homme

Lecancerdureinaussi

• Rémissionsspontanées

• Régressionsimprévisibles

• Evolutionparfoistrèslente

->l’échappementàl’immunosurveillance estprobablementfréquentdanslecancerdurein

11/2000

2/2002

Nephrectomie12/2000

11/2000

2/2001

2/2009

Lecancerurothélial aussi

• Hautementmuté(associationaveclenombredenéo-épitopes)

• UtilisationdelaBCGthérapie danslesformesnoninvasives

Alexandrovetal.Nature2013

Le cancer urothélial est très muté

VACCINE

APCinfusion

TCARcells

Bispecific antibodies

Strategy 1:eliciting tumor-targetingcytolytic lymphocytes

TosupplyoraugmentthefrequencyofTcellsinapatientspecificforoneormoretumor-associatedantigens

cytokines

Cytokinesetcancerdelaprostate

• IL2:stratégieabandonnée.RéponsePSArarissimemalgréuneinfiltrationlymphocytaireTintratumorale

• IL2+INF:bis• Cytokinesintratumorales:ter• GM-CSF:réponseplusfréquente

Enpratique:abandonnées

Tauxderéponse faible(5-10%)maisdurableActuellement:indicationsexceptionnellescompte-tenudelatoxicité

Vaccins

• GVAX:extraitsdePC3etLNCAPmodifiiéespoursurexprimer GM-CSF

• RéponseimmunespécifiquecontreplusieursAg

• MAIS:– Uneétudedephase3:pasdesupérioritéparrapportàlachimiothérapie

– Uneétudedephase3:délétère+++

SIPULEUCEL-T(PROVENGE)

Kantoff etal.NEJM2010

Vaccins

• Unedizainedevaccinsencoursd’évaluation• Placedesvaccinsmaldéterminée• Stratégiesdecombinaisons• Sipuleucel- T:100000$parpatient

TCARcells

Antigènespécifiquedelaprostate:PSMA

Anticorpsbispécifique

Risqued’effets« off-target »MoinscheretmoinsdifficilequelesCARTcells

Strategy 2:disrupting immuneregulation

AntiCTLA4mAb

AntiPD1/PDL1mAb

Lymphocyte Inhibition

Rosenbergetal,Lancet2016

Etude de phase II IMVIGOR monobrasatezolizumab

Hypothèse :tauxderéponse>10%(tauxderéponsehistorique)

Quel est le taux de réponse ?

Letauxderéponsepourunpatientnonsélectionné:15%Letauxderéponseaugmenteavecl’expressiondePDL1surcellulesimmunitairesL’expressiondePDL1n’estpassuffisammentdiscriminantedanslesphasesavancées


Améliore-t-on la survie des patients ?

Quandunpatientrépond, celui-cirépond bienetlongtemps


Y-a-t-il des effets secondaires ?

Latoléranceenmonothérapie estexcellentemaisattentionauxEIimmunologiques


ATEZOLIZUMAB PDL1i PHASE 3

DURVALUMAB PDL1i PHASE 1

NIVOLUMAB PD1i PHASE2

AVELUMAB PDL1i PHASE1

PEMBROLIZUMAB PD1i PHASE3

PD1/PDL1RACE

100

-100

0

SLDchangefrom

PD(%

)

Time

Patie

ntsw

ithCRorPRatbestresponse

Time Time

OS

Similarefficacyplotsforallofthem

Atezolizumab

100

-100

0

SLDchangefrom

PD(%

)

Time

Patie

ntsw


Time Time

OS


Durvalumab

100

-100

0

SLDchangefrom

PD(%

)

Time

Patie

ntsw


Time Time

OS


Nivolumab

Dreicer ASCO2016 PetrylakASCO2015 ApoloGUASCO2016 MassardASCO2016 SharmaASCO2016Plimack ASCO2015ESMO2016

PhaseIBasketStudiesn=310 n=87 n=44 n=42 n=78 n=29

AdaptedfromB.Plimack,presentedatASCO2016

n=265

HistoricalControlwChemo~12%

RosenbergLancet2016

PD-1/PD-L1 INHIBITORS

Overall Response Rates: Post-Platinum

SECONDLINEPHASEIII

KEYNOTE-045StudyDesign (NCT02256436)

EstimatedtimelinesEstimatedcompletion:May2017

Pembrolizumab

SOC:Paclitaxel,DocetaxelorVinflunine

Secondaryendpoints•ORR•Safety

Primaryendpoints

OS&PFS

• Urothelial cancer• Progressionorrecurrence

ofurothelial cancerfollowingafirst-lineplatinum-containingregimen.

