Future Directions in the Treatment of NSCLC

Jean-Charles SORIA

U 981

@jsoriamd

Disclosure Slide

v Consultancy fees from

AstraZeneca, Astex, Covagen, Clovis, GSK, GammaMabs,

Lilly, MSD, Mission Therapeutics, Merus, Pfizer,

Pierre Fabre, Roche-Genentech, Sanofi, Servier, Takeda.

v Company scientific co-founder

Gritstone

Outline

v Non-IO phase 2-3 trialsv IO-based phase 3 trials

ü IO-IOü IO-chemotherapyü IO-targeted therapiesü IO-radiotherapy

R2:1

ArmA1:Targeted therapy

ArmB1:MaintenanceArm

N=650

N=230AZD2014 AZD4547 AZD5363

AZD8931 SelumetinibVandetanib

SAFIR02Lung– IFCT1301

NSCLCmetastaticorlocaly advanced

NoEGFRmutationNoALKtranslocation

platinumBasedregimen4cycles

CR/ PR or SD

YES

NO

R2:1

ArmA2:MEDI4736

N=180

Pemetrexed

ArmB2:MaintenanceArmPemetrexed

SUBS

TUDY

1SU

BSTU

DY 2

Biopsy orprimitivefrozen specimen• NGS• CGHarray/SNParray

PI:JCSoriaCo-PI:FBarlesi

Sponsor:UNICANCER-IFCT

Targetablemolecular alteration

ARCHER 1050: First-lineDacomitinib vs. Gefitinib (Phase 3)

* Per blinded IRC review. Ha: HR≤ 0.667(50%↑) www.clinicaltrials.gov: NCT01774721

Recruiting RANDOMIZE

Key eligibility:• Stage IIIb/IV

NSCLC• EGFR-activating

mutation• ECOG PS 0/1

2:1

Primary endpoint:• PFS*Secondary endpoints: • OS• OS at 30 months• PFS by investigator

assessment• Response• Safety• PROs

Dacomitinib45 mg QD

Gefitinib250 mg QD

Stratification:• Race• EGFR-mutation status (19 vs. 21)

N = 440

ASCO2017Tuesday,June6,2017,9:45 am– 12:45pmDacomitinib versusgefitinib forthefirst-linetreatmentofadvancedEGFRmutationpositivenon-smallcelllungcancer(ARCHER1050):Arandomized,open-labelphaseIIItrial.AbstractLBA9007

SWOG-S1403Phase2/3StudyDesignEstimated enrollment: 605

Afatinib +cetuximab

Afatinib

PrimaryendpointOS(Phase3)SecondaryendpointsincludePFS,ORR,timetotreatmentdiscontinuation,timetotreatmentfailure,toxicity

• StageIVorrecurrent NSCLC

• EGFRexon19 delorexon21L858R

• EGFRT790Mor othermutation allowed ifaccompanied byexon19or exon21mutation

• Nopriorsystemictreatmentforadvancedormetastaticdisease

R

Clinicaltrials.gov.AccessedJune2017(NCT02438722)

PhaseIITrialofT-DM1inHER2-PositiveLocallyAdvancedorMetastaticNSCLC

StinchcombeTetal.ASCO2017;Abstract8509.

T-DM13.6mg/kgD1q3wk(n=49)

• HER2-overexpressing NSCLC

• Previously treated with platinum-based therapy

Responserates(medianfollow-up16.3mo)IHC2+(n=29):0%IHC3+(n=20):20%(4PR)MedianDoR:7.3mo

MedianPFSIHC2+2.6mo IHC3+2.7mo

Phase II Basket Trial of T-DM1 in HER2 Amplified or Mutant Cancers

COHORTS

Lung cancers – HER2 mutant (n = 18)

Lung cancers – HER2 amplified

Bladder/urinary tract cancers –HER2 amplified

Other solid tumors – HER2 amplified

T-DM1 3.6 mg/kgD1 q3wk

• There were 10 HER2 exon 20 insertions and 8 point mutations• Responders were observed across mutation subtypes

LiBTetal.ASCO2017;Abstract8510.

ORR: 33% (5/15)Median DoR: Not reachedMedian PFS: 4 mo

JUNIPERPhase3StudyDesignEstimated enrollment: 450 (closed)

Abemaciclib200mgPOq12hd1-28

+BSC

Erlotinib 150mgPOq24hd1-28

+BSC

PrimaryendpointOSSecondaryendpointsincludePFS, ORR,safety/tolerability,QoL

• StageIVNSCLC• Previousprogressionafterplatinum-basedtherapy

• KRASmutant

NCT02152631 ClinicalTrials.gov. Available at:

https://clinicaltrials.gov/ct2/show/NCT02152631Goldman JW et al. Clin Lung Cancer 2016;17(1):80-4.

