Transcript μεταστατικος ορμονοευαισθητος καρκινος μαστου νεοτερα δεδομενα

Βασικές αρχές ορμονοθεραπείας
• Κάθε ασθενής με ορμονοευαίσθητο καρκίνο
μαστού δικαιούται να ξεκινήσει με ορμονικό
χειρισμό εκτος και αν πάσχει από επιθετική
παρεγχυματική νόσο (VISCERAL CRISIS)
• Κλινικοί παράγοντες ορμονοευαισθησίας μεγάλο
DFS, μεταστάσεις σε λεμφαδένες ή οστά, υψηλά
επίπεδα έκφρασης ER ή και PR, εμφάνιση
αντίδρασης flare μετα τη θεραπεία
• Παράγοντες αντοχής στην ορμονοθεραπεία :
υπερέκφραση (HER2)
• SERMS (Selective Estrogen Receptor Modulators)
• ΤΑΜΟΞΙΦΑΙΝΗ, ΤΟΡΕΜΙΦΑΙΝΗ
• Aromatase inhibitors — decrease circulating levels of
estrogen by blocking the action of the enzyme
aromatase, which converts androgens into estrogens.
• ΑΝΑΣΤΡΑΖΟΛΗ, ΛΕΤΡΟΖΟΛΗ, ΕΞΕΜΕΣΤΑΝΗ
• FULVESTRANT - blocks ER dimerization and promotes
ER degradation
Αναστολείς αρωματάσης vs
ταμοξιφαίνη
Μετα-ανάλυση
1. Υπεροχή σε συνολική επιβίωση (relative
hazard 0.89, 95% CI 0.80-0.99) για τους
αναστολείς αρωματάσης τρίτης γενεάς σε
θεραπεία πρώτης γραμμής
2. Υπεροχή σε συνολική επιβίωση έναντι
προγεστερόνης σαν θεραπεία 2ης και 3ης
γραμμής (relative hazard 0.86, 95% CI 0.790.94)
• ΘΕΡΑΠΕΙΑ ΠΡΩΤΗΣ ΓΡΑΜΜΗΣ
• ΘΕΡΑΠΕΊΑ ΔΕΥΤΕΡΗΣ ΓΡΑΜΜΗΣ
• San Antonio Breast Cancer Conference 2010,2011
• ECCO/ESMO 2011
• ASCO 2011
• ΜΕΛΕΤΗ TANDEM (anastrozole + herceptin vs
anastrozole
• Lapatinib + letrozole vs letrozole
Αποτέλεσμα: διπλασιασμος του PFS και στις δύο
μελέτες
Για γυναίκες (HER2) + ορμονοευαίσθητη νόσο
προτείνεται αντι HER 2 θεραπεία (Grade 1A).
• ΘΕΡΑΠΕΙΑ ΠΡΩΤΗΣ ΓΡΑΜΜΗΣ
FIRST: Study Design
• Randomized, open-label phase II trial
– Primary endpoint: CBR, defined as CR, PR, or SD for
≥ 24 wks
Postmenopausal
women with
previously untreated
hormone receptor–
positive advanced
breast cancer
(N = 205)
Fulvestrant 500 mg by IM injection on
Days 0, 14, 28, and every 28 days thereafter
(n = 102)
Anastrozole 1 mg/day PO
(n = 103)
Robertson JFR, et al. SABCS 2010. Abstract S1-3.
Until disease
progression or
other event
requiring
discontinuation
FIRST: Comparable Clinical Benefit
Rate Observed in Primary Analysis
Outcome Fulvestrant
(n = 102)
Clinical
benefit
rate, %
72.5
Anastrozole
(n = 103)
OR
(95% CI)
P
Value
67.0
1.30
(0.72-2.38)
.386
Robertson JF, et al. J Clin Oncol. 2009;27:4530-4535.
Absolute
Difference, %
(95% CI)
5.6
(-7.8 to 15.8)
Parameter
Patients progressing, n (%)
Median TTP, mos
HR (95% CI)
Robertson JFR, et al. SABCS 2010. Abstract S1-3.
Fulvestrant
(n = 102)
Anastrozole
(n = 103)
63 (61.8)
79 (76.7)
23.4
13.1
0.66 (0.47-0.92); P = .01
FIRST: No Difference in Response
to Subsequent Endocrine Therapy
Patients Receiving Subsequent
Endocrine Therapy, %
Fulvestrant
(n = 34)
Anastrozole
(n = 50)
Achieved CR/PR
8.8
14.0
Achieved clinical benefit
41.2
42.0
Robertson JFR, et al. SABCS 2010. Abstract S1-3.
