Everolimus in Postmenopausal Hormone-Receptor-Positive ...

Everolimus in Postmenopausal Hormone-Receptor-Positive ...

Everolimus in Postmenopausal HormoneReceptorPositive Advanced Breast Cancer N Engl J Med 2012;366:520-9 Jos 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 2 Crosstalk between ER and mTOR Signaling 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. 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

mTOR is a rational target to enhance the efficacy of hormonal therapy 3 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. 4 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% BOLERO-2: Trial Design N = 724 Postmenopausal ER+ HER2- ABC refractory to letrozole or anastrozole 2 1 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 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 OBrien-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), % 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 8

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 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 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.

10 BOLERO-2 Primary Endpoint: PFS Local Assessment HR = 0.43 (95% CI: 0.350.54) 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 11 BOLERO-2 Primary Endpoint: PFS Central Assessment HR = 0.36 (95% CI: 0.270.47) 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 Subgroups (N) Favors PBO + EXE 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 13 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) Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 15 BOLERO-2: Most Common G3/4 AEs Everolimus + Exemestane Placebo + Exemestane (N = 238), % (N = 482), % 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

16 Global Health Status EORTC-QLQ30 QoL Scale Score: Time to 5% deterioration 100 HR = 0.91 (95% CI: 0.681.20) 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. 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, noninfectious pneumonitis and hyperglycemia J. Baselga et al. N Engl J Med 2012;366:520-9 18 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. 19 Participating Countries 20 Acknowledgments

The patients participating Steering committee in this trial, and the study members: Jos Baselga investigators 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. 21

Recently Viewed Presentations

  • Thermodynamics! - Coach Hyde 2016-2017

    Thermodynamics! - Coach Hyde 2016-2017

    in Hooke's Law in which it represents the spring constant! ... The zeroth law of thermodynamics works the same way with temperature. ... Buildings, railroad tracks, bridges, and highways contain thermal expansion joints to prevent cracking and warping due to...
  • ALUMINIUM DOORS & WINDOWS Comprehensive range of products

    ALUMINIUM DOORS & WINDOWS Comprehensive range of products

    Exclusive Hi-Reflex spacer bar thermal break technology . Window U-Value 1.4 with centre pane of 1.2. Externally beaded as standard . 10 year guarantee. Options. Windows can be side hung, top hung or fixed . Corner posts and bay solutions...
  • Media Strategies - WordPress.com

    Media Strategies - WordPress.com

    Media Studies. Media Strategies. Bandwagon. Appeals to desire for conformity. Get with the times, be part of the crowd! Everyone in the know uses this brand. Together - everyone is doing it. Everyone knows! Cartoon/Cute Character. Entertainment value or cute...
  • Viva La Vida - Amazon S3

    Viva La Vida - Amazon S3

    "Now the old king is dead, long live the king," ... Ah, who would ever wanna be king? I hear Jerusalem bells aringing, Roman Cavalry choirs are singing, Be my mirror, my sword and shield, My missionaries in a foreign...
  • Nontariff Trade Barriers - ubalt.edu

    Nontariff Trade Barriers - ubalt.edu

    Other Nontariff Trade Barriers. Government procurement policies. Buy-national policies. 1933, Buy American Act. Federal agencies. Purchase materials and products from U.S. suppliers . If their prices are not "unreasonably" higher than those of foreign competitors. Domestic product. At least 50%...
  • video slide - Winston-Salem/Forsyth County Schools

    video slide - Winston-Salem/Forsyth County Schools

    A flat, sloped surface. aka: ramp. How it works: allows you to exert your input force over a longer distance, thus decreasing input force. Input force - force with which you push or pull the object. Output force - force...
  • Chapter 15 Acids and Bases

    Chapter 15 Acids and Bases

    Acid and Base Strength. ... Acetate is a stronger base than H. 2. O, so the equilibrium favors the left side (K < 1). Autoionization of Water. Water is amphoteric. In pure water, a few molecules act as bases and...
  • The internalist conception on

    The internalist conception on

    Doctorado en la Universidad de Princeton. Primer libro A theory of Human Action combina nociones de metafísica y filosofía de la mente. En la epistemología: el fiabilismo causal como una aproximación al conocimiento y la justificación: Epistemology and Cognition (1986)...