Targeting DNA repair pathways in women’s cancers · 2017. 7. 6. · Targeting DNA repair e...
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Targeting DNA repair pathways in women’s cancers
Natio
nal C
ance
r Ins
titute
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
March 21, 2017Jung-Min Lee, MD
InvestigatorLasker Clinical Research Scholar
Center for Cancer Research, National Cancer Institute
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COI• I have no conflicts of interest.
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Genetic sources of genomic instability
Serous82%
Carcinosarcoma6%
Clearcell6%
Endometrioid3%
Mixed3%
Mutually exclusive events2016
BRCA1somatic4%
BRCA2somatic3%
otherHRD10%
PTENloss6%
BRCA1methylation
CCNE1Amplification
RB1loss15%
NF1loss17%
BRCA2germline
6%BRCA1germline
8%
TCGA Consortium, Nature, 2011Patch and Bowtell et al, Nature 2015
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Molecular drivers and clinical association
Extended Data Figure 7 | Molecular drivers and clinical associations.a, Percentage (n) of primary tumours (total n 5 80) affected by homologousrecombination pathway mutations and CCNE1 copy number gains. One drivermutation counted for samples with more than one change, ranking mutationsin BRCA1/2, followed by other germline, somatic, amplification, deletion andmethylation events respectively. b, Association of driver mutation subgroupwith overall survival in AOCS and TCGA cohorts (Kaplan–Meier analysis, Pvalue calculated by Mantel–Cox log-rank test). c, d, Whole genome (c) and
coding mutations (d) per megabase for samples stratified by primary clinicalresponse group (lines indicate mean). Kruskal–Wallis test P value reported(*P , 0.05, **P , 0.01, Kolmogorov–Smirnov test). e, Boxplots summarizeCCNE1 expression in different driver mutation subgroups (****P , 0.0001,unpaired two-tailed t-test). Middle bar, median; whiskers, data range.f, Proportions of gene expression molecular subtypes between driver mutationsubgroups. HR/CCNE12 subgroup has no detected homologousrecombination pathway mutations or CCNE1 copy number changes.
RESEARCH ARTICLE
G2015 Macmillan Publishers Limited. All rights reserved
TCGA, Nature, 2011AOCS, Clin Ca Res, 2013
Patch et al, Nature 2015
AOCScohort TCGAcohort
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PARP inhibition, synthetic lethality in the clinic
Plummer R Clin Ca Res 2010 Lord et al, Science 2017
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Ledermann J et al. NEJM 2012, Ledermann et al, Lancet Onc, 2015
BRCAm (n=136) BRCAwt (n=118)
Olaparib Placebo Olaparib Placebo
Events: total pts (%) 26:74 (35.1) 46:62 (74.2) 32:57 (56.1) 44:61 (72.1)
Median PFS, mo 11.2 4.3 5.6 5.5
HR=0.1895% CI (0.11, 0.31);
P<0.00001
HR=0.5395% CI (0.33, 0.84);
P=0.007
Olaparib maintenance: maintains clinical benefit after treatment in first or second response
