La Malattia Metastatica 2 Parte ‘Immunoterapia nel ... · Loi S et al, JCO 2013 Luen S et al,...
Transcript of La Malattia Metastatica 2 Parte ‘Immunoterapia nel ... · Loi S et al, JCO 2013 Luen S et al,...
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Luisa Carbognin 1University of Verona, Verona, Italy
2Division of Gynecologic Oncology, Department of Woman and Child Health,
Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
La Malattia Metastatica – 2° Parte
‘Immunoterapia nel carcinoma
metastatico Triplo Negativo’
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• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)
• Single Agent anti-PD1/PD-L1Trials Biomarkers from single agent anti- PD1/PD-L1
• Combination Strategies Chemotherapy
PARP inhibitors
• Conclusion and Future Directions
Outline
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TNBC ER+ (Luminal A)
Mutation rate higher in basal-like and HER2-enriched subtypes compared to other subtypes
Are all cancers equally suitable for immunotherapy?
ER+ (Luminal B)
Banerji S et al, Nature 2012
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TILs expression and Mutational Load according to BC subtypes
Higher TILs rates in TNBC Higher Mutational Load in TNBC
Loi S et al, JCO 2013 Luen S et al, Breast 2016
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TILs expression as a prognostic marker
Higher TILs rates ad better OS: TIL effect is linear
OS
HR 0.84 0.77-0.92
Loi S et al, SABCS 2015
Loi S et al, JCO 2013; Loi S et al, AO 2014
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• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)
• Single Agent anti-PD1/PD-L1Trials Biomarkers from single agent anti- PD1/PD-L1
• Combination Strategies Chemotherapy
PARP inhibitors
• Conclusion and Future Directions
Outline
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Phase I and II studies in advanced TNBC
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Phase I studies
• PD-L1 +
• mDOR n.r.
• mPFS 1.9 months
• mOS 11.2 months
• PD-L1 +/-
• mDOR 21 (1L) and 19 months (2L+)
• mPFS 1.4 months
• mOS 8.9 months
Nanda R et al, J Clin Oncol 2016 Emens LA et al, Jama Oncol 2018
ORR%
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OS according to response and treatment line (ATEZO)
Emens LA et al, Jama Oncol 2018; Schmid et al, AACR 2017
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Phase I and II studies in advanced TNBC
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JAVELIN Study
• Phase I
• Avelumab as single agent
• n=168 MBC pts
• PD-L1 +/-
• 1L-4L
• ORR 3% in overall population
• 58 TNBC pts
• 62% PD-L1 + (≥1% IC)
• ORR 5.2%
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Phase I and II studies in advanced TNBC
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KEYNOTE-086 study
Adams S et al, ASCO 2017; Adams S et al, AACR 2018
*
• Phase II
• 254 TNBC pts
• mOS 16.1 months (Cohort B)
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• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)
• Single Agent anti-PD1/PD-L1Trials Biomarkers from single agent anti-PD1/PD-L1
• Combination Strategies Chemotherapy
PARP inhibitors
• Conclusion and Future Directions
Outline
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19%
9%
TIL high1
Ob
jec
tive
Res
po
ns
e R
ate
(%
)
10%
20%
30%
0%
6.4%
1.9%
Pembrolizumab (Cohort A)
Atezolizumab
TIL low
39.1%
8.7%
TIL low TIL high
Pembrolizumab (Cohort B)
4%
1 ≥ IC 10%; 2</≥ Median (5% in Cohort A and 17.5% in Cohort B)
TIL high2
TIL low
TILs and Response to single agent therapy
Emens LA et al, Jama Oncol 2018; Adams S et al, ASCO 2017; Loi S et al, ESMO 2017