• Nomorethan2priorlinesofsystemicchemotherapy.

RandomizationN=470patients

71

Estimated timelinesEstimatedcompletion:Nov2017

Atezolizumab

SOC:Docetaxel,PaclitaxelorVinflunine

Secondaryendpoints•ORR•PFS•DOR•Safety

Primaryendpoints

OS• Urothelial cancer• Progressionorrecurrence

ofurothelial cancerfollowingafirst-lineplatinum-containingregimen.


IMvigor211StudyDesign(NCT02302807)

KEYNOTE-045 STUDY

Bellmunt etal.NEJM2017

DISPOSITION OF STUDY TREATMENT


BASELINE CHARACTERISTICS


OVERALL SURVIVAL : TOTAL


OVERALL SURVIVAL : CPS ≥ 10%


CONFIRMED OBJECTIVE RESPONSE RATE


OVERALL SURVIVAL IN SUBGROUPS


TOLERANCE


TREATMENT-RELATED AE


Powlesetal.EACR2017

IMVIGOR211study

ORR:13.4%ITTand23%inIC2/31-yearOS:40%inITTpatients

NMIBC MIBC MetastaticUC

Low Grade HighGrade

BCGrefractory

Pembrolizumab/BCGAtezolizumab/BCG

Pembrolizumab/BCG

neoadjuvant Adjuvant fit unfit

Maintenance

Platinum-resistant

DANUBE(durva,tremelimumabMK-3475-361(pembrolizumab)IMVIGOR130(atezolizumab

CA209-901094(nivolumab,ipilimumab)

• Pembrolizumab (KEYNOTE045,PhaseIII)• Atezolizumab (IMVIGOR211,PhaseIII)• Pembrolizumab +Epacadostat (phase III)

2nde line

1ère ligne

Current/futurclinicaltrialsinUC

Atezolizumab (NMvigor010, phase3)Nivolumab (CHECKMATE274,phase3)Pembrolizumab (Ambassador,phase3)

• Avelumab (JAVELIN,phaseIII)

Pembro +Epacadostat (KN672,phaseIII)

Pandore(pembro, phaseII)

IMvigor210 Study: Cohort 1

IRF, independent review facility. ClinicalTrials.gov ID: NCT02108652. a PD-L1 prospectively assessed by a central laboratory, with patients and investigators blinded. b Cockcroft-Gault formula. 1. Galsky J Clin Oncol 2011.

IMvigor210:• Inoperable locally advanced or

metastatic urothelial carcinoma• Predominantly UC histology• Tumor tissue evaluable for

PD-L1 testinga

Cohort 1 (N = 119):1L cisplatin ineligible

Cohort 2:Platinum-treated mUC

Atezolizumab 1200 mg IV q3w until RECIST v1.1 progression

Atezolizumab 1200 mg IV q3w until loss of clinical benefit

Primary endpoint • Confirmed ORR: RECIST v1.1

(per central IRF)

Key secondary endpoints • DOR, PFS, OS, safety

Cohort 1–specific inclusion criteria • No prior treatment for mUC (> 12 mo since perioperative chemo)• ECOG PS 0-2• Cisplatin ineligibility1 based on ≥ 1 of the following:

− Renal impairment: GFR < 60 and > 30 mL/minb

− ≥ Grade 2 hearing loss or peripheral neuropathy− ECOG PS 2

EfficacyResponse to atezolizumab (IRF RECIST v1.1)

• Patients in this analysis had a median of follow-up duration of 14.4 mo (range, 0.2-20.1 mo)

a Includes 19 patients with missing/unevaluable responses. All treated patients had measurable disease at baseline per investigator-assessed RECIST v1.1. PD-L1 IC status: IC2/3 (≥ 5%), IC1 (≥ 1% and < 5%), IC0 (< 1%). Data cutoff: March 14, 2016.

