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.

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

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):6361-6369. Crowder, RJ. Cancer Res 2009;69:3955-62. 3. Miller, TW. J Clin Invest 2010; 120(7):2406-2413.

Everolimus Enhances Activity of Letrozole * * * * *P < 0.001 (synergistic drug interaction). Boulay A, et al. Clin Cancer Res 2005;11:5319-28.

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. 2009. J Clin Oncol 2009;27:2630-7. 5

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

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 7

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

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

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, 2011. Abstract: 9LBA.

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

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

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

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, 2011. Abstract: 9LBA.

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.

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

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, 2011. Abstract: 9LBA.

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

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.

Participating Countries

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.