LungCancer2017:It’sComplicated

CraigReynoldsMDFloridaCancerAffiliatesandResearchInstitute

Ocala,Florida

LungCancer—”TheGoodOldDays”• Smallcellhadnochangesanytimerecently• Histologydidn’tmatterinNSCLC• Doubletofchoice(usuallycarboplatinum/paclitaxelintheUS)followedbydocetaxelfollowedbygefitinib orerlotinib

• Nomolecularsubtypesofdisease

LungCancerisNowComplicated

• SCLC—Finallyprogress?• SquamousNSCLC• Nonsquamous NSCLC—Targetedtherapyupdate• ImmunotherapyUpdate

SmallCellLungCancer(SCLC)

SCLC

• Platinum/etoposideisstandardinitialtherapy• Radiationimprovesoutcomesslightlyinlimiteddisease

• Topotecan hasmodestactivityinrelapsed/refractorydiseasebuthastoxicityissues

• Noprogressfortwentyyears,buttwopromisingapproaches

Rovalpituzumab tesirine (Rova-T)

• TargetsDLL3,acancerstemcelltarget• 74patienttrialrelapsed/refractorySCLCreportedatASCO2016,60evaluable

• 68%stabledisease,18%RR• 12patientsreceivedRova T3rd line,with6responses

• Durabilityofresponsesisencouraging• FasttrackbyFDA,shouldhavemoredatawithinayear

Rudin etalASCO2016

ImmunotherapyinSCLC

• Nivolumab andthecombinationofnivolumab andipilumumab havebeenevaluated

• Nivolumab alonehas10%RRwith13%grade¾toxicity

• Nivo/Ipi hashigherresponserates(about20%)with18-19%grade¾toxicity

• Durableresponsesoccur,largerstudiesunderway• ShouldhavegoodcombinationIOdatainSCLCwithinayearAntonioetalLancetOncology20167:883-95

NotMuchProgressinSquamousNSCLCEither

1980s1,2 1990-20053-5 2005-20096-8 2010-20159-10

18

16

14

12

10

8

6

4

2

0

Med

ian

Surv

ival

(Mon

ths)

Single-agent

platinum

Platinum-based

doublets

Platinum-based

doublets

Pem and platinum-triplet (BEV) Platinum-

baseddoublets

Histology-directedtherapy

Oncogene-driventherapy

NSCLC (all histologies)

SqCLC

Non-SqCLC

Pemetrexed and bevacizumab contraindicated in SqCLC histology; No oncogene-directed targeted therapy in squamous histology to date

BEV, bevacizumab; Pem, pemetrexed. 1. Bonomi et al., J Clin Oncol. 1989;7:1602-1613; 2. Eagan et al., J Clin Oncol. 1988;6:5-8; 3. Schiller et al., N Engl J Med. 2002;346:92-98; 4. Sandler et al., J Clin Oncol. 2000;18:122-130; 5. Spira and Ettinger. N Engl J Med. 2004;350:379-392; 6. Sandler et al., N Engl J Med. 2006;355:2542-2550; 7. Scagliotti et al., J Clin Oncol. 2008;26:3543-3551; 8. Scagliotti et al., Oncologist 2009;14:253-263; 9. Socinski et al., J Clin Oncol. 2012;30:2055-2062; 10. Paz-Ares et al., J Clin Oncol. 2013;31:2895-2902.

MolecularTargetsinSquamousNSCLC

Reference Agent Target N(squamous) Study Description PrimaryEndpoint

Scagliotti,2010 Sorafenib RAF, VEGFR 926

(223)

PhaseIIIadvancedNSCLC,includingsquamous(withpaclitaxel/carboplatin) (HRdetrimentinsquamous)

Negative

Novello,2014 Motesanib VEGFR,

PDGFR1450(360)

PhaseIIIadvancedNSCLC,includingsquamous(withpaclitaxel/carboplatin) (unacceptabletoxicityinsquamous)

Negative

Laurie,2014 Cediranib VEGFR,

PDGFR306(39)

PhaseII/IIIadvancedNSCLC,includingsquamous(withcarboplatin/paclitaxel)(haltedforfutility)