SWOG S0226: Study Design
• Primary endpoint: PFS
• Secondary endpoints: OS, Safety
Stratified by previous adjuvant
tamoxifen
Postmenopausal women
with hormone receptor–
positive MBC
Treatment until disease progression
Anastrozole 1 mg/day PO +
Fulvestrant 500 mg on Day 1,
250 mg on Days 14 and 28,
250 mg every 28 days thereafter
(n = 355)
(N = 707)
Mehta RS, et al. SABCS 2011. Abstract S1-1.
Anastrozole 1 mg/day PO
(n = 352)
Women with
progression
encouraged to cross
over to receive
fulvestrant
SWOG S0226: PFS and OS Overall
and by Previous Adjuvant Tamoxifen
Anastrozole +
Fulvestrant
Anastrozole
HR (95% CI)
P Value
15.0
13.5
0.80
(0.68-0.94)
.007
 No previous adjuvant
tamoxifen (n = 414)
17.0
12.6
0.74
(0.59-0.92)
.0055
 Previous adjuvant
tamoxifen (n = 280)
13.5
14.1
0.89
(0.69-1.15)
.37
47.7
41.3
0.81
(0.65-1.00)
.049
 No previous adjuvant
tamoxifen (n = 414)
47.7
39.7
0.74
(0.56-0.98)
.0362
 Previous adjuvant
tamoxifen (n = 280)
49.6
44.5
0.91
(0.65-1.28)
.59
Endpoint
Median PFS (n = 694),
mos
Median OS (n = 694),
mos
Mehta RS, et al. SABCS 2011. Abstract S1-1.
SWOG S0226: Unplanned Subset
Analysis of PFS
Overall HR: 0.80
Age 65+ yrs
Age < 65 yrs
HER2 positive
HER2 negative
Nonvisceral
Visceral
Bone only
Nonmeasureable
Measureable
10 yrs+
5-10 yrs
0-5 yrs
De novo
No previous chemo
Previous chemo
No previous tam
Previous tam
Overall
Combination better
0.4
0.6
Mehta RS, et al. SABCS 2011. Abstract S1-1.
0.8
Combination worse
1.0
HR
1.2
1.4
1.6
SWOG S0226: συμπεράσματα
• Σε μετεμμηνοπαυσιακές γυναίκες η θεραπεία 1ης
γραμμής με το συνδ. Anastrozole + fulvestrant αύξησε
σημαντικά το PFS και OS έναντι της μονοθεραπείας με
anastrozole
– Ανάλυση υποπληθ. Έδειξε πιθανό όφελος στην ομάδα που
δεν είχε πάρει adj. tamoxifen
• Παρενέργεις ίδιες και στις 2 ομάδες
• S0226 efficacy findings differ from those of FACT
study, which demonstrated a similar median TTP and
OS with anastrozole plus fulvestrant vs anastrozole
alone (2)
1. Mehta RS, et al. SABCS 2011. Abstract S1-1.
2. Bergh J, et al. SABCS 2009. Abstract 23
• ΘΕΡΑΠΕΙΑ ΔΕΥΤΕΡΗΣ ΓΡΑΜΜΗΣ
(ΠΡΟΗΓΟΥΜΕΝΗ ΕΚΘΕΣΗ ΣΕ ΑΝΑΣΤΟΛΕΙΣ
ΑΡΩΜΑΤΑΣΗΣ ΣΑΝ 1Η ΓΡΑΜΜΗ)
ΘΕΡΑΠΕΙΑ ΔΕΥΤΕΡΗΣ ΓΡΑΜΜΗΣ
CALGB 40302: Study Design
• Randomized, double-blind, placebo-controlled phase III trial
– Primary endpoint: PFS
Stratified by previous tamoxifen treatment and
presence of bone disease
Postmenopausal women
with hormone receptor–
positive advanced breast
cancer with previous AI
exposure
Lapatinib* 1500 mg PO QD on Days 1-28 +
Fulvestrant†
(n = 133)
(N = 267)
Placebo on Days 1-28 +
Fulvestrant†
(n = 134)
*Lapatinib dose adjustment for toxicity permitted.
†Fulvestrant administered by IM injection at 500 mg on Day 1, 250 mg on Days 15 and 28, and 250 mg
every 28 days thereafter.
Burstein HJ, et al. SABCS 2010. Abstract PD-05-01.