IC1(n = 48)

IC0(n = 39)

23% (12, 37) 21% (9, 36)

6% 8%

17% 13%

IC2/3(n = 32)

IC1/2/3(n = 80)

All Patients(N = 119)

ORRa (95% CI) 28% (14, 47) 25% (16, 36) 24% (16, 32)

CR 6% 6% 7%

PR 22% 19% 17%

# at Risk: All: 119 101 89 78 71 64 52 33 16 7 1

• With a median follow-up of 14.4 months,a

the event rate is 47%

Ove

rall S

urvi

val,

%

100

80

60

40

20

0

Time, months6 8 102 40 12 14 16 18 20

12-mo OS rate: 57% (48, 66)

a Range, 0.2 to 20.1 mo. Data cutoff: March 14, 2016. 1. De Santis J Clin Oncol 2012. 2. Galsky ECC 2015 [poster 115].

+ censored event

EfficacyOverall Survival (Median and Landmark 12-Month OS)

N = 119

mOS (95% CI):12-mo OS (95% CI):

14.8 mo (10.1, NE)57% (48, 66)

• Atezolizumab compares favorably with historic data from cisplatin-ineligible patients, both from clinical trials and real-world studies1,2

# at Risk: All: 119 101 89 78 71 64 52 33 16 7 1

IC0/1: 87 73 65 57 52 46 37 26 13 6 1IC2/3: 32 28 24 21 19 18 15 7 3 1 0

Ove

rall S

urvi

val,

%

100

80

60

40

20

0

Time, months6 8 102 40 12 14 16 18 20

• With a median follow-up of 14.4 months,a the event rate is 47%

a Range, 0.2 to 20.1 mo. Data cutoff: March 14, 2016.

EfficacyOverall Survival (Median OS) by PD-L1 Status

Subgroup■ All (N = 119)■ IC0/1 (n = 87) ■ IC2/3 (n = 32)

mOS (95% CI)14.8 mo (10.1, NE)15.3 mo (9.8, NE)12.3 mo (6.0, NE)

Ove

rall S

urvi

val,

%

KEYNOTE-052:Pembrolizumab as1stline

Patients(N=370)• CUavancés• Absencedechimiothérapiepréalable pourlesmCU

• ECOGPS0-2• Inéligible pourunechimiothérapie parcisplatine enraisond’≥1élément :- CrCI <60ml/min- ECOGPS2- Toxicité neurologique /auditive grade≥2- Insuffisance cardiaqueNYHAclassIII

Pembrolizumab200mgIV/3sem.

Critèresprincipaux• Tauxderéponsesobjectives(ORR)globales

• ORRchezlespatientsdontlatumeurexprimePD-L1

ORR=29%chezles370patientsinclusdansl’étude.

ORR=51%encasd’expressionPDL1>10%

Signaturede18gènesassociésauxlymphocytesTcorréléeàlaréponseanti-tumorale

Balar etal.ASCOGU2017

FIRSTLINEPHASEIII

KEYNOTE361StudyDesign (NCT02853305)

EstimatedtimelinesEstimatedcompletion:Feb2018

pembrolizumab

SOC:+pembrolizumab


Primaryendpoints

PFS1andOSinPDL1+• MetastaticUrothelialcancer

• Unfitorfitpatients• Nochemotherapy

inmetastatic setting.