(EUROPEAN APPROVAL)
0Timefromrandomization(months)
0
1.0
3 6 9 12 15
OlaparibBRCAm
OlaparibBRCAwt
0.90.80.70.60.50.40.30.20.1
PlaceboBRCAm
PlaceboBRCAwt
Prob
abili
ty o
f PFS
0
0.6
0.80.9
00.10.20.30.40.5
0.7
1.0
3 6 9 12 15 18
Prob
abili
ty o
f PFS
Time from randomization (months)
PlaceboOlaparib 400 mg bid monotherapy
Hazard ratio 0.35(95% CI, 0.25–0.49)P<0.00001
I Olaparib 400 mg bid
II Placebo bid
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Audeh, et al. Lancet 2010
Activity in gBRCA mutation and BRCA-like OvCabasis for FDA approval ≥3 line
Olaparib 100mg bidOlaparib 400mg bid
Gelmon et al., Lancet Oncol, 2011
Efficacy Ovarian(n=64)
ORR in Planned Cohorts
BRCA 4/10 (40%)
Unknown BRCA 14/53 (26%)
ORR by Actual BRCA Status
Mutant BRCA 7/17 (41%)
Non-BRCA 11/46 (24%)
Median PFS 219 days
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Rucaparib: activity in BRCA mutated OvCabasis for FDA approval ≥2 line
Rucaparib 600mg bidBRCA mutationBRCAwt LOH highBRCAwt LOH low
Swisher et al., Lancet Oncol, 2017
Efficacy Ovarian(n=192)
PFS, median (months)BRCA mutation 12.8BRCAwt LOH highBRCAwt LOH low
5.75.2
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Olaparib+carboplatin: active in gBRCAm and BRCAwt HGSOC
ResponseOvCa
gBRCAmN (%), Duration
HGSOCN (%), Duration
Total(N=49)
CR 0 0 0
PR 15/34 (44%)12 mo [3-28+mo]
4/15 (27%)6 mo [3-8mo]
19/49 (39%)
SD>4mo 13/34 (38%)12 mo [4-25+mo]
7/15 (47%)8 mo [4-10.5mo]
20/49(41%)
Lee et al, JNCI, 2014Lee et al, Clin Ca Res 2016
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Olaparib+carboplatin: active in gBRCAm and BRCA wt HGSOC
ResponseOvCa
gBRCAmN (%), Duration
HGSOCN (%), Duration
Total(N=49)
CR 0 0 0
PR 15/34 (44%)12 mo [3-28+mo]
4/15 (27%)6 mo [3-8mo]
19/49 (39%)
SD>4mo 13/34 (38%)12 mo [4-25+mo]
7/15 (47%)8 mo [4-10.5mo]
20/49(41%)
Lee et al, JNCI, 2014
FOX03a R2=0.862p=0.0003
Log(2) normalized value
PFS,
mon
ths
pretx FOXO3a correlates with PFS
Pre-Treat Post-Treat0
200
400
600
800
Num
ber o
f Cel
ls E
xpre
ssin
g FO
XO3a
P < 0.0001
Pretx ~C1d22
#FOX
O3a+/5H
PF
Reduction in FOXO3a+ tumor nuclei with treatment
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Oza et al, Lancet Oncology, 2015
O/P/C P/CEvents: Total patients
(%) 47:81 (58.0) 55:81 (67.9)
Median (mos) 12.2 9.6Hazard ratio = 0.51 95% CI (0.34, 0.77)
P=0.0012
Time from randomization (months)0
PFS
prop
ortio
n
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
2 4 6 8 10 12 16 20
Olaparib + P + C (AUC4)
P + C (AUC6)
14 18
Olaparib adds benefit to carbo and paclitaxel in platinum-sensitive recurrent ovarian cancer
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HRD appears to be a reliable target in ovarian cancer, though validated predictive biomarker(s) beyond BRCAmutation are needed.
DNA-Repair inhibition: New opportunities are arising through the new classes of agents targeting drugs in the DNA repair/cell cycle pathways.