Endpoint, Mos
Lapatinib +
Fulvestrant
Placebo +
Fulvestrant
Log Rank P Value
Median PFS
5.2
4.0
.94
Median OS
22.3
21.9
.64
Burstein HJ, et al. SABCS 2010. Abstract PD-05-01.
Grade 3 Adverse
Events, %
Lapatinib + Fulvestrant
(n = 133)
Placebo + Fulvestrant
(n = 134)
Any
22
0
Diarrhea
9
0
Fatigue
4
0
Acneiform rash
4
0
Transaminitis
3
0
Dyspnea
2
0
Burstein HJ, et al. SABCS 2010. Abstract PD-05-01.
• Randomized, controlled phase II trial
– Primary endpoint: CBR at 6 mos (CR + PR + SD)
Stratified by primary vs secondary
hormone resistance*
Patients with HER2negative, hormone
receptor–positive
metastatic breast
cancer with previous
AI exposure
(N = 111)
Everolimus 10 mg/day +
Tamoxifen 20 mg/day
(n = 54)
Tamoxifen 20 mg/day
(n = 57)
*Primary resistance: relapse during adjuvant AI therapy or progression during first 6 mos of initiating AI
for metastatic disease. Secondary resistance: late relapse (at or after 6 mos) or previous response to AI
therapy for metastatic breast cancer and subsequent progression.
Bachelot T, et al. SABCS 2010. Abstract S1-6.
22
Strong Evidence Links Hormone Resistance to Cross-Talk Between
Signal Transduction Pathways and ER Signaling
IGF-1R, EGFR
ER
PI3K
E ER
AKT
RAS
RAF
TSC2TSC1
MEK
mTOR
mTOR
ERK
E ER
Cell proliferation
22
Yue W. J Steroid Biochem Mol Biol. 2007; 106:102-110.
Everolimus (RAD001)
• Απο του στόματος ισχυρός αναστολέας του
mammalian target of rapamycin (mTOR)
– Έχει έγκριση για renal cell carcinoma
• Έχεί δείξει δραστηριότητα σε in vitro μοντέλα
ορμονοαντοχής1
• Έχει δείξει δράση σε πρώιμε κλινικές
δοκιμές2,3
• Αυξάνει σημαντικά τη δράση της λετροζόλης
σε neoadjuvant θεραπεία 4
1.
2.
Boulay
23 A et al. Clin Cancer Res. 2005; 11:5319-5328. 2. Ellard SL et al. J Clin Oncol. 2009; 27:4536-4541. 3. Awada A et al.
Eur J Cancer. 2008; 44:84-91. 4. Baselga J et al. J Clin Oncol. 2009; 27:2630-2637.
TAMRAD Protocol
Τυχαιοποιημένη μελέτη φάσης II
Ασθενείς με μεταστατικό καρκίνο και προηγούμενη θεραπεία με αναστολείς
αρωματάσης
A: Tamoxifen 20 mg/d (TAM)
B: Tamoxifen 20 mg/d + RAD001 10 mg/d (TAM + RAD)
•
•
•
24
Διαστρωμάτωση : πρωτογενής ή δευτερογενής ορμονική αντίσταση
Πρωτογενής : υποτροπή κατά τη διάρκεια της συμπληρωματικής θεραπείας με
ΑA; Πρόοδος νόσου μεσα σε 6 μήνες από την έναρξη θεραπείας με AΑ σε
μεταστατική νόσο
– Δευτερογενής : καθυστερημένη υποτροπή (≥6 μήνες) ή προηγούμενη
ανταπόκριση και επακόλουθη πρόοδος σε μεταστατική νόσο με αγωγή με ΑΑ
No crossover planned
AI = aromatase inhibitor.
Key Inclusion Criteria
•
•
•
•
Menopausal condition
Hormone-receptor positive and HER2 negative
With or without measurable disease
Treated with AIs in the adjuvant and/or
metastatic setting
– May have received tamoxifen in the
adjuvant setting
– May have received chemotherapy in the
adjuvant/metastatic setting
Statistical Consideration
• Primary endpoint : Clinical benefit rate (CBR) at 6
months (CR + PR + SD at 6 months)
• Secondary endpoints
–
–
–
–
–
Time to disease progression
Overall survival
Objective response rate
Toxicity
Translational studies
• Simon two-stage minimax design, with
alpha = 5% and power = 90%
26
CR = complete response; PR = partial response; SD = stable disease.