Negative

Langer,2014 Figitumumab IGF1R 681

(584)PhaseIIIadvancednon-adenocarcinomaNSCLC(withpaclitaxel/carboplatin) Negative

Sanofi,2013 Iniparib PARP 780

(780)PhaseIIIadvancedsquamousNSCLC(withgemcitabine/carboplatin) Negative

Pirker,2009

Cetuximab(FLEXStudy) EGFR 1125

(377)PhaseIIIadvancedEGFR+NSCLC(withvinorelbine/cisplatin)(HRfavorableinSCCA) Positive

SQUIRETrial

SQUIREResults

GC + N GC

Stratified HR(95%CI) 0.84(0.74,0.96)

Stratified P value(log-rank) 0.01

MedianOS, months(95%CI) 11.5(10.4, 12.6) 9.9(8.9,11.1)

CR, complete response; GC, gemcitabine-cisplatin; N, necitumumab; OS, overall survival; PD, progressive disease; PR, partial response; R, randomization; SD, stable diseaseThatcher et al., Lancet Oncol. 2015;16:763-774.

SQUIREISASQUARE

• Necitumumab didnotsignificantlyimpactpractice• RecentlytakenoutoftheNCCNguidelines• Necitumumab nolongeractivelymarketed

CanWeImprovetheValue?

SQUIRE (EGFR FISH+)1

S0819 (SqCLC-EGFR FISH+)2

FISH, fluorescent in s itu hybridization; GC, gemcitabine and cisplatin; N, necitumumab1. Hirsch et al., WCLC 2015;abstr ORAL32.05; 2. Herbst et al., WCLC 2015;abstr PLEN04.01; 3. Pirker et al., Lancet Oncol. 2012;13:33-42.

FLEX3

aChemotherapy + cetuximabvs chemotherapy

AMAPtoProgressinSquamousNSCLC?

CTBiomarker

profiling (NGS/CLIA) Non-matc

hdrug

Biomarkernon-match

Multiple phase II-III sub-studies with “rolling opening and closure”

Biomarker A

TT A CT

Primary endpointPFS / OS

Biomarker D

TT D+E E

Primary endpointPFS / OS

Biomarker Β

TT B CT

Primary endpointPFS / OS

Biomarker C

TT C+CT CT

Primary endpointPFS / OS

Each sub-study independent of the othersEach sub-study designed for registration of a drug-biomarker combination

Self-sustaining with new sub-studies in planning stages

CLIA, Clinical Laboratory Improvement Amendments; CT, chemotherapy (docetaxel [D] or gemcitabine [G]); E, erlotinib; NGS, next-generation sequencing; OS, overall survival; PFS, progression-free survival; TT, targeted therapy 1. Lung-MAP. Available at: http://www.lung-map.org/healthcare-providers. Accessed February, 2016

MAPInProgress

GDC-0032VsSoC

PalbociclibVsSoc

AZD4547VsSoC

GDC-0032 Palbociclib AZD4547

FGFR1CDK4/6

PI3K

Non-matchSub-studies

Stage1

Stage2

BMN 673VsSoC*

BMN673*

HRD

Nivo/Ipivs

Nivolumab

Checkpoint Naive

MEDI4736/Treme*VsSOC

Checkpoint Refractory

Matched Sub-studies

• Lung-MAP amended to 2nd line therapy & beyond to accommodate Nivolumab approval• Pre-screening added back• Eligibility criteria broadened; *Sub-studies in developmentCDK, cyclin D-dependent k inase; FGFR, fibroblast growth factor receptor; HRD, Homologous

Recombination Defects; Ipi, ipilimumab; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; SoC, standard-of-care1. Lung-MAP. Available at: http://www.lung-map.org/healthcare-providers. Accessed February, 2016

SquamousNSCLCSummary

• Notmuchprogresshereeitherthanimmunotherapy• Necitumumabmightbeconsideredforyounger,motivatedpatients,particularlyifEGFRexpressedathighlevels,thoughaconfirmatorytrialwouldbehelpful

• MAPhasnotfoundtheroadtoprogressyet,butitcontinuesandisanimportanteffort

• Standardapproachisplatinumdoubletchemotherapy(?Withnecitumumab inhighlyselectedpatients)followedbydocetaxelaloneorwithramicurimab andthenafatinib

• We’lltalkaboutimmunotherapylater!

