ImplicationsofMicrosatelliteInstability(MSI)forTreatment

MichaelOverman,MDAssociateProfessor

GastrointestinalMedicalOncologyMDAndersonCancerCentermoverman@mdanderson.org

Disclosures

• Consulting:– Merrimack,BMS,Roche,Karyopharm

• ResearchFunding:– Roche,Merck,Celgene,Medimmune,BMS,Amgen

Testing for Microsatellite Instability (NCCN)

• The panel recommends universal MMR or MSI testing for all patients with a personal history of colon or rectal cancer to identify individuals with Lynch syndrome, to inform use of immunotherapy in patients with metastatic disease, and to inform decisions for patients with stage II disease.

Treatment Recommendations

• FDA label for Pembrolizumab: – “For the treatment of adult and pediatric patients with unresectable or metastatic,

microsatellite instability-high (MSI-H) or mismatch repair deficient”• “solid tumors that have progressed following prior treatment and who

have no satisfactory alternative treatment options”• “colorectal cancer that has progressed following treatment with a

fluoropyrimidine, oxaliplatin, and irinotecan”

• NCCN: – Recommends nivolumab or prembrolizumab as treatment options in patients

with metastatic MMR-deficient colorectal cancer in second- or third-line therapy.

GuidelinesandFDAIndications

NCCNupdate11/23/2016;FDAlabel5/23/2017

dMMR Testing

Intactexpression

Lossofexpression

Immunohisto-chemistry

PolymeraseChainReaction

Panelof5ormoremicrosatelliteswith allelicshiftin2(>30%)ormoremarkers=MSI-high

CompletelossofexpressioninoneoftheMMRproteins=MSI-high

Next-generationSequencing

FoundationMedicine:varianceat114MSIloci

dMMR orMSI-HCRC

2013Kimetal.Cell

Stage MSI-H

II 22%

III 12%

IV 4%

• InheritedmutationsinMMR(HNPCCorLynch).≈1/3

• SporadiclossofMMRbyMLH-1methylationorbiallelic somaticgenomicalteration.≈2/3

MSI-high

N=141

MatsushitaAetal.Nature(2012);482(7385);400-4

Immunogenicmethylcholantherene-inducedsarcomacelllinesfromRag2-/- micedemonstrate≈20%tumorrateinnaïve

wildtype mice

Spectirn β-2R913LmutationpredictedandclonedfromTIL

TumorRejectionandNeoantigens

TumorAntigens:Differentiation(melanocytedifferentiationantigens…)

Overexpressed(HER-2…)Viral(HPVproteins…)

Cancer/testis(MAGE,NY-ESO-1…)Mutational(p53…)

KEYNOTE-028forPDL1+CRC

O’Neiletal.ESMO2015

• Pembrolizumab 10mg/kgIVq2wks• PD-L1+:“membranousPD-L1expressionin≥1%ofcellsintumorandstroma”

33/137(24.1%)PD-L1+with23enrolled

ORR4.3%SD17.4%

(OnlyMSI-highpt wastheoneresponder)

3 6 5 7 3 0

-1 2 5

-1 0 0

-7 5

-5 0

-2 5

0

2 5

5 0

7 5

1 0 0

1 2 5

%C

ha

ng

e f

rom

Ba

se

lin

e S

LD

M M R -d e fic ie n t C R CM M R -p ro fic ie n t C R C

Le DT, et al. NEJM 2015 and ASCO

2016

-1 0 0

-5 0

0

5 0

1 0 0M M R -p ro fic ie n t C R C

M M R -d e fic ie n t C R C

% C

ha

ng

e f

rom

Ba

se

lin

e S

LD

MMR-deficient CRC,N=28

MMR-proficient CRC,N=25

ResponseRate 57% 0%DiseaseControl Rate 89% 16%

dMMR CRC:Nivolumab Monotherapy

Overmanetal.LancetOncology2017inpress

a

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0

- 1 0 0

- 7 5

- 5 0

- 2 5

0

2 5

5 0

7 5

1 0 0

W e e k s

Ch

an

ge

in

Su

m o

f T

ar

ge

t L

es

ion

s S

ize

(%

)

O n

T r e a t m e n tO f f T r e a t m e n t

C o m p l e t e o r P a r t i a l

R e s o p o n s eF i r s t O c c u r r e n c e o f N e w L e s io n

C h a n g e T r u n c a t e d t o 1 0 0 %

On treatmentOff treatmentCR or PRFirst occurrence of new lesion

DiseaseControl≥12weeksin69%

RR31%SD39%PD24%

CharacterizationofResponseandStableDisease

CensoredLastdosewhenpatientofftreatment

FirstresponseDeath

Patie

nts

with

Sta

ble

Dis

ease

(n =

29)

a

Weeks

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108

Patie

nts

with

Res

pons

e(n

= 2

3)a

InvestigatorAssessed• MedianTTR:2.8months• MedianDOR:notreached• 83%(19/23)responsesongoing

DOR,durationofresponse;TTR,timetoresponse.aInvestigatorassesseddMMR/MSI-Hbylocallaboratory.