Study Status as of September 2011
•
•
•
•
•
27
111 patients included (March 2008/May 2009)
Final analysis: May 2011
Median follow-up 24 month
Overall survival update: September 2011
Translational research
– Initial tumor samples from 48 patients
– mTOR pathway markers by immunohistochemistry (IHC)
• pS6K; 4EBP1
– Mutational analysis
• PI3K, exon 9 and 20; KRAS exon 2
Patient Characteristics
TAM
n = 57
TAM + RAD
n = 54
66 (42-86)
62.5 (41-81)
14.4 (0.7-102)
13.2 (1.2-94.8)
Disease stage, n (%)
Bone
Bone only
Visceral
3 or more
45 (78.9)
14 (24.6)
28 (49.1)
16 (28.1)
41 (75.9)
16 (29.6)
31 (57.4)
13 (24.1)
Previous anti-aromatase treatment, n (%)
Adjuvant only
Metastatic only
Adjuvant + metastatic
20 (35.1)
33 (57.9)
4 (7)
17 (31.5)
33 (61.1)
4 (7.4)
Previous adjuvant TAM treatment, n (%)
24 (42.1)
18 (33.3)
Previous chemotherapy, n (%)
Adjuvant
Metastatic
32 (56.1)
15 (26.3)
25 (46.3)
13 (24.1)
Primary hormone resistance, n (%)
28 (49.1)
26 (49.1)
Secondary hormone resistance, n (%)
29 (50.9)
27 (50.9)
Median age, years (range)
Median duration of metastatic disease, months (range)
P = 0.045 (exploratory analysis)
Time to progression
• TAM: 4.5 months
• TAM + RAD: 8.6 months
• HR (95% CI) = 0.54 (0.36-0.81)
• P = 0.0021 (exploratory analysis)
TTP Probability
Clinical benefit rate
CBR, % of Patients (95% CI)
Clinical Benefit Rate and Time to Progression (TTP)
70
60
50
40
30
20
10
0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0 0
At risk
61.1%
(46.9-74.1)
42.1%
(29.1-55.9)
TAM
TAM + RAD
TAM
TAM + RAD
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34
Months
57 44 30 24 22 16 13 11 7 6 4 2
54 45 39 34 28 26 25 20 19 17 14 10
2
3
1
3
0
2
0
1
Overall Survival (as of September
2011)
No crossover was
planned or allowed.
•
TAM
TAM + RAD
At risk
57 56 54 53 52 56 44 43 39 37 37 36 32 26 20 16 8 6 5 2 1
54 54 53 52 50 50 50 50 47 47 47 44 38 33 28 22 15 10 8 3 0
Clinical Benefit in Selected Subgroup
TAM
n = 57
TAM + RAD
n = 54
ALL
24/57 (42.1)
33/54 (61.1)
Visceral metastases
No visceral metastases
11/28 (39.3)
13/29 (44.8)
19/31 (61.3)
14/23 (60.9)
Previous adjuvant tamoxifen
No previous adjuvant tamoxifen
9/24 (37.5)
15/33 (45.5)
12/18 (66.7)
21/36 (58.3)
Previous metastatic chemotherapy
No previous metastatic chemotherapy
4/15 (26.7)
20/42 (47.6)
6/13 (46.2)
27/41 (65.9)
Primary hormone resistance
Secondary hormone resistance
10/28 (35.7)
14/29 (48.3)
12/26 (46.2)
20/27 (74.1)
CBR, n (%)
31
Time to Progression as a Function of
Intrinsic Hormone Resistance TAM
1.0
– TAM + RAD: 5.4 months
– HR = 0.70 (0.40-1.21)
– P = NS (exploratory analysis)
• Secondary resistance
– TAM: 5.5 months
– TAM + RAD: 14.8 months
– HR = 0.46 (0.26-0.83)
– P = 0.0087 (exploratory analysis)
TTP Probability
– TAM: 3.8 months
TAM + RAD
0.9
TTP Probability
• Primary resistance
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
Months
24
0
6
12 18 24
Months
30
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
30
33
• Primary resistance
– N (%) of events
– TAM: 15 (54%)
– TAM + RAD: 12 (46%)
– HR = 0.73 (0.34-1.55)
– P = 0.41 (exploratory analysis)
Probability of Survival
Survival as a Function of Intrinsic
TAM
Hormone Resistance
1,0
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
TAM + RAD
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
Months
• Secondary resistance
– N (%) of events
– TAM: 16 (55%)
– TAM + RAD: 4 (15%)
– HR = 0.21 (0.07-0.63)