Nonsquamous NSCLC—TargetedTherapy• EGFRmutations—useofliquidbiopsies• ALKmutations—standardofcareischanging• Weareinatargetrichenvironment

EGFRmutatedNSCLC

• Osimertinib isnowapprovedfortheT790Mmutation

• Rebiopsy hasbecomeastandardapproach• Liquidbiopsyisspecificbutnotalwayssensitive,sostandardisliquidbiopsyatprogressionwithtissueifliquidbiopsyisnothelpful

• Rb mutationssuggestsmallcelltransformation,butnotallliquidbiopsiesincludeRb

ALKmutatedNSCLC

• EML-ALKmutationwasdescribedasadrivingmutationinNSCLCin2007

• Crizotinib wasapprovedin2011• TherearenowthreeapprovedALKinhibitorsintheUS—crizotinib,ceritinib,andalectinib

J-ALEX

• Randomizedtrialofalectinib vscrizotinib inALKinhibitornaïveALK-positiveNSCLC

• Japanesetrialof207patientsclosedearlybyDSMB• PFSfavoredalectinib withHR0.34(0.17-0.70,p<.0001)• MedianPFSforalectinib notreachedvs10.2monthsforcrizotinib

• Crizotinib hadmoregrade3-4toxicity• Multinationalconfirmatorytrial(ALEX)willbeatASCO;pressrelaease saysitispositive

• Alectinib islikelythenewstandardinALKpositiveNSCLC

• Alectinib ismuchmoreactiveintheCNSNokihara etalASCO2016abstract9008

OtherTargetsinNonsquamousNSCLC• ROS1• KRAS(sofarnodrugsforthis)• RET• BRAF• METexon14mutations• Morecoming—It’sgettingcomplicated!

TargetedTherapyinNonsquamous NSCLC2017• Rebiopsy isimportant;liquidbiopsiesareusefulbutneedtissueattimes

• UnderstandingofEGFRresistancemutationsisevolvingrapidly

• StandardofcareinALK-positiveNSCLCchangingfromcrizotinib toalectinib

• Newmutations,eachofwhichaccountfor1-2%ofNSCLC,arebeingidentified

ImmunotherapyofNSCLC

• Stateoftheart• Useinfirst-linemetastaticNSCLC• Newapproachesinearlierdisease• Theoreticaldiscussionofvariabilityofresponse

NSCLCImmunotherapy2017

• Threedrugsareapprovedinthesecond-lineandbeyond—pembrolizumab,nivolumab,andatezolizumab

• Useinsecond-linedoesnotrequirePD-L1testingforanyofthesedrugs

• Pembrolizumab isapprovedinfirst-lineNSCLCforpatientswithPD-L1expression>50%

Checkmate017:Nivolumab vs.Docetaxel

Spigel et al., ASCO 2015; abstr 8009.

Brahmer et al., N Engl J Med. 2015;373:123-135.

Checkmate017Results

• Phase III RCT of patients with advanced squamous cell NSCLC in whom disease progressed during or after first-line chemotherapy

• Randomized 272 patients to receive nivolumab 3 mg per kg of body weight every 2 weeks or docetaxel 75 mg/m2 every 3 weeks

•Efficacy of nivolumab was independent of PD-L1 status in this SqCLC trial.•Treatment-related AEs grade 3 or 4 occurred in 7% in the nivolumab group vs 55% in the docetaxel group

Median OS Median PFS

Spigel et al., ASCO 2015; abstr 8009.

Brahmer et al., N Engl J Med. 2015;373:123-135.

PD-L1Expressionin017

No apparent prognostic effect of PD-L1 expression.Survival benefit of nivolumab was independent of PDL1 expression levels.

Spigel et al., ASCO 2015; abstr 8009.

Brahmer et al., N Engl J Med. 2015;373:123-135.

Checkmate057:NonsquamousNSCLC

Borghaei et al., N Engl J Med. 2015;373:1627-1639.

PD-L1ExpressionandOutcomein057

Paz-Ares et al., ASCO 2015, abstr LBA109.