3:2R

PD-L1expressionandresponsetoimmunotherapyinpatientswithMET exon14-alteredNSCLC

SabariJKetal.ASCO2017;Abstract8512.

• 41patientswithMETexon14skippingalterations(MET∆14)andPD-L1expressionanalysis

• SubstantialportionofpatientswithMET∆14NSCLCexpressPD-L1(TPS≥50% =44%;TPS1%-49%=17%)

• Immunotherapyadministeredto15patients:• Nivolumab n=5• Ipilimumab+nivolumab n=4• Pembrolizumab n=3

• ORR =2/15(13%)• ORRforTPS≥50%=1/3(33%)

• Atezolizumabn=2• Durvalumabn=1

Outline

v Non-IO phase 3 trialsv IO-based phase 3 trials

ü IO-IOü IO-chemotherapyü IO-targeted therapiesü IO-radiotherapy

Combinationstrategiesarenecessarytoaddressbroadpatientpopulations

I-O

I-O=immuno-oncology.

PhaseICheckMate 012:Response

HellmannMDetal.LancetOncol 2017;18:31-41.

ORR(all): 18/38(47%)ORR(PD-L1≥1%): 12/21(57%)

ORR(all): 15/39(38%)ORR(PD-L1≥1%): 13/23(57%)

Treatment-relatedAEspromptingtreatmentdiscontinuation:4/38(11%)

Treatment-relatedAEspromptingtreatmentdiscontinuation:5/39(13%)

CHECKMATE227

KeyEligibilityCriteria• Chemotherapy-naïve

patientswithstageIVorrecurrentNSCLC

• NoEGFR/ALKmutationssensitivetoavailabletargetedinhibitortherapy

• ECOGPS0–1

Fullyenrolled*

Treatmentuntildisease

progressionorunacceptable

toxicity

Nivolumabmonotherapy240mgQ2W

Platinum-doubletchemotherapy

Nivolumab360mgQ3W+Platinum-doubletchemotherapy

Platinum-doubletchemotherapy

PD-L1+(≥1%)

PD-L1-(<1%)

TumorPD-L1assessmentatscreening

Nivolumab3mg/kgQ2W+Ipilimumab1mg/kgQ6W

Nivolumab3mg/kgQ2W+Ipilimumab1mg/kgQ6W

R1:1:1

I-O

*Stratificationfactoratrandomization:histology(squamousversusnon-squamous).ALK=anaplasticlymphomakinase;ECOGPS=EasternCooperativeOncologyGroupperformancestatus;EGFR=epidermalgrowthfactorreceptor;I-O=immuno-oncology;NSCLC=non-smallcelllungcancer;PD-L1=programmeddeathligand1;Q2W=every2weeks;Q3W=every3weeks;Q6W=every6weeks;R=randomized.1.Clinicaltrials.gov.NCT02477826(CheckMate 227).AccessedApril12,2017.2.Dataonfile.Checkmate227.2017.

NeptuneandMystic:Phase3,open-labeltrialsofanti–PD-L1± anti–CTLA-4vsPt-baseddoubletchemotherapyforfirst-linetreatmentofstageIVNSCLC

N=960

KeyInclusionCriteria• Treatmentnaïve,stageIVNSCLC• NoactivatingEGFR orALKrearrangement

• PD-L1positive*ornegative

Durvalumab+tremelimumab

Histology-basedPtdoubletchemotherapy

R1:1NEPTUNE1,2

Primary Endpoint: OS

PatientsachievingdiseasecontrolmayrestartcombinationtreatmentuponevidenceofPD

KeyInclusionCriteria• Treatmentnaïve,stageIVNSCLC• NoactivatingEGFR orALKrearrangement

R1:1:1

N=1118

MYSTIC3-5

Durvalumab

Durvalumab+tremelimumab

Histology-basedPtdoubletchemotherapy

Primary Endpoints: PFS and OS of durva + treme(PD-L1+ and all-comers) and durva monotherapy (PD-L1+ only)

PatientsachievingdiseasecontrolmayrestartcombinationtreatmentuponevidenceofPD

*PD-L1positivitydefined as≥25%oftumor cellswithmembranestainingasdeterminedbyPD-L1IHCassay.1.Clinicaltrials.gov.NCT02542293.AccessedApril28,2017.2.Mok Tetal.PosterpresentationatESMOAsia2015.480TiP.3.Clinicaltrials.gov.NCT02453282.AccessedApril28,2017.4.PetersSetal.PosterpresentationatELCC2016.191TiP.5.Pressrelease.January17,2017.

