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Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer. N Engl J Med 2012;366:520-9. - PowerPoint PPT Presentation
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Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer
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.
N Engl J Med 2012;366:520-9
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
2
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 endocrine-resistant 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. 3
Everolimus Enhances Activity of Letrozole
*P < 0.001 (synergistic drug interaction).
Boulay A, et al. Clin Cancer Res 2005;11:5319-28.
* *0
20
40
60
80
100
0 0.2 2
Rela
tive
prol
ifera
tion
(%)
Everolimus (nM)
Vehicle100 nM Letrozole500 nM Letrozole
**
4
Ph II Neoadjuvant Letrozole ± Everolimus:Proof of Concept
Everolimus 10 mg/day +Letrozole 2.5 mg/day
Placebo +Letrozole 2.5 mg/day
ORR
Biomarkers:D14 and surgical
specimen
N= 270Postmenopausal ER+ early breast
cancer
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%
Surgery
2
1
Everolimus 10 mg/day +Exemestane 25 mg/day
(N = 485)
Placebo +Exemestane 25 mg/day
(N = 239)
BOLERO-2: Trial Design
ABC: advanced breast cancer, NSAI: non steroidal aromatase inhibitors, HER2-: human epidermal growth factor receptor 2 – negative; PFS: progression-free survival; PK: pharmacokinetics
Stratification:
1. Sensitivity to prior hormonal therapy
2. Presence of visceral disease
No cross-over
J. Baselga et al. N Engl J Med 2012;366:520-9 6
N = 724
Postmenopausal
ER+ HER2- ABC refractory to letrozole or anastrozole
PFS
OSORR
Bone MarkersSafety
PK
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.
7J. Baselga et al. N Engl J Med 2012;366:520-9
BOLERO-2: Baseline Characteristics
Characteristic
Everolimus +Exemestane(N=485), %
Placebo +Exemestane(N=239), %
Median age (range), years 62 (34-93) 61 (28-90)
Race
Caucasian 74 78
Asian 20 19
Performance status 0 60 59
Liver involvement 33 30
Lung involvement 29 33
Measurable diseasea 70 68
a All other patients had ≥ 1 bone lesion.
8J. Baselga et al. N Engl J Med 2012;366:520-9
BOLERO-2: Prior Therapy
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
Purpose of most recent treatment
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 53LET: letrozole, ANA: anastrozole * with or without neoadjuvant or adjuvant therapy
9J. Baselga et al. N Engl J Med 2012;366:520-9
BOLERO-2: Patient Disposition
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
Abnormal laboratory value 0 0.4
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
Everolimus 458 398 294 212 144 108 75 51 34 18 8 3 3 0 Placebo 239 177 109 70 36 26 16 14 9 4 3 1 0 0
Time (weeks)
No. of Patients Still at Risk:
0 126 18 24 30 36 48 6042 54 7266 78
80
60
40
20
100
0
Pro
ba
bil
ity
of
Ev
en
t (%
)
Everolimus + Exemestane (E/N=202/485)Placebo + Exemestane (E/N=157/239)
HR = 0.43 (95% CI: 0.35–0.54)
EVE + EXE: 6.9 monthsPBO + EXE: 2.8 months
P<0.001 by log-rank test
11J. Baselga et al. N Engl J Med 2012;366:520-9
BOLERO-2 Primary Endpoint: PFS Central Assessment
Time (weeks)
HR = 0.36 (95% CI: 0.27–0.47)
EVE + EXE: 10.6 MonthsPBO + EXE: 4.1 Months
P<0.001 by log-rank test
0 126 18 24 30 36 48 6042 54 7266 78
80
60
40
20
100
0
Pro
ba
bil
ity
of
Ev
en
t (%
)
Everolimus + Exemestane (E/N=114/485)Placebo + Exemestane (E/N=104/239)
No. of Patients Still at Risk: Everolimus 458 385 281 201 132 102 67 43 28 18 9 3 2 0Placebo 239 168 94 55 33 20 11 11 6 3 3 1 0 0
12J. Baselga et al. N Engl J Med 2012;366:520-9
BOLERO 2: PFS Subgroup Analyses
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
All (724)
Subgroups (N)
Hazard Ratio
Favors PBO + EXEFavors EVE + EXE
Sensitivity to prior hormonal therapyYes (610)No (114)
RegionAsia (137)Europe (275)North America (274)Other (38)
Age<65 (449)≥65 (275)
Last therapyAromatase inhibitor (532)Antiestrogen (122)Other (70)
Last therapy settingMetastatic (586)Adjuvant (138)
Prior chemotherapyAdjuvant only (306)Metastatic (186)None (232)
Visceral metastasisYes (406)No (318)
13J. Baselga et al. N Engl J Med 2012;366:520-9
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 10.7% 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)
15Presented 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), %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
16J. Baselga et al. N Engl J Med 2012;366:520-9
Global Health Status EORTC-QLQ30 QoL Scale Score: Time to ≥5% deterioration
100
90
80
70
60
50
40
30
20
10
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Time, weeksNo. of patients still at riskEverolimusPlacebo
485 404 236239 190 94
161 112 84 5662 41 23 13
37 23 18 129 5 2 1
2 1 00 0 0
Pro
bab
ilit
y o
f E
ven
t, %
Everolimus + Exemestane (E/N = 226/485)Placebo + Exemestane (E/N = 98/239)
EVE + EXE: 4.5 monthsPBO + EXE: 4.4 months
Log rank P value = 0.217HR = 0.91 (95% CI: 0.68–1.20)
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 17
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, non-infectious pneumonitis and hyperglycemia
18J. Baselga et al. N Engl J Med 2012;366:520-9
BOLERO-2: Conclusions
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
• 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
19
Participating Countries
20
Acknowledgments
• The patients participating in this trial, and the study investigators
• Independent data monitoring committee members–Edith A. Perez
–Toru Watanabe
–David Harrington
–Xavier Pivot
• Steering committee members:– José Baselga
– Gabriel N. Hortobagyi
– 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. 21