OSbenefitcorrelateswithPD-L1expressioninthisNon-SQ trial.Contrastswithtrial017inSQ.It’scomplicated!

OutcomesofSubgroupsin057

0NIVO DOC

1 2

Paz-Ares et al., ASCO 2015, abstr LBA109.

Immunotherapyin2dLineNSCLCSummary• Datafornivolumab,pembrolizumab,andatezolizumab areallcompellingandfairlysimilar

• Nodirectcomparisonshavebeendoneandlikelyneverwill

• TherewillbesomelimiteddataaboutsequentialIOtherapysoon

• Doublettherapywilllikelymakethismoot

Keynote24:Pembrolizumab in1st-LineNSCLC

R 1:1 N=305

PD / toxicity /

other

PD / toxicity /

other

Key eligibility criteria• Untreated stage IV NSCLC• PD-L1 TPS ≥50%• No activating EGFR mutation or

ALK translocation• No untreated brain metastases Platinum-doublet

chemotherapya

(4-6 cycles) (n=151)

Pembrolizumab 200 mgq3w (35 cycles)

(n=154)

Reck M, et al. Ann Oncol 2016;27(Suppl 6):abstr LBA8_PR

Primary endpoint◆ PFS (RECIST v1.1)

aCarboplatin or cisplatin + pemetrexed, carboplatin or cisplatin + gemcitabine, or carboplatin + paclitaxel, with optional pemetrexed maintenance for nonsquamous NSCLC

Secondary endpoints Exploratory endpoint◆ OS, ORR, safety ♦ DOR

Crossover permitted from chemotherapy to pembrolizumab ifPD

Pembrolizumab vs.ChemotherapyinPD-L1Positive*NSCLC

Reck et al., N Engl J Med. 2016 [Epub ahead of print].

45%

28%

0%

20%

40%

60%

80%

100%

ORR

Pembrolizumab

Chemotherapy

mPFS 10.3 mo

mPFS 6.0 mo

6-mo OS: 80%

6-mo OS: 72%

*PD-L1 expression ≥50%

Keynote24Toxicity

Reck M, et al. Ann Oncol 2016;27(Suppl 6):abstr LBA8_PR

◆ Incidence of treatment-related AE, any severity, was lower with pembrolizumab compared with chemotherapy (73.4 vs 90.0%, respectively).

Exposure and AE summary

Keynote24Summary

• ForpatientswithPD-L1positive(>50%)NSCLC,pembrolizumab improvedOS,PFS,andRRcomparedtochemotherapy

• 44%ofchemotherapypatientscrossedovertopembrolizumab afterdiseaseprogression

• Pembrolizumab hadfeweradverseeventsthanchemotherapy

Keynote21:Chemotherapy+Pembrolizumab

R 1:1

N=123• PD-L1 status (TPS ≥1 vs. <1%)

Key patient inclusion criteria• Untreated stage IIIB / IV

nonsquamous NSCLC• No EGFR mutation or ALK

translocation• Provision of sample for PD-L1

assessment• ECOG PS 0–1• No untreated brain metastases

Pembrolizumab + chemotherapyPembrolizumab 200 mg q3w (2 years)

+carboplatin AUC5 mg/mL/min +

pemetrexed 500 mg/m2 q3w (4 cycles)* (n=60)

Stratification

ChemotherapyCarboplatin AUC5 mg/mL/min +

Pemetrexed 500 mg/m2 q3w (4 cycles)* (n=63)

Secondary endpointsPrimary endpoint◆ ORR (RECIST)central review ♦

PFS, DOR, OS, safety, relationship between anti-tumor activity and PD-L1 TPS

Pembro 200 mg q3w

(2 years)

PD

*Pemetrexed 500 mg/m2 q3w permitted as optional indefinite maintenance therapyLanger C, et al. Ann Oncol 2016;27(Suppl 6):abstr LBA46_PR

Keynote21:KeyResults

Keynote 021 - Key Results and Conclusions

Langer C, et al. Ann Oncol 2016;27(Suppl 6):abstr LBA46_PR; Langer et al, Lancet Oncol. Online Oct 9, 2016.