71

SOC:Platinum-based

chemo

H1:PFSinchemo +pembro >chemo inPDL1+(HR=0.6)H2:OSinchemo +pembro >chemo inPDL1+(HR=0.625)H3:PFSinchemo +pembro >chemo inallpatientsH4:OSinchemo +pembro >chemo inallpatients…

FIRSTLINEPHASEIII

IMVIGOR130StudyDesign(NCT02853305)

EstimatedtimelinesEstimatedcompletion:Feb2018

Atezolizumab

SOC:+atezolizumab


Primaryendpoints

PFS1andOSincombovs chemo• MetastaticUrothelialcancer




71

SOC:Platinum-based

chemo

H1:PFSinchemo +pembro >chemo inPDL1+(HR=0.6)H2:OSinchemo +pembro >chemo inPDL1+(HR=0.625)H3:PFSinchemo +pembro >chemo inallpatientsH4:OSinchemo +pembro >chemo inallpatients…

FIRSTLINEPHASEIII

CHECKMATE901StudyDesign(NCT02256436)

EstimatedtimelinesEstimatedcompletion:

Nivolumab +ipilimumab

SOC:Platinum-based

chemo

Secondaryendpoints•OSinallpatients•ORR•Safety

Primaryendpoints

OS&PFSinunfitpatients• MetastaticUrothelialcancer




71

SOC:Platinum-based

chemo+nivolumab

FIRSTLINEPHASEIII

JAVELINStudyDesign(NCT002603432)

EstimatedtimelinesEstimatedcompletion:2020

avelumab

SOC:BSC

Secondaryendpoints•PFS•ORR,duration ofresponse•Safety

Primaryendpoints

OS• MetastaticUrothelial

cancer• CR,PR,SDupon4-6

paltinum-basedchemo


71

NMIBC MIBC MetastaticUC

Low Grade HighGrade

BCGrefractory

Pembrolizumab/BCGAtezolizumab/BCG

Pembrolizumab/BCG

neoadjuvant Adjuvant fit unfit

Maintenance

Platinum-resistant

DANUBE(durva,tremelimumabMK-3475-361(pembrolizumab)IMVIGOR130(atezolizumab

CA209-901094(nivolumab,ipilimumab)

• Pembrolizumab (KEYNOTE045,PhaseIII)• Atezolizumab (IMVIGOR211,PhaseIII)• Pembrolizumab +Epacadostat (phase III)

2nde line

1ère ligne

Current/futurclinicaltrialsinUC

Atezolizumab (NMvigor010, phase3)Nivolumab (CHECKMATE274,phase3)Pembrolizumab (Ambassador,phase3)

• Avelumab (JAVELIN,phaseIII)

Pembro +Epacadostat (KN672,phaseIII)

Pandore(pembro, phaseII)

Autorisationnivolumab secondelignemétastatiquecancerdurein

Tauxderéponse :25%

Pasdefacteurscliniquesoubiologiquesderéponse

Trèsbientoléréeengénérallorsd’uneadministrationenmonothérapie

Concernantlatolérance

CheckMate 214: Study design

IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status; Q2W, every 2 weeks; Q3W, every 3 weeks

Treatment until progression or unacceptable

toxicity

• Treatment-naïve advanced or metastatic clear-cell RCC

• Measurable disease• KPS ≥70%• Tumor tissue

available for PD-L1 testing

TreatmentPatients

Randomize 1:1Arm A

3 mg/kg nivolumab IV + 1 mg/kg ipilimumab IV Q3W

for four doses, then 3 mg/kg nivolumab IV Q2W

Arm B50 mg sunitinib orally once

daily for 4 weeks (6-week cycles)

Stratified by • IMDC prognostic score (0 vs 1–2 vs 3–6)

•Region (US vs Canada/Europe vs Rest of World)

ORR and DOR: IMDC intermediate/poor risk

N = 847

OutcomeNIVO +

IPIN = 425

SUNN = 422

Confirmed ORR,a % (95% CI)

42 (37–47)

27 (22–31)

P < 0.0001Confirmed BOR,a %

Complete responsePartial responseStable diseaseProgressive diseaseUnable to determine/notreported

9b

3231208

1b

25451712

aIRRC-assessed ORR and BOR by RECIST v1.1; bP < 0.0001

SUN

NIVO +IPI

No.atRisk

177 146 120 55 3

112 75 52 17 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24Months

DurationofResponse(Probability)

Co-primary endpoint: ORR

Medianduration ofresponse,months(95%

CI)

Patientswithongoingresponse,

%NIVO +IPI NR(21.8–NE) 72

SUN 18.2(14.8–NE) 63

OS: IMDC intermediate/poor risk

Hazard ratio (99.8% CI), 0.63 (0.44–0.89)P < 0.0001

Median OS, months (95% CI)