I-O

Study JVDF (NCT02443324) Phase 1A/B Study Design

aPatientsmaycontinuetreatmentforupto35cycles,untilconfirmedprogressivediseaseordiscontinuationforanyotherreason.bProtocolwasrecentlyamendedtoaddcohortsA1,A2andE;cohortsarecurrentlyenrolling.DLTdose-limitingtoxicity;PKpharmacokinetics;Ramramucirumab;Pembro pembrolizumab

Herbst RSetal.ProcESMO2016;AbstractLBA38.

Study JVDF (NCT02443324)Cohort C: Interim clinical activity

Herbst RSetal.ProcESMO2016;AbstractLBA38.

PD-L1Status Patients Events MedianPFS,Mo(95%CI)

All patients 27 8 NR(3.98,—)

Negative 10 2 NR

Weakpositive 4 2 3.98(2.76,—)

Strongpositive 7 2 NR

Notreported 6 2 NR

ITTPopulationCohortC

NSCLC(n=27)Objectiveresponserate,n(%) 8(30%)Diseasecontrolrate,n(%) 23(85%)

Progression-free survival

Atezolizumab clinicaldevelopmentprogrammeinfirst-line andadjuvantNSCLC

Squamous&Non-squamous

N=570

ArmAAtezo

ArmBCis/Carbo+Pem/Gem

Non-squamousN=1202

ArmAAtezo+Carbo/Pac

ArmBAtezo+Carbo/Pac/Bev

ArmCCarbo/Pac/Bev

SquamousN=1025

ArmAAtezo+Carbo/Pac

ArmBAtezo+Carbo/Nab-pac

ArmCCarbo/Nab-pac

Non-squamousN=724

ArmAAtezo+Carbo/Nab-Pac

ArmBCarbo/Nab-Pac

Non-squamousN=568

Mon

othe

rapy

Che

mot

hera

py C

ombi

natio

ns

ArmAAtezo

ArmBBestSupportiveCareA

djuv

ant

StageIB-IIIASquamous&

Non-squamousN=1127

ArmAAtezo+Carbo/Cis+Pem

ArmBCarbo/Cis+Pem

R

R

R

R

R

R

I-O

Upcomingrandomizedimmunotherapytrialsin1st lineNSCLCandprojected read-outtimelines

2016 2017 2018 2019 2020

Nivolumabmonotherapy

PDL1+CheckMate-026

Q32016

Pembrolizumabmonotherapy>50%PDL1+Keynote 024Q22016

MYSTICQ12017

Durvalumab ±tremelimumab vs

SoC

Pembrolizumab +platinium /pemetrexed

(non-squamous)Keynote 189Q32017

Avelumab monovsPtdoublet

PD-L1+JAVELINlung 100

Q12018

Atezolizumab +chemo

±bevacizumab vschemo +

bevacizumabIMpower 150

Q12017

Nivolumab monovs

Niv +Ipi vsNiv +Ptdoubletvs

PtdoubletCheckMate-227

Q12018

Pembrolizumabmonotherapy>1%PDL1+Keynote 042Q22018

Atezolizumabmonotherapyallhistologies

PDL1+IMpower 110

Q22018

Atezolizumab +chemo

IMpower 130(non-SCC)

IMpower 131(SCC)Q32018

Durvalumab ±tremelimumab vs

SoCNEPTUNEQ42018

Ipilimumab +paclitaxel +carboplatinsquamousCA184-153Q32019

PD1/PDL1Monotherapy

CTLA4+PD1

PD1orPDL1CTCombo

Legend

OthercandidatecombinationTargetsacrossLungcancer

PARP

Cytokines(eg,IL2)

T-cellCheckpoints (eg,CD137,CD27,GITR,OX40,LAG3,TIGIT,CD73)

PI3K

OncolyticViruses

Vaccines

TGF-B

NKCellModulation(eg,SLAMF7,KIR)

EGFR

cMET

ImmuneStimulation/Modulation TumorCellTargetedPathways

ALK

IDO

CCR4

Antibody-DrugConjugates

BCR-ABL Epigenetic Modifiers (HDAC)

Glypican-3

I-O

KeytrialswithI-Otherapies:Combinations

DURVAPACIFIC

IPI+NIVOCheckMate 227,Lung-MAP

DURVA+TREMEMYSTIC,NEPTUNE,

ARCTIC

NIVOCheckMate 227NCT02309177

PEMBROKEYNOTE-189KEYNOTE-407

ATEZOIMpower 130IMpower 131IMpower 150

PEMBROKEYNOTE-021

NCT02511184

ATEZONCT02013219NCT02630186

NIVOCheckMate 370NCT02393625

I-O

Combinationsofpembrolizumab,ipilimumab,nivolumab,atezolizumab,andtremelimumab andothertherapiesarecurrentlynotapprovedforadvanced/metastaticNSCLC.ClinicalTrials.gov.http://www.clinicaltrials.gov.