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These slides were released by the speaker for internal use by Novartis

These slides were released by the speaker for internal use by Novartis. Extending adjuvant therapy beyond 5 years. William Gradishar (Feinberg School of Medicine, Northwestern University, Chicago, IL, USA). Thousands of patients currently completing tamoxifen therapy.

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These slides were released by the speaker for internal use by Novartis

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  1. These slides were released by the speaker for internal use by Novartis

  2. Extending adjuvant therapy beyond 5 years • William Gradishar • (Feinberg School of Medicine, Northwestern University, Chicago, IL, USA)

  3. Thousands of patients currently completing tamoxifen therapy • Most women on adjuvant endocrine therapy in the EU (> 450,000) are on tamoxifen (> 300,000)1 • Estimated 80,000–100,000 patients finish 5 years of tamoxifen each year in the EU1 • These women exposed to continuing risk of relapse • Majority of breast cancer deaths and recurrences occur post-tamoxifen2 • Risk of late recurrence (> 5 years after diagnosis) particularly high in women with HR+ disease3 1Fletcher-Louis M, Ireland S. Onkos Study 48: Breast Cancer. Decision Resources Inc., Waltham, MA; 2000 2Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717 3Saphner et al.J Clin Oncol 1996;14:2738–46

  4. Most breast cancer recurrences and deaths occur post-tamoxifen Recurrences Breast cancer deaths 15% 17% 9% 18% 100 100 91.4 85.2 73.0 80 80 87.8 68.2 73.7 60 60 % of patients 64.0 % of patients 54.9 40 40 Tamoxifen Control Tamoxifen Control 20 20 0 0 0 5 10 15 0 5 10 15 Years Years Adapted with permission. Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

  5. Late recurrences (> 5 years) more frequent in ER+ and/or PgR+ tumors RFS continues to decrease regardless of ER/PgR status N+ and N– disease 1.0 0.9 ER/PgR– (n = 430) 0.8 Proportion disease-free 0.7 0.6 ER+ and/or PgR+ (n = 778) 0.5 p < 0.001 0.4 5 10 15 20 Years post-diagnosis Hortobagyi et al.Proc ASCO 2004;23:23s(abstract 585) RFS: relapse-free survival

  6. Randomization (all patients disease-free) 0–3months Letrozole 2.5 mg qd (n = 2582) Tamoxifen Placebo qd † (n = 2586) Approx. 5 years adjuvant 5 years extended adjuvant MA.17: trial design • Eligibility criteria: postmenopausal, HR+/unknown, recurrence-free, completed 4.5–6 years’ tamoxifen, ECOG PS 0–2 • Primary endpoint: DFS (ipsilateral, chest wall, local, metastatic, contralateral new) • Secondary endpoints: OS, rate of contralateral BC, safety, QoL • Substudies:BMD/bone markers, lipid profile Goss et al. J Natl Cancer Inst 2005;97:1262–71 Goss et al. N Engl J Med 2003;349:1793–802

  7. Toxicity Efficacy 2003 March Aug Oct 1998 2003 2004 MA.17: initial and final analyses 1Goss et al.N Engl J Med 2003;349:1793–802; 2Goss et al. J Natl Cancer Inst 2005;97:1262–71

  8. DFS: letrozole significantly decreased risk of recurrence 100 80 60 % of patients p = 0.00004 40 20 Letrozole Placebo 0 0 10 20 30 40 50 60 Time from randomization (months) No. at risk (letrozole) 2583 2497 1905 1110 541 176 6 No. at risk (placebo) 2587 2489 1874 1075 519 164 8 Goss et al.Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentation Goss et al.J Natl Cancer Inst 2005;97:1262–71

  9. Distant DFS: letrozole reduced risk of distant metastases by 40% All patients 100 80 p = 0.002 60 % of patients 40 Letrozole Placebo 20 0 0 10 20 30 40 50 60 Time from randomization (months) No. at risk (letrozole) 2583 2497 1905 1110 541 176 6 No. at risk (placebo) 8 2587 2489 1874 1075 519 164 Goss et al.Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentation Goss et al.J Natl Cancer Inst 2005;97:1262–71

