Targeted therapies in ER+ metastatic breast cancer patients

Cancer du sein: best of 2016
Barbara Pistilli
Gustave Roussy Cancer Center
Paris, 3 Décembre 2016
Mon Plan
the best of 2016
EBC
ER +
HER2+
TN
MBC
Mon Plan
the best of 2016
EBC
ER +
HER2+
TN
MBC
Long-term recurrence risks after use
of endocrine therapy for only 5 years
Relevance of breast tumour characteristics
Hongchao Pan, Richard Gray, Christina Davies, Richard Peto,
Jonas Bergh, Kathleen I Pritchard, Mitch Dowsett, Daniel F Hayes,
for the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
Lowest-stage (T1N0) disease: Risk of ANY breast cancer event
21% risk, years 5-20 (14% DISTANT recurrence + 7% only local or contralateral)
Any breast cancer event
21%
T1N0
20
14%
%, CI
10
7%
ET for 5 years
0
0
5
10
15
20 years since diagnosis
Annual event rate (and no. of events), by 5-year time period
T1N0 (n=16K): 1.4% (807) 1.7% (309) 1.8% (54)
MA.17R Trial Design <br />AI x 5 yrs - Following Prior 5 years of AI - preceded or not by Tamoxifen
Presented By Paul Goss at 2016 ASCO Annual Meeting
Slide 15
Presented By Paul Goss at 2016 ASCO Annual Meeting
Slide 18
Presented By Paul Goss at 2016 ASCO Annual Meeting
Slide 16
Presented By Paul Goss at 2016 ASCO Annual Meeting
Slide 21
Presented By Paul Goss at 2016 ASCO Annual Meeting
Conclusion MA17R: extended AI
•
•
•
•
•
•
Population sélectionnée
Bénéfice de 4% en DFS, 0 en OS
Prévention secondaire essentiellement
Bénéfice sur risque de métastases: 1.1%
Rapport bénéfice-risque à évaluer
Option possible si cancer du sein agressif N+,
et rapport bénéfice-risque acceptable?
Metanalysis: TAM > 5y vs < 5y
Mon Plan
the best of 2016
EBC
ER +
HER2+
TN
• ET 10 yrs vs 5
(high risk)
MBC
Methods: TAILORx Design & Rationale for RS Cutpoints
Enrollment period: April 7 , 2006 to October 6 , 2010 (N=10,273 eligible)
Key Eligibility Criteria
•
•
•
•
•
Node-negative
ER-pos, HER2-neg
T1c-T2 (high-risk T1b)
Age 18-75 years
No PBI planned
Sparano J A , and Paik S JCO 2008;26:721-728
18
Mon Plan
EBC
ER +
HER2+
TN
• ET 10 yrs vs 5
(high risk)
• No CT in cH/gL
MBC
Cyclin D1–CDK 4-6 inhibitors: rationale
The CDK 4/6-Cyclin D1-E2F Pathway
MAPKs
(ER/PR/AR)
STATs
•
Wnt/b-catenin
PI3K/AKT
Cyclin D
NF-kB
CDK 4/6
p53
p21
p16
P
M
G1
G0
RB
RB
E2F
E2F
(Tumor suppressor)
G2
S
Evidence suggests that
– In AI resistance models, ER
drives a CDK 4/
E2F-dependent
transcriptional program
– CDK 4/6 inhibition reduces
cell proliferation in both ERdependent and ERindependent,
AI-resistant breast cancer
models
Gene transcription
20
Randomized trials testing CDK4 inhibitors
Treatment
setting
Pre
treatment
Palbo single agent
(Arnedos, AACR, 2016)
early
Letrozole +/palbociclib
(Finn, Lancet Oncol,
2015)
Letrozole +/palbociclib (Finn,
ASCO, 2016)
Letrozole +/- ribociclib
(Hortobagyi, NEJM,
2016)
Fulvestrant +/palbociclib
(Turner, NEJM, 2015)
phase
n
Effect on primary endpoint
none
Window of
opportunity
100
Post-tt lnKi67<1 : 58% vs 12%
(p<0.0001)
Endocrine
sensitive
1st line
Phase II
randomized
165
PFS: 20 versus 10 months
HR: 0.49 (0.32–0.75)
P: 0.0004
meta
Endocrine
sensitive
1st line
Phase III
randomized
666
PFS: 24 versus 14 months (HR=0.58)
meta
Endocrine
sensitive
1st line
Phase III
randomized
668
PFS: NR versus 14
0.556 (0.429–0.720)
Resistant to AI
Registration
trial
meta
meta
521
PFS: 9.2 versus 3.8 months
PFS: HR: 0.42 (0.32–0.56)
<0.001
Safety profile (Palbociclib, PALOMA3)
