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
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Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer
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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
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