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David Planchard (MD, PhD) Department of Cancer Medicine Thoracic Unit Gustave Roussy – Villejuif (France) Evolution de la méthodologie des essais cliniques

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Page 1: Evolution de la méthodologie des essais cliniques - splf.frsplf.fr/wp-content/uploads/2016/09/D.Planchard2016.pdf · Evolution de la méthodologie des essais cliniques . ... Alexander

DavidPlanchard(MD,PhD)DepartmentofCancerMedicine

ThoracicUnitGustaveRoussy–Villejuif(France)

Evolution de la méthodologie des essais cliniques

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Consultancyfeesfrom§  AstraZeneca,BMS,BoehringerIngelheim,GSK,Lilly,MSD,Pfizer,

Roche,Sanofi,PierreFabre,Merck,NovarJs

DisclosureSlide

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Traditional clinical development

Approval

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FromphaseItrialstoregulatoryapproval:climbingtheEverest

PhaseI PhaseII PhaseIII

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PhaseIcancerstudies«themostcriJcalstepfrombenchtobedside»

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ObjecJvesofatypicalphaseItrial

•  PrimaryobjecJve– DefinetherecommendedphaseIIdose(RP2D)

•  Primaryendpoint–  IdenGfythepresenceofdose-limiGngtoxiciGes(DLTs)

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Dose-limiJngtoxicity(DLT)•  “Toxicitythatisconsideredunacceptableduetoseverityand/or

irreversibilityorbecauseitlimitsfurtherdoseescalaGon”•  Specifiedusingstandardizedgradingcriteria,e.g.Common

TerminologyCriteriaforAdverseEvents(CTC-AE,mulGpleversions)

•  DLTisdefinedinadvancepriortobeginningthetrialandishighlyprotocol-specific

•  Typicallydefinedbasedondrug-relatedadverseeventsseeninthefirsttreatmentperiod(=1cycle)

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CTC-AE:standardmethodologyforassessementofadverseeventsandDLT

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PhaseItrialdesign:standard3+3design

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TradiJonalphaseItrialassumpJon•  Assumesincreaseddoseassociatedwithincreasedchanceof

efficacy:“Thehigherthedose,thegreaterthelikelihoodofefficacy”–  Dose-relatedacutetoxicityisregardedasasurrogateforefficacy–  Thehighestsafedoseisthedosemostlikelytobeefficacious

•  Thisdose-effectassumpGonisprimarilyvalidforcytotoxicagents•  Maynotapplyto(all)molecularlytargetedagents

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Dose-response:relaJonbetweenefficacyandtoxicity

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KineJcsofirAEwithimAbs

DLTperiod

C1 C2 C3

RP2D:RECOMMENDEDPHASE2DOSE

•  Shouldencompass

toxiciGesobservedbeyondcycle1

C4

DLTperiod Postel-VinaySetal,EJC2014Kaehler,KCetalSeminOncol2010

IpilumimabirAEtemporality

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Kinetics of Onset and Resolution of Select Nivolumab <br />Treatment-related AEs (Any Grade)

Presented By Michael Postow at 2015 ASCO Annual Meeting

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Special situation: Phase I trials with targeted agents

•  Targeted agents differ from cytotoxic agents, as they can be therapeutically active below toxic doses –  Conventional Phase I trial design, based on dose escalation until

toxicity reached, is likely inappropriate –  Reaching MTD may not be the goal of such Phase I since the

specificity of effect may be lost at MTD

•  Another potencial goal: identify “biologically effective” or “optimal biologically dose” –  Paradox: requires early development and integration of (frequently

unvalidated) measures of biologic effect into Phase I trial (the so-called “surrogate endpoints”)

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Responses in phase I trials

•  Classic cytotoxic agents: response rates in studies from the 80’s and 90’s ranged from 2 – 9% (overall <5%) –  Activity in those Phase I trials in that period suggested that the agent

might find a role in oncology

•  Currently, clinical benefit rates, including prolonged stabilizations of disease, occur in aprox 1 out of 3 patients in ph1 studies –  Activity in these Phase I trials might lead to regulatory approval or fast

track designation

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Evolution of phase I study designs, after MTD achieved

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Fast-track designation or even regulatory approval might be a potential goal!!

Jeffrey Infante at 2016 ASCO Annual Meeting

Early phase trials are getting larger !

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AnaplasJcLymphomaKinase(ALK)InhibiJon

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A8081001 and PROFILE 1005 trials for patients with advanced ALK-positive NSCLC

Crizotinib 250 mg BID p.o.

S C R E E N

ALK positive

Patient not eligible for

PROFILE 1007 or >second-line

v  Primary objectives: safety, ORR

Phase II: PROFILE 1005

Phase I: A8081001

PROFILE 1001: NCT00585195; PROFILE 1005:NCT00932451

ALK+NSCLCcohortAdded2006

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Waterfall plot of best percent change in target lesions from baseline for 133 patients on the basis of investigator assessment

D Ross Camidge et al, lancet onco 2012

Phase I dose (Profil 1001)

ORR: 60.8%

Crizotinib

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ORR61% ORR51%

Response rates to ALKi crizotinib in ALK+ NSCLC patients (phase I&II)

Eunice L. Kwak et al, NEJM 2010

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CourtesyJessicaMenis

5years

à  Crizotinib registered on the basis of phase I and II single arm data by FDA (n= 119 and n=136)

ThecrizoJnibexample

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Crizotinib (n=173)

Chemotherapy (n=174)

Events, n (%) 100 (58) 127 (73)

Median, mo 7.7 3.0

HR (95% CI) 0.49 (0.37 to 0.64)