◆ Pembrolizumab + chemotherapy significantly improved the proportion of patients who achieved an ORR compared with chemotherapy alone (estimated treatment difference 26%)

ORR

, %(9

5%CI

) 10080

60

4020

0 Pembro+ Chemo

Chemo Alone

55%

29%

ConfirmedORR∆26%

p=0.0016

a- alive without subsequent disease progression

Keynote21:KeyResultsKeynote 021 - Key Results and Conclusions

◆ PFS was significantly longer with pembrolizumab + chemotherapy (13.0 mo) compared with chemotherapy alone (8.9 mo) (HR 0.53; p=0.010)

PFS,

%

100

80

60

40

20

00 5 15 2010

Time, months

Pembro + chemo 23

Chemo alone 33

PFS (RECIST v1.1 by Blinded, Independent, Central Review)Events, n HR (95%CI)

0.53

(0.31, 0.91) p=0.0102

Langer C, et al. Ann Oncol 2016;27(Suppl 6):abstr LBA46_PR.

Keynote21:KeyResultsO

RR

,% (9

5%C

I)

ORR by PD-L1 status100

80

60

40

20

0<1% n=21

57% 54% 26% 80% 13% 38% 39% 35%≥1% 1%–49% n=39 n=19

≥50% n=20

<1% n=23

≥1% 1%–49% n=40 n=23

≥50% n=17

Pembrolizumab + chemotherapy Chemotherapy alone

◆ 80% of patients who had a PD-L1 score of ≥50% achieved ORR with pembrolizumab + chemotherapy

Horizontal dotted lines represent the ORR in the total populationLanger C, et al. Ann Oncol 2016;27(Suppl 6):abstr LBA46_PR

Keynote21:KeyResults

Langer C, et al. Ann Oncol 2016;27(Suppl 6):abstr LBA46_PR; Langer et al, Lancet Oncol. Online Oct 9, 2016.

◆ Exposure was 1.6 times longer in the pembrolizumab + chemotherapy group◆ Most treatment-related AEs were mild and grade 1−2 severity

Exposure and AE summary

Keynote21Conclusions

• Pembrolizumab incombinationwithcarboplatinumandpemetrexed hadbetterPFSandRRthanchemotherapyalone

• OSwassimilarbetweentwoarms,butveryimmature

• Safetyprofilewasmanageable• Onlyarandomizedphase2• ConditionalFDAapprovalmaybecomingsoon

First-lineIOSummary

• Pembrolizumab isFDAapprovedforpatientswithPD-L1>50%

• Thechemo/pembro combinationwilllikelygetconditionalapprovalnextmonth

• ThismayhaveanimpactonPD-L1testing• Multipleotherchemo/IOcombinationtrialsareinprogressorhavecompletedaccrual,soawealthofdataiscoming

AndNowForSomethingCompletelyDifferent…

Checkmate026:Nivolumab 1st-LineNSCLC

R 1:1 N=541

Key patient inclusion criteria• Stage IV or recurrent NSCLC• No prior systemic therapy for

advanced disease• No EGFR / ALK mutations sensitive

to targeted inhibitor therapy• PD-L1 expression of ≥1%• CNS mets permitted if adequately trt

at least 2 wks prior to randomization• ECOG PS 0 or 1

Chemotherapy (investigator choice – histology

dependent) for 6 cycles (n=270)

Nivolumab 3 mg/kg IV q2w (n=271)

Primary endpoint◆ PFS (≥5% PD-L1+)

Secondary endpoints◆ PFS (≥1% PD-L1+), OS, ORR

PD / toxicity

PD

Nivolumab (optional)

Stratification

Socinski M, et al. Ann Oncol 2016;27(Suppl 6):abstr LBA7_PR.