NIVO + IPI NR (28.2–NE)

SUN 26.0 (22.1–NE)

Ove

rall

Surv

ival

(Pro

babi

lity)

425 399 372 348 332 318 300 241 119 44 2 0422 387 352 315 288 253 225 179 89 34 3 0

No. at RiskNIVO + IPI

SUN

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.018 21 24 27 30 3315129630

Co-primary endpoint

ORR,PFS,andOS:Intentiontotreat

a23% of patients in the NIVO + IPI arm and 25% of patients in the SUN arm had tumor PD-L1 expression ≥1%bIRRC-assessed by RECIST v1.1cIRRC-assessed

N = 1,096a

Outcome NIVO + IPIN = 550

SUNN = 546

Confirmed ORR,b % (95% CI) 39 (35–43) 32 (28–36)

P = 0.0191

PFS,c median (95% CI), months

12.4 (9.9–16.5)

12.3 (9.8–15.2)

HR(99.1%CI)0.98(0.79–1.23)

P=0.8498

550 523 492 464 443 426 404 339 197 71 4 0546 506 471 432 402 363 334 283 173 66 6 0

Ove

rall

Surv

ival

(Pro

babi

lity)

0.8

0.9

1.0

0.4

0.5

0.6

0.7

0 6 12 18 24

0.1

0.0

0.2

0.3

33303 9 15 21 27Months

No. at RiskNIVO + IPI

HR (99.8% CI) 0.68 (0.49–0.95)P = 0.0003

MedianOS,months(95%CI)

NIVO +IPI NR(NE–NE)SUN 32.9(NE–NE)

Secondary endpoint

284 202 155 119 102 90 70 23 9 1 0

278 200 138 105 83 67 43 25 11 1 0

PFS by PD-L1 expression: IMDC intermediate/poor risk

PD-L1 <1% (n = 562) PD-L1 ≥1% (n = 214)

HR (95% CI) 0.48 (0.28–0.82)P = 0.0003

MedianPFS,months(95%CI)

NIVO +IPI 22.8(9.4–NE)SUN 5.9(4.4–7.1)

HR (95% CI) 1.00 (0.74–1.36)P = 0.9670

MedianPFS,months(95%CI)

NIVO +IPI 11.0(8.1–14.9)SUN 10.4(7.5–13.8)

NIVO

SUN

No.atRisk

100 77 61 54 50 48 41 21 8 2 0

114 63 40 24 17 13 9 4 0 0 3

0.8

0.9

1.0

0.4

0.5

0.6

0.7

0 963 21181512 302724

0.1

0.0

0.2

0.3

0.8

0.9

1.0

0.4

0.5

0.6

0.7

0 963 21181512 302724

0.1

0.0

0.2

0.3

Progression-FreeSurvival(Probability)

MonthsMonths

Exploratory endpoint

CancerdelaprostateetIpilimumab:

mCRPC postchimiothérapie :combinaison ipi +IRvsIRseule

Kwon etal.LO2014

AntiPD1etantiPDL1?

• Danslesétudesdephase1toutetumeuraveclenivolumab (antiPD1):pasderéponseobservéedanslescancersdelaprostate

inhibiteurscheckpointsetcancerdelaprostate

• Peuefficaces(commedanslecancerdusein)– Rôledesautrescheckpoints(TIM-3,LAG3,..)?– Microbiote spécifique?– Chargemutationnellefaible(1-2mut/Mb)?– Rôledelatestostéronedanslesinteractionstumeur-cellulesimmunitaires?

Weneedtotackletheoverallecosystem

22/02/2018 TITRE DU DIAPORAMA Général 65

Pembrolizumab

TauxderéponsePSA:30%

Previous ttt:Caso/zola

200mut(4mut/Mb) 1500mut (30mut/Mb)

Openquestions

• Howtoimproveresponserate?