P <0.0001

Prob

abili

ty o

f sur

viva

l w

ithou

t pro

gres

sion

(%) 100

80

60

40

20

0 0 5 10 15 20 25 Time (months)

173 93 38 11 2 0 174 49 15 4 1 0

No. at risk Crizotinib

Chemotherapy

Shaw, et al. N Engl J Med 2013

BeyongfirstlineProgressionfreesurvival(Profil1007)

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Crizotinib (n=173)

Chemotherapya

(n=174) Events, n (%) 49 (28) 47 (27) Median, mo 20.3 22.8 HR (95% CI) 1.02 (0.68 to 1.54)b

P 0.5394

InterimAnalysisofOS(Profil1007)

a111 patients crossed over to crizotinib outside PROFILE 1007 bHR adjusted for crossover using rank-preserving structural failure time method: 0.83 (0.36 to 1.35)

173 129 83 37 11 1 0 174 129 84 34 10 0

No. at risk Crizotinib

Chemotherapy

Prob

abili

ty o

f sur

viva

l (%

)

100

80

60

40

20

0 0 5 10 15 20 25

30 Time (months)

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DiscoveryofEML4-ALKFusionGene(1)

FirstClinicalResponsesObservedinALK+Tumors(phaseItrial)

Phase3LungCancerTrialIniGated

ASCOplenaryofexpandedALK+cohort(2)

NEJMpublicaGonofALK+Cohort(3)

FDAXALKORIapproval

AMMFrance

ACSetrialforotherALK+solidtumors

1.Sodaetal.Nature2007,448:561.2.BangJYetal.OralpresentaEonatASCO,20103.Kwaketal.NewEnglJMed.2010;363:1693−03

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FirstlineProgression-free-Survival(PROFILE1014)

Benjamin J. Solomon et al, NEJM 2014 10.9(95%CI,8.3to13.9)vs7.0months(95%CI,6.8to8.2)

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OverallSurvival

Benjamin J. Solomon et al, NEJM 2014

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Part 2: Molecularly enriched cohorts

Part 1: Dose escalation

Crizotinib: First-in-human/patient trial (Study A8081001)

Cohort 6 (n=9) 250 mg BID MTD/RP2D

NCT00585195 BID, twice daily; QD, once daily RP2D, randomized phase 2 dose

Cohort 1 (n=3) 50 mg QD

Cohort 2 (n=4) 100 mg QD

Cohort 3 (n=8) 200 mg QD

Cohort 4 (n=7) 200 mg BID

Cohort 5 (n=6) 300 mg BID

ALK METampl ROS1

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Tumor Shrinkage Seen in Intermediate and High MET Cohorts

aConfirmed objective responses. bBased on investigator assessment. cTwo patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment.

Best percent change from baseline in target tumor lesionsa by patient

Low MET n=2

Intermediate MET n=6

High MET n=6

100

80

60

40

20

0

–20 –40

–60

–80

–100

100

80

60

40

20 0

–20

–40

–60

–80

–100

Disease progression Stable disease Partial responseb Complete responseb

% C

hang

e Fr

om B

asel

ine 100

80

60

40

20 0

–20

–40

–60

–80

–100

Threshold for partial response c

c

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AliceT.Shawetal.,NEJM2014

CrizoJnibandROS1pts

Median duration of response 17.6 months (95% CI, 14.5 to not reached [NR])

Overall response rate:72%

3 patients (6%) CR 33 patients (66%) PR 9 patients (18%) SD

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Part 2: Molecularly enriched cohorts

Part 1: Dose escalation

Crizotinib: First-in-human/patient trial (Study A8081001)

Cohort 6 (n=9) 250 mg BID MTD/RP2D

NCT00585195 BID, twice daily; QD, once daily RP2D, randomized phase 2 dose

Cohort 1 (n=3) 50 mg QD

Cohort 2 (n=4) 100 mg QD

Cohort 3 (n=8) 200 mg QD

Cohort 4 (n=7) 200 mg BID

Cohort 5 (n=6) 300 mg BID

ALK METampl ROS1

MET Exon 14

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Antitumor Activity of Crizotinib in Patients with Advanced MET Exon 14-Altered NSCLC (PROFILE 1001 Study)

Response-EvaluablePopulaJon(n=18)

Bestoverallresponse

n(%)

Completeresponse(CR)

ParGalresponse(PR)

Stabledisease(SD)

UnconfirmedCR/PR†

ProgressionofDisease(PD)Indeterminate‡

0

8(44%)

9(50%)

5(28%)

0

1(6%)

Overallresponserate(ORR) 44%(95%CI:22–69),n=8/18

† of the 5 patients: 2 awaiting confirmation, 3 cannot be confirmed ‡ this patient discontinued therapy in cycle 1, response imaging could not be performed but response-evaluable per protocol

Alexander Drilon MD et al, ASCO 2016

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-100

-80

-60

-40

-20

0

20

%cha

ngefrom

baseline

Antitumor Activity

Partial response (PR), confirmed Stable disease (SD): includes 4 unconfirmed PRs

* *

MET Exon 14 Alteration Co-Occurrence with High-Level MET Amplification

conc

urre

nt M

ET A

mpl

ifica

tion

Central testing for both MET exon 14 alterations and high-level MET amplification via ThermoFisher Scientific Inc., Ion Torrent (Cancer Genetics, CA)

▵ ▵ ▵ ▵ ▵ ▵ ▵ ▵ ▵ ▵

Alexander Drilon MD et al, ASCO 2016

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Antitumor Activity

baseline week 8

•  54 year-old female with MET exon 14-altered lung adenocarcinoma - metastatic disease involving lung and lymph nodes, treatment-naive