TIL positive patients present higher response rate
KEYNOTE-086 study
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OS according to PD-L1 and TILs (ATEZO)
Emens LA et al, Jama Oncol 2018
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12%
0%
PDL1- PDL1+*
Ob
jec
tive
Re
sp
on
se
Ra
te (
%)
10%
20%
30%
0%
5.7% 4.7%
Pembrolizumab (Cohort A)
Atezolizumab
*PD-L1+: baseline PD-L1 expression on ICs ≥ 1%
PDL1- PDL1+
Emens LA et al, Jama Oncol 2018; Adams S et al, ASCO 2017; Loi S et al, ESMO 2017
PD-L1 expression & Response to single
agent therapy
PD-L1 expression not good predictive of response
#PD-L1+: baseline combined positive score [PD-L1 expression on ICs or TCs ≥ 1%]
#
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13%
18%
TMBlow TMBhigh
OR
R R
ate
(%
)
10%
20%
0%
8%
15%
BCRA- BRCA+
18%
13%
LOHlow LOHhigh
0 20 40 60 800
5
10
15
20
TILs (% tumor area)
TM
B (M
ut/M
b)
TMB vs TILs
r = 0.13
p = 0.24TMBHigh
TMBLow
<14% ≥14%0
10
20
30
40
50
Genomic Loss
of Hetezygosity
TIL
s (%
tu
mo
r a
rea
)
LOH and TILsns
0 5 10 150
5
10
15
20
TMB vs CD8
CD8 (% tumor center)
TM
B (M
ut/M
b)
r = 0.10
p = 0.38TMBHigh
TMBLow
<14% ≥14%0
2
4
6
8
10
Genomic Loss
of Hetezygosity
CD
8
(% o
f T
um
or
Ce
nte
r)
LOH and CD8
0 10 20 30 40 500
5
10
15
20
PDL1 IC (% tumor area)
TM
B (M
ut/M
b)
TMB vs PDL1 IC
r = 0.13
p = 0.24TMBHigh
TMBLow
<14% ≥14%0
10
20
30
40
50
Genomic Loss
of Hetezygosity
PD
-L1
IC (%
tu
mo
r a
rea
)
LOH and PDL1 ICns
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
0
5
10
15
20
TMB (Mutations/Megabase)
Fre
qu
en
cy
(%
)Distribution of Mutations/Megabase
0 20 40 60 800
5
10
15
20
TILs (% tumor area)
TM
B (M
ut/M
b)
TMB vs TILs
r = 0.13
p = 0.24TMBHigh
TMBLow
<14% ≥14%0
10
20
30
40
50
Genomic Loss
of Hetezygosity
TIL
s (%
tu
mo
r a
rea
)
LOH and TILsns
0 5 10 150
5
10
15
20
TMB vs CD8
CD8 (% tumor center)
TM
B (M
ut/M
b)
r = 0.10
p = 0.38TMBHigh
TMBLow
<14% ≥14%0
2
4
6
8
10
Genomic Loss
of Hetezygosity
CD
8
(% o
f T
um
or
Ce
nte
r)
LOH and CD8
0 10 20 30 40 500
5
10
15
20
PDL1 IC (% tumor area)
TM
B (M
ut/M
b)
TMB vs PDL1 IC
r = 0.13
p = 0.24TMBHigh
TMBLow
<14% ≥14%0
10
20
30
40
50
Genomic Loss
of Hetezygosity
PD
-L1
IC (%
tu
mo
r a
rea
)
LOH and PDL1 ICns
TILs PDL1
Molinero L et al, SABCS 2017
Mutational load & Response to Atezolizumab
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• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)
• Single Agent anti-PD1/PD-L1Trials Biomarkers from single agent anti- PD1/PD-L1
• Combination Strategies Chemotherapy
PARP inhibitors
• Conclusion and Future Directions
Outline
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Chemotherapy as a trigger for immune activation
Modified from Curigliano G, ESMO 2018
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Modified from Curigliano G, ESMO 2018
Chemotherapy and Immune System
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Phase Ib, n=33
PD-L1 +/-
mFU 21.4 months
50% PD-L1 +
ORR 39%
mPFS 5.5 months
mOS 14.7 months
Nab-paclitaxel plus Atezolizumab
Pohlmann PR et al, AACR 2018; Adams J et al, JAMA Oncol 2018
OS
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Eribulin plus Pembrolizumab
(ENHANCE study)
Phase Ib/II, n=107
PD-L1 +/-
ORR 26%
• ORR 1L 29.2%
• ORR 2L+ 22%
mPFS 4.2 months
mOS 17.7 months
Tolaney S et al, SABCS 2017
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TONIC Trial
ORR
Phase II, n=66 Max 3 lines for MBC; 23% 1L 85% prior anthracyclines (operable); 58% prior platinum (metastatic) Induction Nivolumab The doxorubicin cohort as an «immune induction» will be expanded in the stage II of the trial.