Expanding beyond the nucleus: leveraging the cellular and tumor microenvironment targeting agents
Lessons from PARPi in BRCA mutated OvCa
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An alternative DNA repair pathway target in HGSOC
DNA replication
stress
ATR
CHK1
CDC25C
CHK2
CDC25A
CDK1CyclinBCyclinA/E
DSBs
Cell Cycle
p21
p53
ATM ATRi
CHK1i
Oncogenic stress
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Prexasertib (LY2606368): a second generation Chk1/2 inhibitor
Tumor count Ascites fluid volume
• Potent ATP-competitive inhibitor of both Chk1/2• Single agent activity in ovarian cancer mouse model• Safety and activity in FIH study
McNeely et al. AACR-NCI-EORTC 2011Hong et al. JCO 2016
LY2606368 in SKOV3-Luc IP tumor
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A phase II single arm study of prexasertib (LY2606368)
Cohort 2HGSOC
BRCA wild typeNegative FHx
C1D1 C1D15 C2D1
tumor and uninvolved skin
PBMCs, CTCs for translational correlative studies
Cohort 1Germline BRCA
mutationOv ca
14-C-0156 Study Design
LY2606368 105 mg/m2 IV q 2 weeks…
Study objectivesPrimary: ORR (CR+PR) by RECISTv1.1 Secondary: Safety and tolerability, Progression-free intervalExploratory correlatives: Potential predictive and PD biomarkers
Optional 2nd and at progression bx
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BRCA mutant OvCa(n=7)
HGSOC(n=25)
Age; median (range)
58.5 (36-67) 62.6 (46.6-83)
ECOG PS (0/1/2) 1/6/0 4/19/2Recurrent OvCa Platinum-
Sensitive Resistant/refractory
Sensitive Resistant/refractory
# of patients 1 5/1 7 14/4# of prior lines oftherapy; median (range)
3 7 (3-12) 5 (1-6) 5 (1-13)
Prior PARPi Prior Bevacizumab
1Yes/0No1Yes/0No
6Yes/0No5Yes/1No
2Yes/5No4Yes/3No
4Yes/14No13Yes/5No
Baseline patient characteristics
Lee et al. ESMO 2016
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Prexasertib: single agent activity in BRCAwt HGSOC
gBRCAm OvCa(n=6 evaluable)
HGSOC(n=20 evaluable)
CR 0 0PR 0 7/20 (35%)
6mo (2+-13)SD≥4mo 4/6 (67%)
4mo (4-5)5/20 (25%)5mo (4-7+)
Response rate 0% 35%Disease control rate(CR+PR+SD≥4mo)
4/6 (67%) 12/20 (60%)
Lee et al. ESMO 2016
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-80
-60
-40
-20
0
20
40
60
80
100
120
Cha
nge
from
bas
elin
e in
sum
of l
onge
st d
iam
eter
s (%
)
+ +
+
+
+
+
++
HGSOC (n=20)gBRCAm OvCa (n=6)
White: platinum-sensitive diseaseGrey: platinum-resistant or refractory disease
Best response for target lesions by patient Prexasertib activity in platinum-resistant recurrent HGSOC
Lee et al. ESMO 2016
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68 yo F with platinum-resistant recurrent BRCAwt HGSOC with 13 prior tx regimens (PR, 6+mo)
Pretreatment PR: post-2 cycles
0
100
200
300
400
C1D1 C2D1 C3D1 C4D1 C5D1
CA125
Confirmed PR: post-3 cycles
Lee et al, manuscript in preparation
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CAOV3 OV90 PEO1 PEO40
20
40
60
80
100
120
Cel
l Via
bilit
y (%
)DMSOLY2606368 (5nM)Olaparib (5µM)LY + O
****
**
***
*** ******
Augmented cytotoxicity by combining PARPi with prexasertib in HGSOC cell lines
CAOV3 OV90 PEO1 PEO40
20
40
60
80
100
120
Cel
l Via
bilit
y (%
)
DMSOLY2606368 (5nM)Olaparib (5µM)LY + O
****
**
***
*** ******
CAOV3 OV90 PEO1 PEO40
20
40
60
80
100
120
Cel
l Via
bilit
y (%
)
DMSOLY2606368 (5nM)Olaparib (5µM)LY + O
****
**
***
*** ******
Brill and Lee et al, manuscript in preparation
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Rad51
DAPI
Merged
CAOV3
DMSO LY2606368 Olaparib LY + O
0
20
40
60
% o
f cel
ls w
ith ≥
5 R
AD
51 fo
ci
Rad51 Foci counting
***
**
**
- + - + - + - + - + - + - + - +- - + + - - + + - - + + - - + +
LY2606368Olaparib
CAOV3 OV90 PEO1 PEO4
* **
*
0
20
40
60
% o
f cel
ls w
ith ≥
5 R
AD
51 fo
ci
Rad51 Foci counting
***
**
**
- + - + - + - + - + - + - + - +- - + + - - + + - - + + - - + +
LY2606368Olaparib
CAOV3 OV90 PEO1 PEO4
* **
*
Chk inhibition reduces RAD51 foci formation
RAD51 foci by IF
Brill and Lee et al, manuscript in preparation
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Leveraging DNA repair pathwaysoptimizing therapeutic targets
McLornan, et al NEJM 2014
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Leveraging DNA repair pathways expanding beyond the nucleus
McLornan, et al NEJM 2014
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Olaparib and cediranib: Synergy between hypoxia and inhibition of DNA repair
Unpublished data, courtesy of AZEconomopoulou et al, Nat Med, 2009
Loss of H2AX diminishes proliferative drive in endothelial cells, only in hypoxic background, suggesting interaction between DNA repair and angiogenesis.
