2011 European
Multidisciplinary Cancer
Congress
Stockolm, 23-27 September 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
Discussant: F. Andre
(France)
September 26, 2011 3
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, 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.
4
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
Biomarkers:
D14 and
surgical
specimen
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.
BOLERO-2: Trial Design
N = 724
Postmenopausal 2
ER+ HER2- ABC
refractory to
1
letrozole or
anastrozole
Everolimus 10 mg/day +
Exemestane 25 mg/day
(N = 485)
Placebo +
Exemestane 25 mg/day
(N = 239)
PFS
OS
ORR
Bone Markers
Safety
PK
 Stratification:
1. Sensitivity to prior hormonal therapy
2. 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
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
6
Participating Countries
7
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.
8
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
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
9
BOLERO-2: Patient Disposition
Everolimus +
Exemestane
(N=485), %
Placebo +
Exemestane
(N=239), %
Protocol therapy ongoing
47
29
Discontinued
53
71
Disease progression
37
66
Adverse event
6.6
2.5
Subject withdrew consent
6.8
2.1
Death due to AE
1.4
0.4
New cancer therapy
0.4
0
Protocol deviation
0.6
0
0
0.4
Disposition
Abnormal laboratory value
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
10
BOLERO-2 Primary Endpoint: PFS
Local Assessment
HR = 0.43 (95% CI: 0.35–0.54)
Log rank P value = 1.4 x 10 -15
Probability of Event (%)
100
80
EVE + EXE: 6.9 months
PBO + EXE: 2.8 months
60
40
20
Everolimus + Exemestane (E/N=202/485)
Placebo + Exemestane (E/N=157/239)
0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
51
14
34
9
18
4
8
3
3
1
3
0
0
0
Time (weeks)
No. of Patients Still at Risk:
Everolimus 485
398
294
Placebo
239
177
109
212
70
144
36
108
26
75
16
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
11
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
48
54
60
66
72
78
43
11
28
6
18
3
9
3
3
1
2
0
0
0
Time (weeks)
No. of Patients Still at Risk:
Everolimus 485
385
281
Placebo
239
168
94
201
55
132
33
102
20
67
11
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
12
BOLERO 2: PFS Subgroup Analyses
Favors EVE + EXE
Favors PBO + EXE
Subgroups (N)
All (724)
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
Hazard Ratio
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
1.4
1.5
BOLERO-2: Overall Response Rate and
Clinical Benefit Rate by Local Assessment
P < 0.0001
P < 0.0001
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
14
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)
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
15
BOLERO-2: Most Common G3/4 AEs
Everolimus + Exemestane
(N = 482), %
Placebo + Exemestane
(N = 238), %
All
Grades
Grade
3
Grade
4
All
Grades
Grade
3
Grade
4
Stomatitis
56
8
0
11
1
0
Fatigue
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
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
16
BOLERO-2: Summary
• Addition of everolimus to exemestane prolongs PFS in
patients with ER+ HER2- breast cancer refractory to
initial non-steroidal aromatase inhibitors
– 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
• Benefit is observed in all subgroups
• Adverse events are consistent with previous experience
with everolimus including stomatitis, fatigue and
hyperglycemia
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
17
BOLERO-2: Conclusions
• Everolimus is the first agent to enhance the clinical
benefit of hormonal therapy in refractory ER+ patients
• Our results could represent a paradigm shift in the
management of patients with hormone receptor-positive
breast cancer
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
18
Conclusiones
• Everolimus en combinación con Examestane
aumenta significativamente la SLE y respuestas
vs. Examestane en pacientes refractarias a
Anastrozole – Letrozole
• Puede ser otra alternativa terapéutica en
pacientes con cáncer de mama avanzado
19
Muchas Gracias!