- confirmed partial response with crizotinib (-48%), ongoing at 5+ months*

*response duration as of May 2016, Images courtesy of Ross Camidge, University of Colorado Cancer Center

Alexander Drilon MD et al, ASCO 2016

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•  87 year-old female with MET exon 14-altered sarcomatoid lung cancer - history of stage IIB disease, recurrent metastatic disease involving the adrenal - durable partial response (-60%) with crizotinib, ongoing at 8+ months*

Antitumor Activity

baseline week 8

*response duration as of May 2016, Images courtesy of Alexander Drilon, Memorial Sloan Kettering Cancer Center

Alexander Drilon MD et al, ASCO 2016

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Standardprecisionmedicineapproach

Tumorsample StructuralDNAanalysisMutaGonalprofile

Matchedtargetedtherapy

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GenotypingUnselectedPhaseIpopulaJonORRbelow10%

EnrichedPhaseIpopulaJonORR>30%,andeven>50%ififtruemechanism-basedapproach(oncogende-addicGon,syntheGclethality)

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ON-PURPOSEFRESHTUMORBIOSPSY&

PATHOLOGYCONTROL

•  Monocentric(GustaveRoussy)

•  TargetAccrual=900paGentsMOLECULARPROFILING

(CGH&NGS)MOLECULAR

TUMORBOARD

Median14days(95%CI:7-35days)

TREATMENT

MOSCATO-01prospecJvemolecularscreeningprogram

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High-throughputmolecularprofilingusing‘on-purpose’biopsies

FGFR1 amplification

IonTorrentPGM–LifeTechnologies(AmpliseqCHP2+customn=74genes,Dec2013)

CGHarrayAgilent(180K,Wholegenomecoverage)

+

Torrent_Suite+v2.2++Confimed+by+Sanger+Sequencing+

DNA+extrac=on+10+–+50+ng+

Mul=plex+PCR++1450+amplicons+IonTorrent/PGM+(>+500X+coverage)++

Standardized++Report+

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MainmolecularaberraJons

40

TP53

_mut

MYC_

amp

CDKN

2B_d

elCD

KN2A

_del

PTEN

_del

PIK3C

A_mu

tTP

53_d

elFG

F4_a

mpCC

ND1_

amp

FGF3

_amp

KRAS

_mut

PIK3C

A_am

pFG

FR1_

amp

EGFR

_amp

MDM2

_amp

FGFR

1_de

lAP

C_mu

tCD

K4_a

mpER

BB2_

amp

MET_

mut

PIK3C

B_am

pAT

M_mu

tFG

F19_

amp

MET_

amp

FGF6

_amp

RB1_

del

CCND

2_am

pFG

FR2_

del

CCNE

1_am

pKR

AS_a

mpFH

IT_de

lNO

TCH2

_amp

CDKN

2A_m

utBR

AF_a

mpCC

NE2_

amp

CDK6

_amp

E2F1

_amp

PDGF

RA_a

mpEG

FR_m

utCD

K2_a

mpKD

R_mu

tPT

EN_m

utAR

_amp

DCC_

del

HRAS

_del

JAK2

_del

NOTC

H1_a

mpNO

TCH1

_del

NRAS

_del

PIK3R

5_de

lJA

K3_m

utPT

K2_a

mpRO

S1_d

elSM

AD4_

mut

AKT2

_amp

AKT3

_amp

BRCA

2_am

pCC

ND2_

del

FGF6

_del

NOTC

H2_d

elRE

T_am

pSR

C_am

pVE

GFC_

del

KIT_m

utMA

P3K1

_mut

AKT1

_del

ATM_

del

CDKN

1B_d

elFG

F10_

amp

FGF2

0_de

lFG

FR3_

del

IDH2

_amp

KRAS

_del

MTOR

_del

PIK3C

G_am

pSU

FU_d

elTU

SC3_

del

BRAF

_mut

CTNN

B1_m

utFB

XW7_

mut

STK1

1_mu

tAP

C_de

lAU

RKA_

amp

BCL2

_del

BRAF

_del

CCNA

1_de

lCD

KN1B

_amp

CHEK

1_de

lFG

F17_

del

FGF5

_del

FGFR

3_am

pFZ

D6_a

mpHR

AS_a

mpIG

F1R_

amp

KIT_a

mpME

T_de

lNK

D2_a

mpPA

K1_a

mpPT

EN_a

mpRB

1_am

pRE

T_de

lSM

AD4_

del

TERT

_amp

TGFB

2_am

pBR

CA2_

mut

FGFR

3_mu

tER

BB4_

mut

ALK_

amp

CCND

3_de

lCD

K1_a

mpER

G_am

pER

G_de

lFG

F3_d

elFG

F4_d

elFG

FR2_

amp

FHIT_

amp

FOXO

1_de

lFO

XO3_

del

KIT_d

elMY

CC_a

mpNM

YC_a

mpNO

TCH2

_rear

PDGF

A_am

pPD

GFB_

del

PDGF

RA_d

elPIK

3CD_

del

PIK3R

2_am

pPR

KC1_

amp

ROCK

1_am

pRU

NX1_

amp

SMAD

2_de

lSO

S2_a

mpVE

GFA_

amp

WNT3

_amp

AKT1

_mut

FGFR

2_mu

tNO

TCH4

_mut

NRAS

_mut

RB1_

mut

BRCA

2_de

l

Frequ

ency

(%)