Vehicle3mg/kg cediranib 5d on/2d off100mg/kg olaparib qdCediranib 5/2 + olaparib qd
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Olaparib and cediranib Clinical synergy between hypoxia and DNA repair inhibition
Cediranib/olaparib
Olaparib
Olaparib Ced/OlapPFS events 28 19Median PFS 9.0 mo 17.7 mo
p=0.005, HR 0.42 (95% CI: 0.23-0.76)
0 5 10 15 20 250
2
4
6
Data 1
PFS
CE
C fo
ld c
hang
e
r=0.88, R2=0.7795%CI 0.55-0.97p<0.001
Circulating endothelial cells d3/d0
PFS, monthsC
EC, f
old
chan
ge
Liu et al, Lancet Oncol, 2015; Lee et al, Front Oncol 2015
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Subgroup BRCA Mutation Carrier BRCA Mutation Non-Carrier/Unknown
Treatment Olaparib Ced/Olap Olaparib Ced/Olap
PFS events 13 8 14 6
Median PFS 16.5 mo 20.2 mo 5.7 mo 17.7 mo
P-Value p=0.07 p=0.003
Hazard Ratio HR 2.24 (95% CI: 0.94-5.73) HR 3.89 (95% CI: 1.55-11.05)
gBRCAm BRCAwt/unknown
ArmA:olapArmB:olap/ced
ArmA:olapArmB:olap/ced
Marked activity in non-BRCA mutation carriers
Liu et al. Lancet Oncol. 2014
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Olaparib and Cediranib: Registration trials now open
Platinum-sensitive OvCaNRG GY-004 (PI: J Liu)
Platinum-refr/resistant OvCaNRG GY-005 (PI: J Lee)
PlatS HGSOCStratify by gBRCAm
R
Platinum-based SoC
Olaparib
Olaparib + Cediranib
PlatR HGSOC R
SoC
Olaparib
Olaparib + Cediranib
Cediranib
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Taking DNA repair inhibitors and VEGFR inhibitors to the next level: augmenting immunotherapy?
HYPOXIA iDNA repair
Increasing neoantigens through h DNA damageVEGF suppresses lymphocyte trafficking into tumor and
increases Treg proliferationPD-L1 upregulation in hypoxic condition
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Rationale for DNA repair inhibition + immune checkpoint blockade
Snyder et al, NEJM, 2014
discoverysetof
candidateepitopes,validated
Tcellactivationpeptideantigens
h likelihoodthatsomemutations
conserved
peptidesignaturepredicts
ipibenefit
\]
mutationh OSinipi-txpts peptidesignatureh OSinipi-txpts
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Neoantigens and potential response to immune checkpoint inhibition in human cancer
Schumacher et al. Science 2015
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Higher mutational loads correlate with clinical benefit in colon cancer with DNA repair deficiency
Le et al, NEJM 2015
Progression-FreeSurvival
MMR-deficient tumors
MMR-proficient tumors
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Le et al, NEJM 2015Nichols Fader et al, SGO 2016
Progression-Free Survival Endometrial cancer from this cohort
Pilot results: MSI endometrial cancer benefits from pembrolizumab
ORR: 56% (5/9)DCR (CR+PR+SD): 88.9% (8/9)
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Some monotherapy activity of PD-1/PD-L1 blockade in recurrent ovarian cancer
Hamanishi et al JCO 2015Disis et al ASCO 2016
Nivolumab single agent activity in recurrent platinum-resistant ovarian cancer
No correlation with tumor PD-L1 labeling
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Hypothesis
Increased DNA damage by PARP inhibition and/or reduced angiogenesis by VEGFR1-3 inhibition will result in greater neoantigen
expression, creating a more antigenic environment in which to stimulate the immune
microenvironment.