– P = 0.002 (exploratory analysis)
34
PI3K and KRAS Mutational Status
• Mutational analysis was performed for PI3K
and KRAS in 48 patients (primary tumor)
– PI3K, exon 9 mutation: 1/48 (2%)
– PI3K, exon 20 mutation: 2/47 (4.2%)
– KRAS mutation: 4/48 (8.3%)
• Incidence of PI3K and KRAS mutation was
lower than expected; no statistical analysis
was performed
35
mTOR Activation Biomarker
•
•
Assessed in 35 patients (primary tumor)
Cut-off (high/low) as the median percentage of
marked cell
pS6K
+
−
4EBP
36
Treatment Effect as a Function of
Biomarker Expression (TTP)
High pS6K
Low pS6K
TAM
TAM + RAD
Treatment Effect as a Function of
Biomarker Expression (TTP)
High 4EBP
Low 4EBP
TAM
TAM + RAD
Adverse Events
TAM
n = 57
Incidence, n (%)
Grade
Most Common Adverse Events (AEs)
Fatigue
Stomatitis
Rash
Anorexia
Diarrhea
Nausea
Vomiting
Pneumonitis
Thromboembolic
Pain
Dose reduction due to AE
Treatment discontinuation due to AE
TAM + RAD
n = 54
Any
3/4
Any
3/4
30 (52.6)
4 (7.0)
4 (7.0)
10 (17.5)
5 (8.8)
20 (35.1)
7 (12.3)
2 (3.5)
4 (7.0)
49 (90.7)
6 (10.5)
0
0
2 (3.5)
0
0
2 (3.5)
2 (3.5)
4 (7.0)
10 (18.5)
39 (72.2)
30 (55.6)
24 (44.4)
23 (42.6)
21 (38.9)
19 (35.2)
9 (16.7)
9 (16.7)
5 (8.8)
44 (81.5)
3 (5.6)
6 (11.1)
2 (3.7)
4 (7.4)
1 (1.9)
2 (3.7)
0
1 (1.9)
3 (5.6)
5 (9.3)
0 (0)
11 (20)
4 (7.0)
12 (22)
38
Συμπεράσματα
• In this randomized phase II trial of an mTOR inhibitor and anti-estrogen
combination in AI-pretreated patients:
– CBR, TTP, and survival increased with the addition of everolimus to
tamoxifen compared with tamoxifen alone
• CBR: 61 vs 42 %
• TTP: HR = 0.54; 95% CI, 0.36-0.81
• Survival: HR = 0.45; 95% CI, 0.24-0.81
– Clinical benefit may favor patients with secondary hormone resistance
– Preliminary results of translational analysis show a possible correlation
between biomarkers of mTOR activation and everolimus efficacy
– Toxicity was manageable and consistent with previous studies
39
AMG 479: Background
• IGF-1R widely expressed transmembrane
tyrosine kinase
– Activates PI3-kinase/AKT and Ras/MAP signal
transduction cascades upon IGF-1 or IGF-2
binding
– Coexpressed with ER in a subset of ER-positive
breast cancers
– Increased signaling may drive resistance to
hormonal therapy
• AMG 479: investigational monoclonal IGF-1R
antibody
– Inhibits IGF-1 and IGF-2 binding to IGF-1R
Kaufman PA, et al. SABCS 2010. Abstract S1-4.
AMG 479: Study Design
• Randomized, placebo-controlled, double-blind phase II trial
– Primary endpoint: PFS
Randomized 2:1; stratified by exemestane
vs fulvestrant and disease extent
Postmenopausal women
with hormone receptor–
positive metastatic or locally
advanced breast cancer
with history of disease
progression on endocrine
therapy
AMG 479 12 mg/kg IV every 2 wks +
Exemestane or Fulvestrant*
(n = 106)
(N = 156)
Until disease
progression
Placebo IV every 2 wks +
Exemestane or Fulvestrant*
(n = 50)
*Exemestane or fulvestrant selected by investigator. Exemestane dosed at 25 mg/day PO. Fulvestrant
dosed at 500 mg on Day 1, 250 mg on Days 15, 29, and every 4 wks thereafter, by IM injection.
Kaufman PA, et al. SABCS 2010. Abstract S1-4.
AMG 479: Treatment History
Characteristic, %
AMG 479
(n = 106)
Placebo
(n = 50)
 Adjuvant setting
49
46
 Metastatic setting
18
18
Previous radiotherapy
84
82
 ≥ 1 regimen
100
100
 Adjuvant setting
75
74
 Metastatic setting
52
58
Previous chemotherapy
Previous hormone therapy
Kaufman PA, et al. SABCS 2010. Abstract S1-4.