ImmuneCheckpointBlockadeforTherapeuticAction

againstMultipleCancerClones

αPD-1

αPD-L1

αCTLA4

αOX40

α4-1BB

αCD47

αKIR

αCD40

αLAG-3

αTIM-3

αGITR

ImmunostimulatorymAbsAgonisiticAntagonistic

Openquestions

• Howtoimproveresponserate?• Howtoselectpatients?

Ø PDL1expressionØ TCRexpansionØ ImmunesignatureØ CD8infiltrateØ MutationalloadØ Hostfactors:microbiotaØ (…)

QUESTFORPATIENTSELECTION

Y-a-t-il des facteurs prédictifs de réponse ?

L’infiltration lymphocytaireCD8estassociéeà:- ExpressionfortedePDL1- Signatured’activationlymphocytaireT- Réponseantitumorale


Y-a-t-il des facteurs prédictifs de réponse ?

Lephénotype basalestassociéà:- Expressionplus fortedePDL1surlescellulesimmunitaires- Expressionplus fortedePDL1surlescellulestumorales

Laréponseantitumorale semblesupérieuredanslecluster2Laréponseantitumorale estplusfortesihautechargemutationnelle

IMvigor210: TCGA Subtype in mUC

• Luminal I tumors have low Teff expression

• Luminal II tumors have high Teff and low stromal gene expression

• Basal tumors have high Teff and high stromal gene expression

Luminal BasalPapillary like Squamous

ResponseIC statusTC status

FGFR3CDKN2AKRT5

EGFRGATA3FOXA1ERBB2

KRT14

Mesenchymal

CD8A

GZMBGZMA

IFNGCXCL9CXCL10PRF1TBX21COL4A1COL4A2PDGFRBBGNNUAK1

Z: - 3 -2 -1 0 1 2 3

CR PR SD PD IC3 IC2 IC1 IC0 TC3 TC2 TC1 TC0

Stromal

Teff

TCGASubtype

I II III IV

Data cutoff: March 14, 2016.

IMvigor210: TCGA Subtype in mUC

• IMvigor210 subtypes have distinct tumor-immune landscapes that reflect responsiveness to atezolizumab

TIL, tumor-infiltrating lymphocyte. a High myeloid, inflammatory, activated stromal/fibroblast markers. Data cutoff: March 14, 2016.

Immune desert Inflamed Immune suppresseda

Increased responses

Tumor cellsTIL/immune cells

Tumor stroma

Luminal BasalPapillary like Squamous

ResponseIC statusTC status

MesenchymalI II III IV

• mUC has a high mutation load and thus potential for neoantigen generation and recognition by the immune system1-3

• Median load was significantly higher in responders vs non-responders– This relationship was statistically independent of other predictors of response

Mutation load by FoundationOne and response

1. Lawrence Nature 2013. 2. Cancer Genome Atlas Research Network Nature 2014. 3. Kandoth Nature 2013. Data cutoff: March 14, 2016.

II IIILuminal Basal

IVAll(n = 150)

Mut

atio

n Lo

ad/M

B

I0

102030

40

IC0/1 IC2/3

0102030

40

50

Mut

atio

n Lo

ad/M

Brespondernon-responder

RECIST v1.1response

Strategy 3:altering thetumor microenvironment

MDSC

TregCellsIL10IDO

Howtoimprovetheefficacyofimmunotherapy

22/02/2018 TITRE DU DIAPORAMA Général79Twyman-Saint Victor et al, Nature 2015 22/02/2018Pili et al, JCO 2011

Conclusion• Lescancersurologiquessontsensiblesauximmunothérapies• Lesinhibiteursdescheckpointssontlesplusétudiés

– AMMsouspeupourlenivolumab danslecancerdureinensecondeligneaprèstraitementanti-angiogénique

– AMMen2017danslecancerdelavessieendeuxièmelignemétastatique

• Latendance:– Combinaisonsdesinhibiteursdecheckpointsentreeux– Combinaisonsvaccins/chimiothérapie/antiangiogéniques– Évaluationprécocedanslesstadeslocalisés

• Lesproblèmes:– Lecoût– Pasdefacteurprédictifrobuste

l’immunothérapie en onco-urologie...durvalumab. 100-100 0) time ... dreicer asco 2016 petrylak...

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