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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!