• PD-L1 expression (<5% vs. ≥5%)• Histology (squamous vs. nonsquamous)

Checkmate026:Results

Nivolumab

Chemotherapy

Months

PFS,

%

2421181512963 27

100

80

60

40

0

20

0

Primary endpoint (PFS per IRRC in ≥5% PD-L1+)CheckMate 026: Nivolumab vs. chemotherapy in first-line NSCLC

All randomized patients (≥1% PD-L1+): HR 1.17 (95%CI 0.95, 1.43)

Socinski M, et al. Ann Oncol 2016;27(Suppl 6):abstr LBA7_PR

HR 1.15 (95%CI 0.91, 1.45); p=0.2511

Checkmate026:Conclusionsn

Socinski M, et al. Ann Oncol 2016;27(Suppl 6):abstr LBA7_PR

§ Nivolumab did not meet the primary endpoint of superior PFS compared with chemotherapy

§ Safety results were consistent with the known safety profile of nivolumab; there were fewer treatment-related grade 3–4 AEs in the nivolumab vs. chemotherapy arm

§ OS was similar in the nivolumab and chemotherapy arms and both compared favourably with historical controls§ 60.4% of patients in the chemotherapy arm received

subsequent nivolumab

NewfromAACR2017

• Impact of Tumor Mutation Burden (TMB) on the Efficacy of First-Line Nivolumab in Stage IV or Recurrent Non-Small Cell Lung Cancer: An Exploratory Analysis of CheckMate 026

Petersetal,AACR2017

TMBinCheckmate026

• TMBhasbeenshowntobepredictiveofoutcomesinimmuno-oncology(Rizvietal,Science2015348:124-8)

• Anexploratoryanalysisof026wasdonetotestthehypothesisthathighTMBmightpredictbenefitfromnivolumab vs.chemotherapy

• MatchedtumorandgermlineexomesequenceswereperformedforTMBanalysis

• 312patients(58%ofpopulation)hadmatchedsamplesforanalysis

• TMBin026patientsgenerallysimilardistributiontothatseeninpreviousreportofTCGAPetersetalAACR2017

TMBinCheckmate026

• AnalysisofbaselinecharacteristicsverysimilarinoverallpopulationandTMB-evaluable(TMB-E)population

• OSANDPFSweresimilarineacharmforoverallandTMB-E

• Patientsweredividedintothreesubgroupsbasedonnumbersofmutations(<100,100-242,>243)

PetersetalAACR2017

PFSbyTMBTertile inCheckmate026

50

100

90

80

70

60

50

40

30

20

10

00 3 6 9 12

Months15 18 21 24

PFS(%)

High

Low

Medium

Mediumn=49 n=47

3.6(2.7,6.9)

Lown=62

4.2(1.5,5.6)

9.7(5.1,NR)

MedianPFS,months(95%CI)

High Mediumn=53 n=60

6.5(4.3,8.6)

Lown=41

6.9(5.4,NR)

5.8(4.2,8.5)

MedianPFS,months(95%CI)

High100

90

80

70

60

50

40

30

20

10

00 3 6 9 12

Months15 18

High

Low

Medium

21

Nivolumab Chemotherapy

PetersetalAACR2017

PFSandRRbyTMBSubgroupinCheckmate026

OUTCOME HIGH TMB LOW/MED TMB

Nivolumab Chemotherapy Nivolumab Chemotherapy

PFS(months) 9.7 5.8 4.1 6.9

HR0.62(0.38,1.0) HR1.82(1.3,2.55)

RR 47% 28% 23% 33%

PetersetalAACR2017

OSandTMBinCheckmate026

• OSwasnotimpactedbyTMBsubgroup• HighTMBNivo 18.3vChemo18.8mos (HR1.1)(68%crossovertonivo)

• Low/medTMB12.7v13.2mos (HR0.99)(55%crossovertonivo)

PetersetalAACR2017

TMBinCheckmate026

• Current/formersmokershadhigherTMBthannever-smokers

• TherewasnoassociationbetweenTMBandPD-L1expression

PetersetalAACR2017

ORRbyTMBsubgroupandPD-L1Expression

HighTMB Low/Med TMB

PD-L1>50% 75% 34%

PD-L11-49% 32% 16%

HighTMB Low/Med TMB

PD-L1>50% 25% 46%

PD-L11-49% 32% 23%

Nivolumab Chemotherapy

PetersetalAACR2017

PFSbyTMBandPD-L1in026

55

Months

100

75

50

25

0

6 18930 12 15 21Months

100

75

50

25

0

6 1893

PFS(%)