Turner N, NEJM, 2015
MONARCH 1: essai de phase II Abemaciclib
Évaluation de la réponse
Variation par rapport à
l’inclusion (%)
100
Réponse selon les investigateurs a
Abémaciclib 200 mg
(n = 132)
Taux de réponse objective (RC + RP)
19,7 %
50
Maladie stable > 6 mois
22,7 %
Taux de bénéfice clinique (taux de réponse objective +
maladie stable > 6 mois)
42,4 %
20
0
–30
–50
–100
Taux de contrôle (RC + RP + MS) = 67,4 %
Progression (n = 34)
Maladie stable (n = 63)
Réponse partielle (n = 26)
Non évalué (n = 9)
Durée médiane avant réponse
3,7 mois
Durée de réponse médiane
Taux de réponse à 6 mois
Taux de réponse à 12 mois
8,6 mois
70,4 %
28,2 %
SSP médiane
SG médiane
aLes
13,3-27,5
0%
19,7 %
IC95
Réponse complète
Réponse partielle
6,0 mois
(IC95 : 4,2-7,5)
17,7 mois
(IC95 : 16,0-NA)
évaluations selon la revue indépendante étaient comparables
ASCO® 2016 - D’après Dickler MN et al., abstr. 510, actualisé
ER+ Her2- MBC: current trts
 7000 pts/year in France
AI sensitive
AI-resistant
AI + palbociclib
PFS1
24 months
(USA, ong EU)
nsAI +
everolimus
PFS2
Fulvestrant +
Palbo
Visceral crisis /
early relapse
Fulvestrant +
Fulvestrant
palbociclib
9-10 months
nsAI +
PFS3everolimus
?months
chemo
OS 36 months
Quels sont les biomarquers predictifs de la
réponse au CDK4/6 inh ?
CCND1 amplification
P16 loss
Cell signaling
(not validated in Finn et al)
Cyclin D1 expression
Cyclin D
CDK 4
p53
p21
p16
P
M
G1
G0
RB
RB
E2F
E2F
(Tumor suppressor)
G2
S
Gene transcription
Loss of Rb
25
Predictive biomarkers: POP study
Biomarker
Interaction test
Rb
0.641
pRB
0.856
p16
0.218
pAKT (Ser473)
0.484
pER
0.856
CCND1 at baseline
Control
N = 26
Palbociclib
N = 74
Non-Amplified
16 (67)
53 (73)
Amplified
8 (33)
20 (27)
Interaction test p=0.388
Arnedos, AACR, 2016
Predictive biomarkers: POP study
PIK3CA
lnKi67<1 surgery
lnKi67<1 surgery
NonMutated
Mutated
Missing
Contro Palboci
l
clib
N = 23 N = 61
17 (81) 32 (58)
4 (19)
2
HR+/HER2- tumors
23 (42)
6
PIK3CA mutation was not
significantly associated
with lnKi67<1 (Interaction
test p=0.478)
Only 2 AKT1
mutations found
PIK3CA mutations and CDK4/6 inh
Paloma 3 PIK3CA mutations + 33%
Turner Lancet Oncol 2016
Mon Plan
EBC
ER +
HER2+
TN
• ET 10 yrs vs 5
(high risk)
• No CT in cH/gL
MBC
•
CDK4/6 inh
ESR1 mutations and resistance to endocrine therapy
Mutatitons activatrices ont été
identifiées dans les 11-55%
des cancer du sein
métastatique
RE+ résistants à l’HT
Plus particulièrement chez les
patientes traitées par IAs
Toy, Nature Genetics
SoFEA Trial: fulvestrant +/– exemestane vs
exemestane in HR+ AI-resistant ABC patients
ESR1wt
100
Fulvestrant
Median PFS, 5.7 months
(95% CI, 3.0-8.5)
75
Exemestane
Median PFS, 2.6 months
(95% CI, 2.4-6.2)
Progression-Free Survival, %
ESR1 mutation
in 39% patients
Progression-Free Survival, %
ESR1-mutated
50
25
100
Fulvestrant
Median PFS, 8.0 months
(95% CI, 3.0-11.5)
75
Exemestane
Median PFS, 5.4 months
(95% CI, 3.7-8.1)
50
25
HR = 1.07 (95% CI, 0.68-1.67); P = 0.77
HR = 0.52 (95% CI, 0.30-0.92); P = 0.02
0
0
6
12
18
24
Time From Random Assignment, months
No. at risk (events)
6
12
18
24
Time From Random Assignment, months
No. at risk (events)
Exemestane
18
(12)
6
(4)
2
(2)
0
(0)
0
Exemestane
39
(18)
21
(9)
12
(5)
5
(0)
3
Fulvestrant-containing
45
(23)
22
(10)
12
(5)
6
(5)
1
Fulvestrant-containing
59
(31)
27
(7)
19
(8)
8
(2)
5
Reprinted from Fribbens C, et al. J Clin Oncol. 2016;34:2961-2968.
