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Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer. 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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  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 NCT00863655 • 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 BiolChem 2009; 284(10):6361-6369. • Crowder, RJ. Cancer Res 2009;69:3955-62. • 3. Miller, TW. J Clin Invest 2010; 120(7):2406-2413.

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

  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= 270Postmenopausal 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.

  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 ORRBone MarkersSafety 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

  7. BOLERO-2: Statistical Design 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. • 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 J. Baselga et al. N Engl J Med 2012;366:520-9

  8. BOLERO-2: Baseline Characteristics 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 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 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.

  11. BOLERO-2 Primary Endpoint: PFS Local Assessment HR = 0.43 (95% CI: 0.35–0.54) 100 P<0.001 by log-rank test EVE + EXE: 6.9 months 80 PBO + EXE: 2.8 months 60 Probability of Event (%) 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 Time (weeks) No. of Patients Still at Risk: 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 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) 100 P<0.001 by log-rank test EVE + EXE: 10.6 Months 80 PBO + EXE: 4.1 Months 60 Probability of Event (%) 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 Time (weeks) No. of Patients Still at Risk: Everolimus 458 385 281 201 132 102 67 43 28 18 9 3 2 0 Placebo 239 168 94 55 33 20 11 11 6 3 3 1 0 0 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) Region Asia (137) Age <65 (449) Europe (275) ≥65 (275) North America (274) Other (38) Last therapy setting Metastatic (586) Adjuvant (138) Last therapy Aromatase inhibitor (532) Sensitivity to prior hormonal therapy Antiestrogen (122) Yes (610) Other (70) No (114) Prior chemotherapy Adjuvant only (306) Visceral metastasis Metastatic (186) Yes (406) None (232) No (318) 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 P < 0.0001 P < 0.0001 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. 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, 2011. Abstract: 9LBA.

  16. BOLERO-2: Most Common G3/4 AEs AE: Adverse Event; AST: Aspartate aminotransferase J. Baselga et al. N Engl J Med 2012;366:520-9

  17. 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) 0 0 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 0 Placebo 239 190 94 62 41 23 13 9 5 2 1 0 0 0 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. 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, 2011. 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, 2011. Abstract: 9LBA.

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