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Phase I study: Primary Objective: To determine the RP2D of durvalumab+olaparib (D+O) and durvalumab+cediranib (D+C) in women’s cancer.Secondary Objectives:• Doublet safety • RECIST response rate • Doublet PK and correlation
with safety• PD-L1 expression
Phase II study: Primary Objective: To determine the response rate (CR+PR) of the doublets in recurrent OvCa.
Secondary Objectives:• Toxicity between two
doublets• PFS• Correlative studies for
potential predictive biomarkers
Phase I/II D+O and D+C study in women’s cancer (15-C-0145)
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Phase I safety evaluationDose
Level
(DL)
D+O (N=12) D+C (N=14)O tablets
q12h
D
intravenous
N C tablets
q24h
D
intravenous
N
DL 1 200mg 10mg/kg
q2wk
3 20mg daily 10mg/kg
q2wk
4*
DL 2 300mg 10mg/kg
q2wk
3 30mg daily 10mg/kg
q2wk
4*
DL 3 300mg 1500mg q4wk
6 20mg 5 days on/2 days off**
1500mg q4wk 6
1 pt (DL1) withdrew consent on cycle 1, 1 pt (DL2) took C 20mg instead of 30mg for a week during cycle 1.
Lee et al. JCO 2017
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D+O: durable response in non-BRCA carriers
MONTHS
Lee et al. JCO 2017
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-100-80-60-40-20
0204060
0 2 4 6 8 10 12 14 16
Perc
ent C
hang
e in
Sum
of
Long
est D
iam
eter
s of
Ta
rget
Les
ions
Time since baseline measurement (months)
D+O DL 1DL 2DL 3Still on study
MONTHS
D+O: durable response in non-BRCA carriers
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Durvalumab+Olaparib: Recurrent HGSOC patient with BRCA wild type
Before Treatment On Treatment – 15+ months
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D+C: early clinical activity in women’s cancer
Datacut-offOct13,2016
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-80
-60
-40
-20
0
20
40
60
0 2 4 6 8 10
Perc
ent C
hang
e in
Sum
of
Long
est D
iam
eter
s of
Tar
get
Lesi
ons
Time since baseline measurement (months)
D+C DL 1DL 2DL 3Still on study
PR3/7OvCa,2/2CxCa,1/3EnCa
D+C: early clinical activity in women’s cancer
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Conclusions and future directionHow can we build on this progress?
• We now have a critical mass of information and DNA repair inhibitor(s) to address actionable ideas to improve quality and quantity of life for women with ovarian cancer.
• Predictive biomarkers are necessary to optimize treatment benefits and treatment outcome interpretation.
• Unanswered questions in mechanisms of clinical resistance in both BRCA mutated and BRCA-like ovarian cancer
• Optimal uses of DNA repair inhibitors in combination therapies
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Acknowledgments:
LeeLaboratoryTeamJayakumarNair,PhDEthanBrill,BSDana-AdrianaBotesteanu,BS
CollaboratorsGenitourinaryMalignanciesBranch,CCR/NCIWilliamDFigg,PharmDCodyPeer,PharmDTristanSissung,PhDMPHMolecularGeneticsBranch/CCR/NCILiangCao,PhDDevelopmentalTherapeuticsBranch/CCR/NCIJaneTrepel,Min-JungLee,PhDYvesPommier,MDPhD,JunkoMurai,MDPhDUniversityofWashingtonElizabethSwisher,MDTheJohnsHopkinsMedicalInstitutionAshleyCimino-Mathews,MDJanisTaube,MD
Women’sMalignanciesClinicWomen’sMalignanciesBranch,NCIStanleyLipkowitz,MDPhDChristinaAnnunziata,MDPhDEliseC.Kohn,MDLoriMinasian,MDAlexZimmer,MDMargaretGatti-Mays,MDSanazSoltani,MDAnaNunes,MDNicoleHouston,RNIreneEkwede,RNErinNichols,RNMireyaGomez,PCC
NCIReferralOffice;1-888-NCI-1937CynthiaBoyle,RN(240)760-6050,MireyaGomez,PCC(301)451-1304
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