0 %2 %

5 %

10 %

15 %

20 %

25 %

30 %

35 %

Not actionableActionable

“longtailphenomenon”

Mutations (17%)

Copy numberalterations (83%)

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Thesuccessivephasesinoncologydrugdevelopment

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Thenewtrendofdrugdevelopmentinoncology

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Postel-VinaySAnnalsofOncology2014

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20-30pts

Phaseescaladededose

Phased’expansion

EtudedephaseI"classique"

EtudedephaseIavecmulJplescohortesd’expansion

100-1000paJents+/-enrichissementselonbiomarqueurs

Phaseescaladededose

Phased’expansion

CohorteA

CohorteB

CohorteC

PhaseIdesignmodificaJons

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Part 2: Molecularly enriched cohorts

Part 1: Dose escalation

Crizotinib: First-in-human/patient trial (Study A8081001)

Cohort 6 (n=9) 250 mg BID MTD/RP2D

NCT00585195 BID, twice daily; QD, once daily RP2D, randomized phase 2 dose

Cohort 1 (n=3) 50 mg QD

Cohort 2 (n=4) 100 mg QD

Cohort 3 (n=8) 200 mg QD

Cohort 4 (n=7) 200 mg BID

Cohort 5 (n=6) 300 mg BID

ALK METAmp ROS1

MET Exon14

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Is this the end of single-arm Phase 2 studies ?

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Ongoingdose-expansionphase

RCC

1. All- comers 2. PD-L1 selected

Melanoma

All-comers

NSCLC

1. All- comers 2. PD-L1 selected

Other Tumor Types

1. PD-L1 selected 2. All- comers

UBC

1. PD-L1 selected 2. All- comers

TNBC

1. PD-L1 selected 2. All- comers

Atezolizumab(MPDL3280A):PhaseIaStudy

ORRrangingfrom10%to80%accordingtoPDL1statusandtumortypeN>350paJents

NCT01375842

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PembrolizumabanJtumoracJvity

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KEYNOTE-001 NSCLC Cohorts (N = 550)

•  Pembrolizumab IV over 30 minutes until intolerable toxicity, disease progression, investigator decision, or patient withdrawal

•  Primary endpoint: ORR per RECIST v1.1 by independent central review

•  Secondary endpoints: PFS, OS, and duration of response

•  Data cutoff: September 18, 2015

•  Median follow-up: 22.2 months (range, 17.8-30.5) for treatment naive; 23.3 months (range, 14.2-40.1) for previously-treated patients

Nonrandomized (N=38)

• PD-L1+ or PD-L1- tumors

• ≥2 previous therapies

Nonrandomized (N=33)

• PD-L1+ tumors • ≥2 previous therapies

Nonrandomized (N=43)

• PD-L1- tumors • ≥1 previous therapy

Nonrandomized (N=55)

• PD-L1+ tumors • ≥1 previous therapy

Randomized (N=280)

• PD-L1+ tumors • ≥1 previous therapy

Randomized (N=101)

• PD-L1+ tumors • Treatment naive

R (3:2)

Ra

(1:1)

Pembro 10 mg/kg

Q3W

Pembro 10 mg/kg

Q3W

Pembro 10 mg/kg

Q2W

Pembro 10 mg/kg

Q3W

Pembro 10 mg/kg

Q2W

Pembro 2 mg/kg

Q3W

Pembro 2 mg/kg

Q3W

Pembro 10 mg/kg

Q3W

Pembro 10 mg/kg

Q2W

aFirst 11 pts randomized to 2 mg/kg Q3W vs 10 mg/kg Q3W; 90 randomized to 10 mg/kg Q3W vs 10 mg/kg Q2W.

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Vertical dotted lines represent 18 months and 24 months; the horizontal line at 50% drops vertically to the x-axis at the time of the median OS. Data cutoff: September 18, 2015.

Previously Treated

Overall Survival Treatment Naive

Median (95% CI), mo 18-mo Rate, % 24-mo Rate, %

Total 22.1 (16.8-27.2) 58.1 44.5

No. at risk 0 5 10 15 20 25 30 35 40

100

0 10 20 30 40 50 60 70 80 90

Time, months 101 85 76 65 33 8 0 0 0

OS,

%

Time, months No. at risk 449 304 222 172 103 32 11 8 0

0 5 10 15 20 25 30 35 40 0

10 20 30 40 50 60 70 80 90

100

OS,

% Median (95% CI), mo 18-mo Rate, % 24-mo Rate, %

Total 10.6 (8.6-13.3) 36.6 30.4

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OS by PD-L1 TPS ≥50%, 1%-49%, <1%

Patients with unknown PD-L1 TPS were excluded. Data cutoff: September 18, 2015.

Median, mo (95% CI) 18-mo Rate, % 24-mo Rate, % TPS ≥50% NR (22.1-NR) 72.7 60.6 TPS 1%-49% 19.5 (10.7-22.2) 50.1 32.5 TPS <1% 14.7 (3.4-NR) 50.0 37.5

Median, mo (95% CI) 18-mo Rate, % 24-mo Rate, % TPS ≥50% 15.4 (10.6-18.5) 43.4 38.0 TPS 1%-49% 8.2 (6.0-12.7) 32.9 28.2 TPS <1% 8.6 (5.5-12.0) 31.7 23.5

