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.