Kok M et al, ASCO 2018
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IMpassion130 study design
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Statistical design
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Baseline characteristics
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PFS Analysis
Schmid P et al, ESMO 2018
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OS Analysis
Schmid P et al, ESMO 2018
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Secondary Efficacy Endpoints
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Toxicity
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PFS subgroup analysis: ITT population
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• First Phase III trial demonstrated a benefit with first-line immunotherapy in advanced TNBC • Atezolizumab + Nab-paclitaxel resulted in statistically significant
PFS benefit in ITT (HR=0.80) and PD-L1+ population (HR=0.62)
• At the first interim analysis, OS improvement in PD-L1+ population (mOS 15.5 vs 25.0 months)
• No detrimental effect in PD-L1 negative sub-groups
• The combination was well tolerated
Open Question
• Nab-paclitaxel is the optimal chemo backbone? • Dose of Nab-paclitaxel?
• Formal OS testing in PD-L1+ pts not permitted according to study design
• Duration of atezolizumab (longer=better?)
• Role of Atezolizumab alone?
• BRCA status?
IMpassion130 Conclusions
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• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)
• Single Agent anti-PD1/PD-L1Trials Biomarkers from single agent anti- PD1/PD-L1
• Combination Strategies Chemotherapy
PARP inhibitors
• Conclusion and Future Directions
Outline
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Rationale for Parp + Checkpoint Inhibitors
Rationale for combining PARP inhibitors and immune checkpoint inhibitors
Jiao et al, Clin Cancer Res 2017
Accumulating DNA damage has the potential to modify tumor immunogenicity
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Phase II Basket study gBRCAmut HER2 neg MBC (n=25)
MEDIOLA study
Domcheck et al, SABCS 2017
12/25 (48%) DCR at 7 months Median DOR/PFS/OS not yet reached Response independent of HR status and BRCA mutation type
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TOPACIO: Niraparib + Pembrolizumab (n=46)
Presented By Kevin Kalinsky at 2018 ASCO Annual Meeting
ORR: 28% all; 60% tBRCAmut, 36% PD-L1+
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• Rational for Immunotherapy in advanced Triple Negative Breast Cancer (TNBC)
• Single Agent anti-PD1/PD-L1Trials Biomarkers from single agent anti- PD1/PD-L1
• Combination Strategies Chemotherapy
PARP inhibitors
• Conclusion and Future Directions
Outline
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Single-agent anti-PD-L1/PD1
• Durable response
• Better response in earlier lines of therapy
• Well tolerated
• Biomarkers not good predictive of response
Combination of CT and anti-PD-L1/PD1
• First promising results from combination IO + CT for 1st line PD-L1+ advanced TNBC (IMpassion130 study)
• Well tolerated
• Ongoing phase III in metastatic, neoadjuvant and adjuvant studies
Combination of PARPi and anti-PD-L1/PD1
• Further evaluation (small cohort with heterogenous population) and maturity of data in BRCAmut HER2- are needed
Conclusions-1
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Biomarkers:
• Optimize patients selection
• Higher evidence for TILs than PD-L1 status as a predictive biomarker of response
• Advanced TNBC presents ‘low’ TILs levels
• Need to increase host anti-tumor immunity
• How to define and best to test PD-L1 positive population?
• Mutational load is not predictive of response
• MSI? MSI-H less than 2%
• Gut microbiome? Ongoing studies in BC
Conclusions-2
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Title of the slide
Thank you for your attention