AMG 479 Had No Significant Effect
on PFS
Patients Event Free (%)
Outcome, Mos
Median PFS
100
AMG 479
(n = 106)
Placebo
(n = 50)
HR*
(80% CI)
P
Value†
3.9
5.7
1.17
(0.91-1.50)
.435
80
60
40
Placebo
AMG 479
20
0
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21
Mos
Patients at Risk, n
50 50 36 33 30 27 24 24 19 18 11 9 6
106 102 72 64 50 47 42 40 35 30 20 15 12
*Stratified by endocrine therapy + extent of disease.
†Stratified log rank test.
Kaufman PA, et al. SABCS 2010. Abstract S1-4.
5
8
5
8
4
4
3
4
1
3
1
3
1
0
1
0
AMG 479: Response Rates Among Pts
With Measureable Disease at Baseline
Response, %
AMG 479
(n = 63)
Placebo
(n = 32)
35
31
 CR
0
0
 PR
8
13
 SD ≥ 24 wks
27
19
 SD < 24 wks
21
34
 PD
35
34
 Unevaluable
10
0
CBR
Best response
Kaufman PA, et al. SABCS 2010. Abstract S1-4.
ΕCCO ESMO 2011
Everolimus in combination with exemestane for
postmenopausal women with advanced breast
cancer who are refractory to letrozole or
anastrozole: results of the BOLERO-2 phase III trial
J. Baselga, M. Campone, T. Sahmoud,
M. Piccart, H. Burris, H. Rugo, S. Noguchi, M. Gnant,
P. Mukhopadhyay, G. Hortobagyi
On behalf of the BOLERO-2 Investigators
Crosstalk between ER and mTOR Signaling
• mTORC1 activates ER in a
ligand-independent fashion1
• Estradiol suppresses apoptosis
induced by PI3K/mTOR
blockade2
• Hyperactivation of the
PI3K/mTOR pathway is
observed in endocrineresistant breast cancer cells3
• mTOR is a rational target to
enhance the efficacy of
hormonal therapy
1.
Yamnik,
46 RL. J Biol Chem 2009; 284(10):6361-6369. 2. Crowder, RJ. Cancer Res 2009;69:3955-62. 3. Miller, TW. J Clin Invest 2010; 120(7):2406-2413.
Ph II Neoadjuvant Letrozole ± Everolimus:
Proof of Concept
N= 270
Postmenopausal
ER+ early breast
cancer
Everolimus 10 mg/day +
Letrozole 2.5 mg/day
ORR
Surgery
Placebo +
Letrozole 2.5 mg/day
Results:
•
•
Significantly higher response rate (primary endpoint)
Everolimus arm 68% vs placebo arm 59%
Significantly greater decrease in Ki67 proliferation index
Everolimus arm 57% vs placebo arm 30%
Baselga J. 2009. J Clin Oncol 2009;27:2630-7.
Biomarkers:
D14 and
surgical
specimen
BOLERO-2: Trial Design
N = 724
Postmenopausal
ER+ HER2- ABC
refractory to
letrozole or
anastrozole
Everolimus 10 mg/day +
Exemestane 25 mg/day
(N = 485)
2
1
Placebo +
Exemestane 25 mg/day
(N = 239)
 Stratification:
1.
2.
Sensitivity to prior hormonal therapy
Presence of visceral disease
 No cross-over
ABC: advanced breast cancer, NSAI: non steroidal aromatase inhibitors, HER2-: human epidermal growth factor receptor 2 – negative;
PFS: progression-free
survival; PK: pharmacokinetics
48
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
PFS
OS
ORR
Bone Markers
Safety
PK
BOLERO-2: Baseline Characteristics
Everolimus +
Exemestane
(N=485), %
Placebo +
Exemestane
(N=239), %
62 (34, 93)
61 (28, 90)
Caucasian
74
78
Asian
20
19
Performance status 0
60
59
Liver involvement
33
30
Lung involvement
29
33
Measurable diseasea
70
68
Characteristic
Median age (range), years
Race
a
All other patients had ≥ 1 bone lesion.
