1. Everolimus in Postmenopausal Hormone-Receptor–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.

2. Disclosures Study supported by funding from Novartis
ClinicalTrials.gov identifier NCT
J Baselga, MD, PhD, is a consultant to Novartis, Roche, Merck, Sanofi-Aventis, Verastem, Bayer, Chugai, Exelixis, Onyx, Constellation

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 endocrine- resistant breast cancer cells3
mTOR is a rational target to enhance the efficacy of hormonal therapy
Yamnik, RL. J Biol Chem 2009; 284(10):
Crowder, RJ. Cancer Res 2009;69:
3. Miller, TW. J Clin Invest 2010; 120(7):

4. Everolimus Enhances Activity of Letrozole* * * *
*P < (synergistic drug interaction).
Boulay A, et al. Clin Cancer Res 2005;11:

5. Ph II Neoadjuvant Letrozole ± Everolimus: Proof of Concept
Everolimus 10 mg/day +
Letrozole 2.5 mg/day
ORR
Biomarkers:
D14 and surgical specimen
N= 270 Postmenopausal ER+ early breast cancer
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 J Clin Oncol 2009;27: 5

6. 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)
PFS OS
ORR Bone Markers Safety PK 2 1
Placebo +
Exemestane 25 mg/day
(N = 239)
Stratification:
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
J. Baselga et al. N Engl J Med 2012;366:520-9 6

7. 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 <
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, Abstract: 9LBA.
J. Baselga et al. N Engl J Med 2012;366:520-9 7

8. BOLERO-2: Baseline Characteristics
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
Measurable diseasea 70 68
a All other patients had ≥ 1 bone lesion.
J. Baselga et al. N Engl J Med 2012;366:520-9

9. BOLERO-2: Prior Therapy
Everolimus + Exemestane
(N=485), %
Placebo + Exemestane
(N=239), %
Sensitivity to prior hormonal therapy 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
Previous treatment with tamoxifen 47 49
Previous treatment with fulvestrant 17
Previous chemotherapy for treatment of metastatic disease* 26
Number of prior therapies: ≥3 54 53
LET: letrozole, ANA: anastrozole * with or without neoadjuvant or adjuvant therapy
J. Baselga et al. N Engl J Med 2012;366:520-9

10. 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
Protocol deviation
0.6
Abnormal laboratory value
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA.

11. BOLERO-2 Primary Endpoint: PFS Local Assessment
Time (weeks)
No. of Patients Still at Risk: 12 6 18 24 30 36 48 60 42 54 72 66 78 80 40 20
100
Probability of Event (%)
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 months
PBO + EXE: 2.8 months
P<0.001 by log-rank test
Everolimus
458
398
294
212
144
108 75 51 34 18 8 3 3
Placebo
239
177
109 70 36 26 16 14 9 4 3 1
J. Baselga et al. N Engl J Med 2012;366:520-9

12. BOLERO-2 Primary Endpoint: PFS Central Assessment
HR = 0.36 (95% CI: 0.27–0.47) 12 6 18 24 30 36 48 60 42 54 72 66 78 80 40 20
100
Probability of Event (%)
Everolimus + Exemestane (E/N=114/485)
Placebo + Exemestane (E/N=104/239)
P<0.001 by log-rank test
EVE + EXE: 10.6 Months
PBO + EXE: 4.1 Months
Time (weeks)
No. of Patients Still at Risk:
Everolimus
458
385
281
201
132
102 67 43 28 18 9 3 2
Placebo
239
168 94 55 33 20 11 11 6 3 3 1
J. Baselga et al. N Engl J Med 2012;366:520-9

13. 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
1.4
1.5
Hazard Ratio 13
J. Baselga et al. N Engl J Med 2012;366:520-9

14. BOLERO-2: Overall Response Rate and Clinical Benefit Rate by Local Assessment
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA.

15. 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, Abstract: 9LBA.

16. BOLERO-2: Most Common G3/4 AEs
Everolimus + Exemestane (N = 482), %
Placebo + Exemestane
(N = 238), %
All Grades
Grade 3
Grade 4
Stomatitis 56 8 11 1
Fatigue 33 3
<1 26
Dyspnea 18 4 9
Anemia 16 5
Hyperglycemia 13 2
AST 6
Pneumonitis 12
AE: Adverse Event; AST: Aspartate aminotransferase
J. Baselga et al. N Engl J Med 2012;366:520-9

17. No. of patients still at risk
Global Health Status EORTC-QLQ30 QoL Scale Score: Time to ≥5% deterioration
100
HR = 0.91 (95% CI: 0.68–1.20) 90
Log rank P value = 0.217 80
EVE + EXE: 4.5 months 70
PBO + EXE: 4.4 months 60
Probability of Event, % 50 40 30 20 10
Everolimus + Exemestane (E/N = 226/485)
Placebo + Exemestane (E/N = 98/239) 6 12 18 24 30 36 42 48 54 60 66 72 78
Time, weeks
No. of patients still at risk
Everolimus
485
404
236
161
112 84 56 37 23 18 12 2 1
Placebo
239
190 94 62 41 23 13 9 5 2 1
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA.

18. 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
J. Baselga et al. N Engl J Med 2012;366:520-9

19. 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, Abstract: 9LBA.

20. Participating Countries

21. 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, Abstract: 9LBA.