Treatment Naive

Previously Treated

No. at risk 0 5 10 15 20 25 30 35 40 0

10 20 30 40 50 60 70 80 90

100

Time, months 138 100 81 65 34 13 3 168 112 77 57 33 8 4

3 1

0 0

90 57 36 28 21 3 0 0 0

OS,

%

0 5 10 15 20 25 30 35 40 0

10 20 30 40 50 60 70 80 90

100

Time, months 27 25 24 22 11 3 0

No. at risk 52 42 36 29 16 2 0

0 0

0 0

12 9 7 6 3 1 0 0 0

OS,

%

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BrahmerJetal,NEJM2015;RoyS.Herbstetal,ESMOAsia2015,lancet2015;LFehrenbacheretal,lancet2016

Phase III trials Nivolumab(SQCC)CheckMate017

Pembrolizumab(NSCLC)Keynote010

Atezolizumab(NSCLC)POPLAR

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Cohort120mg

PosiJve

Cohort240mg

Cohort380mg

Cohort4160mg

PosiJve

NegaJve

PosiJve

NegaJve

PosiJve

NegaJve

Phase1EscalaJonNotpreselectedbyT790Mstatus

Phase1ExpansionEnrolmentbylocaltesGngfollowedbycentrallaboratoryconfirmaGon(cobas™EGFRMutaGonTest)ofT790MstatusorbycentrallaboratorytesGngalone

Cohort5240mg

PosiJve

1st-lineEGFRm#

Rollingsixdesign

Tablet##

1st-lineEGFRm#

PrimaryobjecJve–assessmentofthesafety,tolerabilityandefficacy(ORR)ofOsimerGnibinpaGentswithacquiredresistancetoEGFR-TKIs

T790Mcohorts

Cytology§

Biopsy* Biopsy*

PhaseI/IIdoseescalaJon-expansionOsimerJnib

PasiAJänneatal;ELCC2015-AnnOncol2015;26(Suppl1)LBA3,NEJM2015

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BaselinedemographicsanddiseasecharacterisGcs

CharacterisJc EscalaJonN=31

ExpansionN=252

Gender,n(%)Male/Female

11/20(35/65)

97/155(38/62)

Age,median(range);years 61(39–81) 60(28–88)

Race,n(%)Caucasian/Asian/Other/Notreported

5/21/1/4(16/68/3/13)

84/152/5/11(33/60/2/4)

Histology,n(%)Adeno/Squamous/Other/Missing

29/1/1/0(94/3/3/0)

TBC

Priorlinesofsystemictherapy,median(range) 3(1–12) 3(1–12)

PriorEGFR-TKIs,median(range)Regimen,n(%)GefiGnibErloGnibAfaGnib

1(1–4)

22(71)15(48)1(3)

2(1–5)

150(60)146(58)59(24)

EGFRmutaGontypebycentraltestExon19/L858R/Other/None/Unknown,nExon19/L858R/Other/None/Unknown,%

CentraltesGngnot

performedforescalaGon

136/73/10/13/2054/29/4/5/8

PopulaGon:pre-treated,capsule-dosedpaGents(excludingJapanesecytologycohort).Datacut-off2Dec2014

PasiAJänneatal;ELCC2015-AnnOncol2015;26(Suppl1)LBA3,NEJM2015

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20mg 40mg 80mg 160mg 240mg Total

N(157) 10 32 61 41 13 157

ORR(95%CI)

50%(19,81)

59%(41,76)

66%(52,77)

51%(35,67)

54%(25,81)

59%(51,66)

*ImputedvaluesforpaGentswhodiedwithin14weeks(98days)ofstartoftreatmentandhadnoevaluabletargetlesionassessmentsNinepaGents(seveninthe160mgcohort)currentlyhaveabestoverallresponseofnotevaluable,astheyhavenotyethada6-weekfollow-upRECISTassessmentPaGentsareevaluableforresponseiftheyweredosedandhadabaselineRECISTassessment.Datacut-off2Dec2014CI,confidenceinterval;CR,completeresponse;D,disconGnued;DCR,diseasecontrolrate;PR,parGalresponse;RECIST,ResponseEvaluaGonCriteriaInSolidTumors;SD,stabledisease

DCR(CR+PR+SD)inpaJentswithcentrallytestedT790MposiJvetumourswas90%(141/157;95%CI84,94)

40mg80mg160mg240mg

20mg

-100-90-80-70-60-50-40-30-20-100

1020304050

DD*D*

DDDD

DDDDD

DDDDD

DD

DDDD DDD D D DD

DDDDDDDD DDDDDDD

D D DDD DD

DDD

DD

D

Bestpercentagechangefrombaselineintargetlesion

PasiAJänneatal;ELCC2015-AnnOncol2015;26(Suppl1)LBA3,NEJM2015

ResponserateinT790MposiJvecohorts(centraltest)-OsimerGnib

Ladose80mgd’OsimerGnibestladosedel’AMM

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DCR(CR+PR+SD)inpaJentswithcentrallytestedT790MnegaJvetumourswas64%(44/69;95%CI51,75)

20mg 40mg 80mg 160mg Total

N(69) 3 17 29 20 69

ORR(95%CI)

67%(9,99)

12%(2,36)

21%(8,40)

30%(12,54)

23%(14,35)

*ImputedvaluesforpaGentswhodiedwithin14weeks(98days)ofstartoftreatmentandhadnoevaluabletargetlesionassessmentsPaGentsareevaluableforresponseiftheyweredosedandhadabaselineRECISTassessment.Datacut-off2Dec2014

