Transcript Everolimus in Postmenopausal Hormone

Everolimus in Postmenopausal HormoneReceptor–Positive Advanced Breast Cancer
N Engl J Med 2012;366:520-9
José Baselga, M.D., Ph.D., Mario Campone, M.D., Ph.D., Martine Piccart,
M.D., Ph.D., Howard A. Burris III, M.D., Hope S. Rugo, M.D., Tarek Sahmoud,
M.D., Ph.D., Shinzaburo Noguchi, M.D., Michael Gnant, M.D., Kathleen I.
Pritchard, M.D., Fabienne Lebrun, M.D., J. Thaddeus Beck, M.D., Yoshinori
Ito, M.D., Denise Yardley, M.D., Ines Deleu, M.D., Alejandra Perez, M.D.,
Thomas Bachelot, M.D., Ph.D., Luc Vittori, M.Sc., Zhiying Xu, Ph.D., Pabak
Mukhopadhyay, Ph.D., David Lebwohl, M.D., and Gabriel N. Hortobagyi, M.D.
Disclosures
• Study supported by funding from Novartis
– ClinicalTrials.gov identifier NCT00863655
• J Baselga, MD, PhD, is a consultant to Novartis,
Roche, Merck, Sanofi-Aventis, Verastem, Bayer,
Chugai, Exelixis, Onyx, Constellation
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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
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.
• mTOR is a rational target
to enhance the efficacy of
hormonal therapy
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Everolimus Enhances Activity of Letrozole
Relative proliferation (%)
100
Vehicle
100 nM Letrozole
500 nM Letrozole
80
60
40
*
20
*
*
*
0
0
0.2
Everolimus (nM)
2
*P < 0.001 (synergistic drug interaction).
Boulay A, et al. Clin Cancer Res 2005;11:5319-28.
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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
J. Baselga et al. N Engl J Med 2012;366:520-9
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BOLERO-2: Statistical Design
• Primary end point: progression-free survival
– 26% risk reduction (hazard ratio = 0.74)
– 528 events to achieve 90% power
– One interim analysis after ~60% of events
– O’Brien-Fleming boundary: P < 0.0065
– Assessment by investigator and independent
central review
PFS crossed prespecified boundaries at interim analysis,
cut-off February 11, 2011
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
J. Baselga et al. N Engl J Med 2012;366:520-9
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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.
J. Baselga et al. N Engl J Med 2012;366:520-9
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BOLERO-2: Prior Therapy
Everolimus +
Exemestane
(N=485), %
Placebo +
Exemestane
(N=239), %
Sensitivity to prior hormonal therapy
84
84
LET or ANA as most recent treatment
74
75
Adjuvant therapy
21
16
Treatment of advanced
or metastatic disease
79
84
Previous treatment with tamoxifen
47
49
Previous treatment with fulvestrant
17
16
Previous chemotherapy for treatment
of metastatic disease*
26
26
Number of prior therapies: ≥3
54
53
Therapy
Purpose of most recent treatment
LET: letrozole, ANA: anastrozole
J. Baselga et al. N Engl J Med 2012;366:520-9
* with or without neoadjuvant or adjuvant therapy
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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.
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BOLERO-2 Primary Endpoint: PFS
Local Assessment
HR = 0.43 (95% CI: 0.35–0.54)
P<0.001 by log-rank test
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 458
398
294
Placebo
239
177
109
J. Baselga et al. N Engl J Med 2012;366:520-9
212
70
144
36
108
26
75
16
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BOLERO-2 Primary Endpoint: PFS
Central Assessment
HR = 0.36 (95% CI: 0.27–0.47)
P<0.001 by log-rank test
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 458
385
281
Placebo
239
168
94
J. Baselga et al. N Engl J Med 2012;366:520-9
201
55
132
33
102
20
67
11
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
Hazard Ratio
J. Baselga et al. N Engl J Med 2012;366:520-9
0.8
0.9
1.0
1.1
1.2
1.3
1.4
1.5
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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.
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BOLERO-2: Overall Survival
 As of PFS interim analysis: 83 deaths
 10.7% 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.
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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
J. Baselga et al. N Engl J Med 2012;366:520-9
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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
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.
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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 < 0.001
– Central: median 10.6 vs 4.1 months, HR = 0.36, P < 0.001
• Benefit is observed in all subgroups
• Adverse events are consistent with previous experience
with everolimus including stomatitis, fatigue, noninfectious pneumonitis and hyperglycemia
J. Baselga et al. N Engl J Med 2012;366:520-9
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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.
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Participating Countries
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Acknowledgments
• The patients participating • Steering committee
in this trial, and the study
members:
investigators
– José Baselga
– Gabriel N. Hortobagyi
• Independent data
monitoring committee
members
– Edith A. Perez
– Toru Watanabe
– David Harrington
– Xavier Pivot
– Martine Piccart
– Howard Burris
– Hope S. Rugo
– Shinzaburo Noguchi
– Michael Gnant
– Kathleen I. Pritchard
– Pabak Mukhopadhyay
– Luc Vittori
– Tarek Sahmoud
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
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