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2: Prior Therapy
Everolimus +
Exemestane
(N=485), %
Placebo +
Exemestane
(N=239), %
Sensitivity to prior hormonal therapy
84
84
Last treatment: LET/ ANA
74
75
Adjuvant
21
16
Metastatic
79
84
Prior tamoxifen
47
49
Prior fulvestrant
17
16
Prior chemotherapy for metastatic BC
26
24
Number of prior therapies: ≥3
54
53
Therapy
Last treatment
LET: letrozole, ANA: anastrozole
50
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2 Primary Endpoint: PFS
Local Assessment
Everolimus 485 398 294 212 144 108 75
Placebo
239 177 109 70 36 26 16
51
14
34
9
18
4
8
3
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
3
1
3
0
0
0
BOLERO-2 Primary Endpoint: PFS
Central Assessment
HR = 0.36 (95% CI: 0.27–0.47)
Log rank P value = 3.3 x 10 -15
Probability of Event (%)
100
EVE + EXE: 10.6 Months
PBO + EXE: 4.1 Months
80
60
40
20
Everolimus + Exemestane (E/N=114/485)
Placebo + Exemestane (E/N=104/239)
0
0
6
12
18
24
30 36 42
Time (weeks)
No. of Patients Still at Risk:
Everolimus485 385 281 201 132 102 67
Placebo 239 168 94 55 33 20 11
52
43
11
48
54
60
66
72
78
28
6
18
3
9
3
3
1
2
0
0
0
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO 2: PFS Subgroup Analyses
Favors EVE + EXE
Subgroups (N)
All (724)
Favors PBO + EXE
Age
<65 (449)
≥65 (275)
Region
Asia (137)
Europe (275)
North America (274)
Other (38)
Sensitivity to prior hormonal therapy
Yes (610)
No (114)
Visceral metastasis
Yes (406)
No (318)
Last therapy
Aromatase inhibitor (532)
Antiestrogen (122)
Other (70)
Last therapy setting
Metastatic (586)
Adjuvant (138)
Prior chemotherapy
Adjuvant only (306)
Metastatic (186)
None (232)
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5
Hazard Ratio
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2: Overall Response Rate and
Clinical Benefit Rate by Local Assessment
P < 0.0001
P < 0.0001
54 by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
Presented
BOLERO-2: Overall Survival
 As of PFS interim analysis: 83 deaths
 10.6% in everolimus arm
 13.0% in placebo arm
 OS interim analysis after 173 events
 OS final analysis at 392 events
 80% power to detect 26% reduction in hazard
ratio (0.74)
55
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2: Most Common G3/4 AEs
Everolimus + Exemestane
(N = 482), %
All
Grades
Grade 3
Stomatitis
56
Fatigue
Placebo + Exemestane
(N = 238), %
Grade 4
All
Grades
Grade 3
Grade 4
8
0
11
1
0
33
3
<1
26
1
0
Dyspnea
18
4
0
9
1
<1
Anemia
16
5
<1
4
<1
<1
Hyperglycemia
13
4
<1
2
<1
0
AST
13
3
<1
6
1
0
Pneumonitis
12
3
0
0
0
0
AE: Adverse Event; AST: Aspartate aminotransferase
56
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
Global Health Status EORTC-QLQ30
QoL Scale Score: Time to ≥5% deterioration
100
HR = 0.91 (95% CI: 0.68–1.20)
Log rank P value = 0.217
90
Probability of Event, %
80
EVE + EXE: 4.5 months
PBO + EXE: 4.4 months
70
60
50
40
30
20
10
Everolimus + Exemestane (E/N = 226/485)
Placebo + Exemestane (E/N = 98/239)
0
0
6
No. of patients still at risk
Everolimus
485
404
Placebo
239
190
57
12
18
24
30
36
42
48
54
60
66
72
78
37
9
23
5
18
2
12
1
2
0
1
0
0
0
Time, weeks
236
94
161
62
112
41
84
23
56
13
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2: Συμπεράσματα
• Η προσθήκη του everolimus στην εξεμεστάνη
παρατείνει το PFS σε ασθενείς με μεταστατικό καρκίνο
του μαστού ER+ HER2- ανθεκτικού σε αρχικό ορμονικό
χειρισμό με μη στεροειδικούς ΑΑ
– Local: median 6.9 vs 2.8 months, HR = 0.43, P < 0.0001
– Central: median 10.6 vs 4.1 months, HR = 0.36, P < 0.00
• Κλινική ωφέλεια παρατηρήθηκε σε όλες τις υποομάδες
• Οι παρενέργεις ήταν οι αναμενόμενες με βάση την ήδη
υπάρχουσα εμπειρία με το everolimus και περι
λαμβάνει τη στοματίτιδα, κόπωση, και υπεργλυκαιμία.
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
BOLERO-2: Συμπεράσματα
• Το Everolimus είναι ο πρώτος παράγοντας που
φαίνεται ότι ενισχύει την κλινική ωφέλεια της
ορμονικής θεραπείας σε ανθεκτικό ER+ καρκίνο του
μαστού
• Τα αποτελέσματα της μελέτης θα μπορούσαν να
αλλάξουν την ήδη υπάρχουσα κλινική πρακτική για τον
μεταστατικό καρκίνου του μαστού με θετικούς
ορμονικούς υποδοχείς.