ResponserateinT790MnegaJvecohorts(centraltest)-OsimerGnib

40mg80mg160mg

20mg

-100-90-80-70-60-50-40-30-20-100

102030405060

D D DD DD

D D*D*D*D*D*D D

D D D D D D D D D D D D DD D D D D D D D D D D D D

D D D

D DD D

D D D D D

Bestpercentagechangefrombaselineintargetlesion

PasiAJänneatal;ELCC2015-AnnOncol2015;26(Suppl1)LBA3,NEJM2015

BrasT790MnégaGf-donnéesnonenregistrées

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PhaseIIdoseextension

Cohort120mg

PosiJve

Cohort240mg

Cohort380mg

Cohort4160mg

PosiJve

NegaJve

PosiJve

NegaJve

PosiJve

NegaJve

EscalaJonNotpreselectedbyT790Mstatus

ExpansionEnrolmentbylocaltesGngfollowedbycentrallaboratoryconfirmaGon(cobas™EGFRMutaGonTest)ofT790MstatusorbycentrallaboratorytesGngalone

Cohort5240mg

PosiJve

1st-lineEGFRm#

Rollingsixdesign

Tablet##

1st-lineEGFRm#

PrimaryobjecJve–assessmentofthesafety,tolerabilityandefficacy(ORR)ofAZD9291inpaGentswithacquiredresistancetoEGFR-TKIs

T790Mcohorts

OsimerJnib80mgoncedailyinpaJentswithT790M+NSCLCwhohaveprogressedonEGFR-TKI

Cytology§

Biopsy* Biopsy*

PhaseIIextensionPhase2extensionEnrollmentbycentralLaboratoryconfirmtaGonofT790Mstatus

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PhaseIIextensionTumorreponsebyindependentcentralreview-OsimerGnib80mg/d

Chih-HsinYangetal,IASLC2015

(+200pts)

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Studydesigns

AURAPhIdatacut-off4January2016;AURApooledPhIIdatacut-off1November2015*TheEGFRT790MmutaGonstatusofthepaGent’stumourwasprospecGvelydeterminedbythedesignatedcentrallaboratoryusingtheCobas®EGFRMutaGonTest(RocheMolecularSystems)bybiopsytakenazerconfirmaGonofdiseaseprogressiononthemostrecenttreatmentregimen;†PairedbiopsycohortpaGentswithT790MposiGvetumours;safetyandefficacydataonlyreportedhere;Datafromcohortsingrayedoutboxesarenotincludedintheanalysesreportedhere.aNSCLC,advancedNSCLC;qd,oncedaily

JamesC-HYangetal,ELCC2016,Geneva;AbstractLBA2_PR. EUROPEANLUNGCANCERCONFERENCE2016

31pts

252pts

201pts 210pts

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–100–80

–40–60

–20020406080

TumourresponsetoOsimerJnibtreatment

AURAPhI(80mg)N=61 AURApooledPhII(80mg)N=397

ConfirmedORR 71%(95%CI57,82) 66%(95%CI61,71)

Diseasecontrolrate† 93%(95%CI84,98) 91%(95%CI88,94)

BestobjecGveresponseCompleteresponseParGalresponseStabledisease≥6weeksProgressivedisease

142142

62569925

CompleteresponseParGalresponseStablediseaseProgressivediseaseNotevaluable

Bestpercentagechangefrom

baselineinta

rgetlesio

nsiz

e(%

)

*********

100 AURApooledPhII

–100–80–60–40

02040

80

–20

100

Bestpercentagechange

from

baselineinta

rget

lesio

nsiz

e(%

)

AURAPhI

CompleteresponseParGalresponseStablediseaseProgressivediseaseNotevaluable

JamesC-HYangetal,ELCC2016,Geneva;AbstractLBA2_PR. EUROPEANLUNGCANCERCONFERENCE2016

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OsimerJnib….

TheclinicaldevelopmentprogrammeforosimerJnibisthemostrapidtodate,takingjust2years8monthsand1weekfromthefirstpaJentdosedtothefirstapprovedindicaJon(FDAApprovalNov2015)

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Tagrisso in NCCN guidlines…

FDA's approval of Tagrisso

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AURA 3 Study Design

P

T790M+ (n=470)

T790M- Not eligible for enrolment

AZD9291 (80 mg p.o. qd) (n=407)

Platinum-based doublet chemotherapy* every

3 weeks (n=203)

Central testing of ~ 1540 biopsy

samples

Randomise ~470 patients 2:1

*Pemetrexed 500 mg/m2 + carboplatin AUC5 or Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2

AUC5, area under the plasma concentration–time curve 5 mg/mL−1 per minute; EGFRm+, EGFR mutation-positive; EGFR-TKI, EGFR tyrosine kinase inhibitor;

NSCLC, non-small cell lung cancer; p.o., orally; qd, once daily; T790M+, T790M mutation-positive; T790M-, T790M mutation-negative

Primary endpoint:

PFS

PI: T Mok YL Wu

No cross over to AZ9291 at start, now change to cross-over

18 July 2016

AstraZeneca today announced that the Phase III AURA3 trial met its primary

endpoint, demonstrating superior progression-free survival (PFS) compared

to standard platinum-based doublet chemotherapy.

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Cohort120mg

T790M+

Cohort240mg

Cohort380mg

Cohort4160mg

T790M+T790M-

T790M+T790M-

T790M+T790M-

EscalaJonNotpreselectedbyT790Mstatus

ExpansionEnrollmentbylocaltesGngfollowedbycentrallaboratoryconfirmaGon(cobasEGFRMutaGonTest)ofT790MstatusorbycentrallaboratorytesGngalone

Cohort5240mg

T790M+

1st-lineEGFRm+*Biopsy#

Rollingsixdesign

Tablet##

1st-lineEGFRm+*Biopsy#

*Priortherapynotpermissibleinthiscohort.#PairedbiopsycohortpaGentswithT790M+tumours.##NotselectedbymutaGonstatus,USonly.