31
ER degraders: preclinical activity
Weir et al, Cancer Res 2016
Mon Plan
EBC
ER +
HER2+
TN
• ET 10 yrs vs 5
(high risk)
• No CT in cH/gL
MBC
•
•
CDK4/6 inh
ER degraders for ESR1
mut ?
Mon Plan
EBC
ER +
HER2+
TN
• ET 10 yrs vs 5
(high risk)
• No CT in cH/gL
MBC
•
•
CDK4/6 inh
ER degraders for ESR1
mut?
Neratinib as Extended Adjuvant
Therapy:
The ExteNET Trial
• HER2+ breast
cancer
• Prior adjuvant
trastuzumab/
chemotherapy
• LN+/- or residual
invasive disease
after neoadjuvant rx
• ER/PR +/-
R
neratinib x 1
year
240 mg/d
placebo x 1
year
N=2840
24% node negative, 47% 1-3+ nodes; 57% HR+
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•
Summary of changes:
3 sponsors from 2009 to 2011
• Study population decreased
from 3850 to 2840
2nd sponsor:
• Change to stage 2-3; LN+
and <1 year from
trastuzumab, endpoint iDFS
3rd sponsor:
• FU truncated to 2 years for
all patients
Now extended to 5 years
Primary endpoint: Invasive DFS (iDFS)
Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS metastases, OS, safety
Other: Biomarkers, QOL
Stratification: Nodes 0, 1-3+, vs 4+, ER/PR status, concurrent vs sequential trastuzumab
Median time from trastuzumab N vs P: 4.4 (0.2-30.9) vs 4.6 (0.3-40.6) months
Chan A, et al. Lancet Oncol. 2016;17(3):367-377
Primary Endpoint: Invasive DFS
(ITT)
97.8%
100
93.9%
95.6%
Disease-free survival (%)
90
91.6%
2.3%
80
Hormone receptor-positive tumors
(n=1631; HR=0.51, 95% CI 0.33–0.77;
P = .001)
70
P-value = 0.009
HR (95% CI) = 0.67 (0.50–0.91)
60
50
0
0
3
Neratinibtumors
Hormone receptor-negative
Placebo
(n=1209; HR=0.93, 95% CI 0.60–1.43;
P =6 .735)
15
9
12
18
21
24
2.3% absolute
difference
2.5%
3 year difference
in centrally
confirmed
HER2+ disease
Safety
95% diarrhea
39.9% grade 3/4
Months after randomization
No. at risk
Neratinib 1420
Placebo 1420
1291
1367
1260
1324
1229
1292
1189
1243
1150
1209
1108
1163
1033
1090
662
704
Diarrhea prophylaxis
Intensive loperamide prophylaxis reduced grade 3 diarrhea to 17% in one study
Ongoing studies evaluating this effect
Chan A, et al. Lancet Oncol. 2016;17(3):367-377
3-year iDFS Analysis:
Hormone receptor-positive & centrally confirmed HER2+
98.1%
100
96.1%
94.4%
92.8%
94.7%
90
Disease-free survival (%)
89.9%
86.3%
88.0%
Absolute
difference:
6.5%
80
70
Two-sided *P-value <0.001
HR (95% CI) = 0.43 (0.26–0.70)
60
Neratinib
Placebo
50
0
0
6
12
18
24
30
36
42
48
252
262
237
245
200
205
Months after randomization
No. at risk
Neratinib
Placebo
455
448
426
426
410
406
398
385
342
336
258
275
Chan A, et al. Cancer Res. 2016;76(4 Suppl):Abstract S5-02.
Increases to 7.7%
in HR+, completing
adjuvant
trastuzumab < one
year before study
* p value descriptive
Mon Plan
EBC
ER +
• ET 10 yrs vs 5
(high risk)
• No CT in cH/gL
HER2+
• Extended adjuvant
NERATINIB ?