0 12 15 2421

High TMB, PD-L1 ≥50%

High TMB, PD-L1 1–49%

Low/medium TMB, PD-L1 1–49%

Low/medium TMB, PD-L1 ≥50%

Low/medium TMB, PD-L1 ≥50%

High TMB, PD-L1 1–49%

Low/medium TMB,

PD-L1 1–49%High TMB,

PD-L1 ≥50%

Nivolumab Arm Chemotherapy Arm

PetersetalAACR2017

TMBinCheckmate026--Summary

• Nivolumab improvedRRandPFSvschemotherapyinpatientswithhighTMB

• PFSwaslongerinpatientswithhighTMBregardlessofPD-L1status

• PatientswithhighTMBandPD-L1>50%benefitedthemostfromnivolumab

• Patientswithmed/lowTMBhadgreaterbenefitfromchemotherapy

• Thesesubsetsareexploratoryandnumbersaresmall,sothesefindingsshouldbeviewedcautiouslyPetersetalAACR2017

NeoadjuvantNivolumab

Study Design & Endpoints

NewlydiagnosedresectablestageI

(>2cm)/II/IIIANSCLC

Nivolumab3mg/kgIV

onDay-28&Day-14Surgical

resectiononDay0

Standardofcare

postoperative

treatmentSafety

followupfor30days

aftersurgery

TUMOR BIOPSY

BLOOD DRAWS

VIABLE TUMOR

TILS

LYMPH NODE CELLS

BLOOD DRAW

FordeetalESMO2016

StudyEndpoints

Ø Primary Endpoint: Safety and feasibility

Ø Exploratory Endpoints: Correlatives in blood and tumor, percent pathologic response, RFS, OS

Ø Planned enrollment: 6 patient safety & feasibility run-in followed by expansion to enroll up to 20 resected patients.

FordeetalESMO2016

Treatment-relatedAEs

Ø Treatment-related toxicities were consistent with those seen in other studies of nivolumaband there were no treatment-related deaths

Ø One death occurred during the postoperative safety evaluation period that assessed as unrelated to study treatment Data is based on a Sept 15, 2016 database lock

FordeetalESMO2016

AnalysisofResponse(Exploratory)

Tumor pathologic response after neoadjuvant anti-PD-1 (N=17)

Ø 39% (95% CI 20-61% ) of per protocol patients, 7 of 18, had <10% residual viable tumor at resection

Ø 1 patient had a pathologic complete response

0 10 20 30 40 50 60 70 80 901001

4

7

10

13

16

Percent Pathologic Response

Majorpathologicresponse <10% residual viable

tumor cells defines major pathologic response per Pataeret al. JTO 2012

Resected Tumors

FordeetalESMO2016

NeoadjuvantNivolumab Summary

• Neoadjuvantnivolumab didnotinterferewithsurgeryandtherewerenosurprisingsafetyissues

• 39%ofpatientshadamajorpathologicresponsewithtumorinfiltrationbyimmunecells

• ResponseswereseeninPD-L1positiveandnegativepatients

• Verysmallnumbers;Needconfirmationinlargerstudies

FordeetalESMO2016

WhyIsImmunotherapyComplicated?• UnchangeablehostimmunefactorssuchasHLAtype• Changeablehostimmunefactorssuchaslymphocytesubsetscanbeinfluencedbychemotherapyandothertreatment

• Tumorimmunogenicitycanchangeovertimeandcanbeinfluencedbychemotherapyandothertreatment

• Tumorimmunogenicitymayinherentlyvaryaswell(e.g.EGFRmutatedtumorsinnon-smokerswithlowTMB)

• ConcomitantchemotherapyandImmunotherapymayhavesignificantinteractionsspecifictothedrugsused

What’sNextforImmunotherapyofNSCLC?• Combinationsarealreadybeingevaluated(IOandIO,IOandchemo,IOandantibodies)

• Literallythousandsofpotentialcombinationstobestudied

• Broadclinicaltrialparticipationinthecommunityisvitaltomakingprogress!

“Whenpeoplecomplainofyourcomplexity,theyfailtoremembertheymadefunofyoursimplicity.”

--MichaelBassey Johnson