PhaseIdoseescalaJon/expansionstudydesign(NCT01802632)§  Forthefirst-linecohorts,paJentswithadocumentedEGFR-TKI-sensiJsingmutaJonandwhohavereceivedno

priortherapyforadvancedstageNSCLCwereenrolled§  PaJentsreceivedAZD9291oncedailyasan80mgor160mgcapsule

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PFS in osimertinib EGFRm first-line cohorts (investigator assessed)

Population: safety analysis set; data cut-off: 4 January 2016 Progression events that do not occur within 14 weeks of the last evaluable assessment (or first dose) are censored

Circles on the Kaplan-Meier plot denote censored observations *Progression-free survival is the time from date of first dosing until the date of objective disease progression or death

†Calculated using the Kaplan-Meier technique

Prob

abilit

y of P

FS su

rviva

l

Number of patients at risk: 1st line 80 mg

1st line 160 mg 30 30

26 29

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

0 3 6 9 12 15 18 21 24 27

23 27

22 23

20 20

16 19

14 7

7 0

0 0

0 0

Month

80mgn=30

160mgn=30

TotalN=60

MedianPFS,*months(95%CI) NC(12.3,NC)

19.3(11.1,19.3)

19.3(13.7,NC)

Remainingaliveandprogression-free,†%(95%CI)12months18months

75(55,88)57(36,73)

69(49,83)53(32,70)

72(59,82)55(41,67)

PresentedbySureshSRamalingamatthe6thIASLC/ESMOEuropeanLungCancerConference,13–16April2016,Geneva,Switzerland;AbstractLBA1_PR.

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EtudesdedéveloppementOsimerJnib

AURAPhaseI/II

PhaseI:

escalade/expansiondedose

PhaseII:extensiondedose

CBNPCàunstadeavancé

AURA2

PhaseII

Etudeenouvert,monobras

TraitementdesecondeligneoupluschezdespaGents

a�eintsd’unCBNPClocalementavancéoumétastaGqueavec

mutaGonsEGFRmetT790MquiontprogresséaprèsuntraitementparTKI-EGFR

AURA3

PhaseIII

Etuderandomisée,VSchimiothérapieàbasede

plaGne

TraitementdesecondelignechezlespaGentsa�eintsd’unCBNPClocalementavancéoumétastaGqueavec

mutaGonsEGFRmetT790MquiontprogresséaprèsuntraitementparTKI-EGFR

FLAURA

PhaseIII

Etuderandomisée,VSgefiGnibouerloGnib

CBNPClocalementavancéoumétastaGqueavecmutaGonacGvatricede

l’EGFR

PhaseI/II≥2èmeLigne

PhaseII≥2èmeLigne

PhaseIII2èmeLigne

PhaseIII1èreLigne

DonnéesnonenregistréespourFLAURAETAURA3

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Marker-straJfied

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InteracJontest

Study population

Treatment A

Treatment B

Patients With

biomarker

Treatment A

Treatment B

Patient without

biomarker

Treatment A

Treatment B

HR <1.0

HR >1.0

InteracGontest

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Progression-free survival in EGFR mutation positive and negative patients

EGFR mutation positive EGFR mutation negative

Treatment by subgroup interaction test, p<0.0001

HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001

No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.0%)

Gefitinib (n=132) Carboplatin / paclitaxel (n=129)

ITT population Cox analysis with covariates

HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001

No. events gefitinib , 88 (96.7%) No. events C / P, 70 (82.4%)

132 71 31 11 3 0 129 37 7 2 1 0

108 103

0 4 8 12 16 20 24

Gefitinib C / P

0.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty o

f pro

gres

sion

-free

su

rviv

al

At risk : 91 4 2 1 0 0 85 14 1 0 0 0

21 58

0 4 8 12 16 20 24 0.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty o

f pro

gres

sion

-free

su

rviv

al

Gefitinib (n=91) Carboplatin / paclitaxel (n=85)

Months Months

Mok et al. NEJM 361:947-957. 2009.

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Randomized studies on first line EGFR TKI Author Study N (EGFR mut

+) RR Median PFS

Mok et al IPASS 132 71.2% vs 47.3 9.8 vs 6.4 months

Lee et al First-SIGNAL 27 84.6% vs 37.5% 8.4 vs 6.7 months

Mitsudomi et al WJTOG 3405 86 62.1% vs 32.2% 9.2 vs 6.3 months

Maemondo et al NEJGSG002 114 73.7% vs 30.7% 10.8 vs 5.4 months

Zhou et al OPTIMAL 154 83% vs 36%

13.1 vs 4.6 months

Rosell et al EURTAC 135 56% vs 18% 9.2 vs 4.8 months

Yang et al LUX Lung 3 345 56% vs 22% 11.1 vs 6.9 months

Wu et al LUX Lung 6 364 67% vs 23% 11.0 vs 5.6 months

Mok et al. NEJM. 2009; Lee et al. WCLC. 2009; PRS4; Mitsudomi et al. Lancet Oncology. 2010; Maemondo et al. NEJM. 2010; Zhou et al. Lancet Oncol. 2011; Yang et al JCO. 2013; Wu et al Lancet Oncol. 2014.