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
Entinostat: Epigenetic Modulation of
Hormonal Therapy in Breast Cancer
• AI resistance characterized by estrogenindependent growth of breast cancer cells
– Mechanisms of resistance may include
decreased ER expression and increased growth
factor signaling (eg, via HER2)
• Entinostat, a selective HDAC inhibitor,
associated with increased expression of ERα
and aromatase in preclinical studies
– ERα and aromatase upregulation sensitizes
breast cancer cells to effects of estrogen and AI
therapy
Sabnis GJ, et al. Cancer Res. 2011;71:1893-1903.
ENCORE 301: Study Design
• Primary endpoint: PFS
• Secondary endpoints: ORR, clinical benefit rate
Treatment until disease
progression or unacceptable
toxicity
Postmenopausal
women with ERpositive advanced
breast cancer who
progressed on previous
nonsteroidal AI therapy
(N = 130)
Exemestane 25 mg/day +
Entinostat 5 mg/wk
(n = 64)
Exemestane 25 mg/day +
Placebo
(n = 66)
Yardley DA, et al. SABCS 2011. Abstract PD01-04.
ENCORE 301: PFS Overall and by
Subgroup
Median PFS, Mos
Exemestane + Entinostat
(n = 64)
Exemestane + Placebo
(n = 66)
4.28
2.27
 Per protocol population
4.74
2.20
 Visceral involvement
4.28
2.20
 PgR positive
4.28
1.97
• Sensitive
4.87
3.36
• Resistant
3.72
1.78
ITT population
HR
(95% CI)
0.73
(0.49-1.09)*
Patient subgroups
0.74
(0.49-1.13)
0.69
(0.42-1.14)
0.66
(0.42-1.04)
 AI sensitivity
0.90
(0.55-1.45)
0.61
(0.30-1.25)
 Setting of AI progression
•
Adjuvant
3.49
1.78
•
Advanced
4.87
2.27
*P = .06. Statistically significant based on protocol-defined 1-sided significance level (P = .10).
Yardley DA, et al. SABCS 2011. Abstract PD01-04.
0.61
(0.21-1.72)
0.78
(0.51-1.19)
Adverse Events, %
Exemestane + Entinostat
(n = 64)
Exemestane + Placebo
(n = 66)
All Grades
Grade 3/4
All Grades
Grade 3/4
Fatigue
46
13
26
3
Nausea
40
5
15
2
Weight loss
17
0
18
0
Anemia
19
2
12
3
Back pain
14
0
17
2
3
11
19
Dyspnea
Arthralgia
11
2
17
0
Diarrhea
16
0
12
2
Constipation
10
0
15
2
Neutropenia
25
13
0
0
Peripheral edema
21
0
5
0
Vomiting
21
5
5
0
Thrombocytopenia
17
0
6
2
2
6
2
Pain
16
Yardley DA, et al. SABCS 2011. Abstract PD01-04.
ENCORE 301: Συμπεράσματα
• Ο συνδυασμός exemestane με entinostat
παρατείνει σημαντικά τη διάμεση PFS σε
μετεμμηνοπαυσιακές γυναίκες με
μεταστατικό καρκίνο μαστού που
προοδευσε μετα από ΑΑ
– Το όφελος παρατηρήθηκε σε όλες τις
υποομάδες
Yardley DA, et al. SABCS 2011. Abstract PD01-04.
ΟΡΜΟΝΟΕΥΑΙΣΘΗΤΟΣ ΚΑΡΚΙΝΟΣ
ΜΑΣΤΟΥ - ΣΥΜΠΕΡΑΣΜΑΤΑ
• Σε HER 2 + νόσο προτείνεται προσθήκη αντι ΗΕR
2 παράγοντα (grade 1A)
• Για μεταεμμηνοπαυσιακές γυναίκες προτείνεται
θεραπεία με αναστολείς αρωματάσης 3ης γενιας,
με αναστραζόλη ή λετροζόλη ή εξεμεστάνη για
πρωτο ορμονικό χειρισμό (Grade 1A).
• Σαν θεραπεία 2ης γραμμής φαίνεται ότι η
προσθήκη του everolimus σε ορμονικό
παράγοντα αυξάνει το PFS και ίσως αποτελέσει
την επόμενη λογική επιλογή θεραπείας