TN
MBC
•
•
CDK4/6 inh
ER degraders for ESR1
mut
Mon Plan
EBC
ER +
• ET 10 yrs vs 5
(high risk)
• No CT in cH/gL
HER2+
• Extended adjuvant
NERATINIB ?
TN
MBC
•
•
CDK4/6 inh
ER degraders for ESR1
mut
Anti PD-1 : Pembrolizumab
Essai KEYNOTE-012
•
TN
•
M+/Localement
avancées
PS 0 ou 1
> 1 lésion mesurable
Pas de M+ cérébrales
actives
•
•
•
•
PD-L1+
Pembrolizumab
10 mg/kg i.v.
toutes les 2 sem.
Réponse complète
ou partielle
ou maladie stable
Traitement
de 24 mois ou
jusqu’à progression
ou toxicité
Maladie progressive
confirmée ou
toxicité inacceptable
Arrêt du
pembrolizumab
Évaluation
de la réponse /8 semaines
*PD-L1+ = > 1% des cellules (tumorales ou stromales) sur tissu archivé ;
58% des patientes screenées étaient PD-L1 positives
Nanda R et al. J Clin Oncol 2016;20:2460-7.
Nanda et al. SABCS 2014; Abs S1-09.
Anti PD-1 : Pembrolizumab
n =32
Confirmed complete response
Confirmed partial response
Stable disease
Progressive disease
Taux de réponse objective : 18,5% - (1RC – 4 RP)
Stabilité : 25,9% (7 SD)
Nanda R et al. J Clin Oncol 2016;20:2460-7.
Nanda et al. SABCS 2014; Abs S1-09.
Anti PD-1 : Pembrolizumab
Confirmed complete response
Confirmed partial response
Stable disease
Progressive disease
n =32
Taux de réponse objective : 18.5% - (1RC – 4
RP)
Stabilité : 25,9% (7 SD)
Change from baseline,
%
Réponse
durable
10
80
0
60
40
20
0
-20
-40
-60
-80
-100
On treatment
Discontinued treatment
0
Nanda R et al. J Clin Oncol 2016;20:2460-7.
Nanda et al. SABCS 2014; Abs S1-09.
8
16
24
32
Time (weeks)
40
48
56
Anti PDL-1 : Atezolizumab + Nabpaclitaxel
Phase Ib
Sécurité
et tolérance
•
•
•
•
•
TN
< 2 lignes de chimiothérapie
Maladie mesurable
PS 0-1
Non sélectionné sur
l’expression
de PD-L1
Nab-paclitaxel
125 mg/m2 QW 3/4
+
Atezolizumab
800mg Q2W
BOR
par RECIST 1.1
PK
Adams S et al. SABCS 2015; Abs 850477.
Anti PDL-1 : Atezolizumab + Nabpaclitaxel
PDL1(n = 7)
PDL1+
(n = 9)
Unknown
(n = 8)
57.1%
(18.4, 90.1)
77.8%
(40.0, 97.2)
75%
(34.9, 96.8)
CR
0
0
12.5%
PR
57.1%
77.8%
62.5%
SD
42.9%
22.2%
0
PD
0
0
25%
ORR
(IC 95%)
Adams S et al. SABCS 2015; Abs 850477.
Anti PDL-1 : Atezolizumab + Nabpaclitaxel
Etude IMpassion130 (NCT02425891) : Phase III, 1ère ligne, TN
•
•
TN
1ère ligne
•
PS 0-1
•
Maladie Mesurable
RECIST v1.1
•
•
M+ cérébrale stable
Effectif: ~350 pts
Stratification:
•
•
•
Nab-paclitaxel
100 mg/m2 QW 3/4
+
Atezolizumab
840 mg Q2W
M+ hépatique
Traitement antérieur par taxane
Statut PD-L1 (centralisé par IHC)
R
1:1
Nab-paclitaxel
100 mg/m2 QW 3/4
+
Placebo Q2W
Objectifs primaires:
• SSP
• SSP en fonction du statut
PD-L1
Objectifs secondaires:
• SG
• TRG
• Durée réponse
• Tolérance
• PK
• Qualité de vie
Conclusions
EBC
ER +
MBC
• ET 10 yrs vs 5
(high risk)
• No CT in cH/gL
•
•
CDK4/6 inh
ER degraders for ESR1
mut
we are making
progress
HER2+
TN
• Extended adjuvant when escalate
NERATINIB ?
and de-escalate?
Immunotherapie
?
new
strategies
are urgently
required