6months 1year 2years

12/8/2015 2/28/2017

Nivolumab 1yr2m

MLH1/PMS2lossBRAFV600E

11/11/2014

Nivolumab 2yr1m

LynchsyndromeMLH1germline

BRAFwt

12/30/2016

6/12/2014 11/22/2015

Nivolumab 1yr5m

LynchsyndromeBRAFwt

ReductioninTargetLesionsRegardlessofPD-L1Expression,BRAForLynchHistory

≥1%<1%

+ConfirmedCR/PR

Investigator-AssessedBe

stChangeinTargetLesionSize(%

)

TumorPD-L1Expression100

-50

-100

50

0

BRAFMutationStatus100

-50

-100

50

0

Investigator-AssessedBe

stChangeinTargetLesion

Size(%

)

MutantWildtype

+ConfirmedCR/PR

ClinicalHistoryofLynchSyndrome100

-50

-100

50

0

Investigator-AssessedBe

stChangeinTargetLesion

Size(%

)

YesNo

+ConfirmedCR/PR

OvermanLancetOnc 2017inpressAndreetal.ASCO2017a3531

dMMR CRCNivolumab vs.Nivolumab/Ipilimumab:Checkmate142

ORR55%≥12wkDCR79%12mPFS77%

Nivolumab/Ipilimumab,N=84

ORR31%≥12wkDCR69%12mPFS48%

Nivolumab,N=77

0

Prob

abili

ty o

f Pr

ogre

ssio

n-fr

ee S

urvi

val 1.0

0.8

0.6

0.4

0.2

0.00 3 6 9 12 15 18 21 24

74 48 22 14 12 10 7 3 0Time (Months)

No.at RiskNIVO

84 65 35 17 13 8 1 0NIVO+IPI

NIVO3mg/kgQ2WNIVO3mg/kg+IPI1mg/kgQ3W

MSI-h/dMMR Phase III CRC Trials

NRG-G1004/SWOG-1610COMMIT

MSI-high mCRC R

mFOLFOX6/Bevacizumab

mFOLFOX6/Bevacizumab+ Atezolizumab

Atezolizumab

PI:JamesLeeandMichaelOverman

KEYNOTE 177MSI-high mCRC R

mFOLFOX6/Bevacizumab

PembrolizumabPI:LuisDiaz

FrontlineMetastatic

StageIIIAdjuvant

mFOLFOX6(12cycles)

mFOLFOX6+Atezolizumab (12cycles)then Atezolizumab x6months

R

PI:FrankSinicrope

Alliance 021502Resected Stage III

N=720

N=439

N=270

Cancertype(n=7,817)

MSI-highrate

Uterine 39/277(14.1%)

Smallbowel 6/70(8.6%)

Prostate 11/178(6.2%)

CRC 42/1185(3.5%)

CUP 22/815(2.7%)

Hepatobiliary 9/389(2.3%)

Gastroesophageal 6/400(1.5%)

Neuroendocrine 1/431(0.2%)

Pancreatic 1/459(0.2%)

NSCLC 5/2112(0.2%)

Breast 2/1459(0.1%)

AnalSCC 0/42(0%)

HalletalASCO2016andGIASCO2016andLeeetalASCO2016,Pembrolizumab FDAlabel

Pembrolizumab:non-CRC

RateofdMMR

Conclusions• StandardofCarefor≥2nd linemetastaticdMMR CRCisnowanti-

PD1therapy– NCCNrecommendseitherPembrolizumab orNivolumab

• Pembrolizumab isFDAapprovedfordMMR CRCafterfluoropyrimidine/oxaliplatin/irinotecan

– TestallpatientswithmetastaticCRCfordMMR– PhaseIIITrialsforadjuvantandfront-linemetastaticdMMR CRCare

ongoing

• StandardofCarefor≥2nd linemetastaticdMMR cancersisnowanti-PD1therapy– Pembrolizumab isFDAapprovedfordMMR cancers– TestingmethodologynotspecifiedbyFDAlabel

• PredictiveFactors– PD-L1expressionisnotapredictivefactorforMSSorMSI-highCRC– ImprovedunderstandingofdMMR intrinsicresistanceisneeded– dMMR isthebestpredictivemarkerwehaveforanti-PD1therapy!