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SchemaJcexampleofabaskettrial:Onedrug,onemolecularalteraJon,severaltumourtypes

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SchemaJcillustraJonoftheVemurafenibbaskettrial

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BASKETTrial:VemurafenibinMulJpleNon-melanomacancerswithBRAFV600MutaJons

DavidM.Hymanetal.,NEJM2015ECD/LCHErdheim–ChesterdiseaseorLangerhans’-cellhisGocytosis

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French national AcSé Program

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Biomarker-driven access to crizotinib In ALK, MET or ROS1 positive malignancies

in adults and children: the French national AcSé Program

Gilles Vassal, Denis Moro Sibilot, Marie-Cécile Le Deley, Natalie Hoog-Labouret, Frédérique Nowak, Marta Jimenez, Christophe Tournigand, Roch Houot, David Malka, Thomas Aparicio, Bernard Escudier, Isabelle Ray Coquard, Yann Godbert, Luc Taillandier, Ivan Bièche, Sylvie

Lantuejoul, Gilbert Ferretti, Yves Menu, Jean-Yves Blay, Agnès Buzyn.

12LBA – September 26, 2015, Vienna

Onedrug,severalmolecularalteraJons,severaltumourtypes

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1uterineleiomyosarcoma-ALKtranslocaGon,1pancreaGccancer-ROS1mutaGon,1neuroblastoma-ROS1mutaGon,1kidneycancer-ROS1amplificaGon,3NSCLC-METmutaGon,1NSCLC-ALKmutaGon,1NSCLC-ALKamplificaGon,1SCLC-METmutaGon+ROS1mutaGon,1adenoca.ouraque-METamplificaGon,1cholangiocarcinoma-METamplificaGon,1gallbladder-METamplificaGon,1Blymphoma,largecell-ALKtranslocaGon,1carcinomaoftheesophagus-METamplificaGon,1sarcomatoidcarcinomahail-ALKtranslocaGon,1unknownprimarycarcinoma.-ALKtranslocaGon.

Results : 24 cohorts

STOPSTO

PSTOP

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Results: ROS1+ NSCLC

Tumor shrinkage at best response

Best response ORR = 26/36 72 % [55% ; 86%] DCR = 32/36 89 % [74% ; 97%]

44% PFS at 12 months

GillesVassaletal,2015

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Tumor shrinkage at best response

No correlation observed between the number of MET copies and best response (p=0,10).

Best response

ORR = 7/25 28 % [12% ; 49%]

DCR = 15/25 60 % [41%;79%]

METAMP NSCLC

G.Vassaletal2015

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Tumor shrinkage at best response

Results: METAMP Colon Cancer

No response in 13 patients

STOP accrual at stage 1

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Umbrellatrial(Onediseasetype,mulGplemolecularalteraGon)

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BATTLE trial in NSCLC

Kim ES et al. Cancer Discov 2011; 1: 44

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Progression

Stade IV CBNPC EGFR Négatif ALK Négatif

Biopsies fraiches lors des 2 premiers cycle de chimiothérapie Etude moléculaire: •  CGH •  NGS

@ 4 cycles

Traitement bioguidé (AstraZeneca pipeline: AZD2014, AZD4547, AZD5363, AZD8931, selumetinib, vandetanib)

Chimiothérapie standard Pemetrexed (Non épi) Erlotinib (Epidermoides)

R2:1 Jusqu’à progression

MEDI4736 (durvalumab)

Jusqu’à progression R2:1 Absencedeciblemoléculaireciblable

N=230

N=180

SAFIR02Lung(UNICANCER0105-1305/IFCT1301)

Co-principal investigateurs : Pr JC.Soria / Pr F. Barlesi

CancerdupoumonmétastaJque1èreligne

chimiothérapie4cycles

Chimiothérapie

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UmbrellaTrials:Movingbeyondonemarker/drug

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AdapJvedesigns

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In Summary….Non-linear clinical development

Approval

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???

BurockS,EJC2013PaulS,NatrevDrugDiscovery2010

MedianDuraGon8to10years

DuraGonisshortened(4years+)

TherevoluJonindrugdevelopmenthasprofoundimplicaJons

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P1

30-50unselectedpaGents

TradiGonalPKLimitedPD

ImportantPK/PDmodelling WeakPK-PDrelaGonship

TradiGonal3+3dose-escalaGondesign

3+3dose-escalaGondesignwithlargeexpansioncohortsinselectedpopulaGons

AcceleratedGtraGon/adapGvedesignMulGpleparallelexpansioncohortsLong-termfollow-up+Drugrechallenge

MTDquasi-systemaGcally

reached

MTDunconstantlyreached

MTDrarelyreached->MAD

Drugapproval

PaGentsnumber

Toxicity

PK/PD-biomarkers

Design

Basedonlaterphase2or3trials

CondiGonaloracceleratedapprovalbasedonlargemolecularlyselected

expansioncohorts

CondiGonaloracceleratedapprovalbasedonhistologyandimmune-biomarkerselected

expansioncohorts

RouteofadministraGon

NovelroutesofadministraGon(intra-tumoral)

IV>oral Oral>IV

DrugdevelopmentGmeframe

10years 5-8years <5years

100-1000immunologicallyselectedpaGents

30-200molecularlyselectedpaGents

Unse

-lecte

d

Select

ed

Pts#

Targetenrichment

Immuneenrichment

OBD MIAD?

DLTs

20-30pts

EscalaGon Expansion

30-300selectedptsMolecularenrichment

EscalaGon Expansion100-1000pts+/-immuneenrichmentEscalaGon Expansion

P1 P3P2 Approval P1-2 P3 ApprovalCondiGonal/AcceleratedApproval

CondiGonal/AcceleratedApproval

P3 Approval

Cytotoxicchemotherapy MolecularlyTargetedAgents Immuno-sJmulatoryAgents> >

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Acknowledgments Jean-CharlesSORIABenjaminBESSE

ThierryLECHEVALIER

THANK YOU [email protected]