  10. OS: letrozole reduced mortality by 39% in patients with N+ disease 100 80 60 Letrozole p = 0.04 % Surviving Placebo 40 20 0 0 10 20 30 40 50 60 Months from randomization • No significant increase in OS in total study population or N– disease • Similar reduction in breast cancer events occurred in N– and N+ disease Goss et al.J Natl Cancer Inst 2005;97:1262–71

  11. MA.17: summary of key efficacy results *Statistically significant benefit of letrozole • A similar reduction in local recurrences, new primaries, and distant recurrences occurred in patients with N+ and N– disease Goss et al.Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentation Goss et al.J Natl Cancer Inst 2005;97:1262–71

  12. MA.17 safety profileLetrozole is comparable to placebo *90% of AEs grade 1or 2 Goss et al. J Natl Cancer Inst 2005;97:1262–71

  13. ABSCG-6a extended adjuvant trial • Postmenopausal women completing 5 years’ tamoxifen (n = 450) or tamoxifen plus aminoglutethimide (n = 409) • Re-randomized to anastrozole or no treatment for 3 years (no placebo control) • Median follow-up 5 years • Anastrozole significantly reduced recurrence: HR = 0.64, 95% CI 0.41–0.99, p = 0.047 • No significant difference in OS • No safety data reported Jakesz et al. J Clin Oncol 2005;23:10S(abstract 527)

  14. NCIC CTG MA.17 update • Duration of therapy • Ingle et al.Breast Cancer Res TreatMarch2006 published online • Post-unblinding analysis • Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)

  15. Increasing benefit of letrozole with longer duration of treatment • Purpose • To assess impact of duration of treatment on outcomes for extended adjuvant letrozole vs placebo in MA.17 as measured by hazard ratios over 48 months • End points: DFS (primary), distant DFS, OS • Cohorts evaluated • All randomized patients (n = 5170) • N+ (n = 2360) • N– (n = 2568) Ingle et al.Breast Cancer Res Treat Mar2006 published online

  16. 0.0035 Placebo 0.0030 0.0025 0.0020 Hazard rate 0.0015 Letrozole 0.0010 0.0005 0.0000 0 6 12 18 24 30 36 42 48 Months after randomization Hazard rates for DFS over 48 months(letrozole vs placebo) Hazardratio 0.52 0.35 0.45 0.19 Letrozole 2583 2531 2425 2060 1555 1110 768 464 244 Placebo 2587 2528 2409 2020 1530 1075 723 436 231 Ingle et al.Breast Cancer Res Treat Mar2006 published online

  17. Increasing benefit of letrozole with longer duration of treatment: DFS Upper 95% confidence limit Ratio estimate 0.52 I Hazard ratio Lower 95% confidence limit 0.19I p < 0.0001 for HR trends based on time-dependent Cox model Months after randomization Ingle et al.Breast Cancer Res Treat Mar2006 published online

  18. Increasing benefit of letrozole with longer duration of treatment: summary HR~0.6–~0.25 HR ~0.35–~0.25 HR ~0.55–~0.4p = 0.0004 p = 0.0005 p = 0.038 N+disease DFS Distant DFS OSHR0.52–0.19 HR 0.43–0.21 HR 0.87–0.79p < 0.0001 p = 0.0013 p = NS HR ~0.7–~0.5 HR ~0.25–~0.2 HR ~2.0–~2.25p = 0.027p = NS p = NS N–disease *Statistically significant benefit of letrozole • Significant improvements in HR between 12 and 48 months of letrozole vs placebo for DFS and distant DFS overall, for all three endpoints in N+ disease and for DFS in N– disease Ingle et al.Breast Cancer Res Treat Mar2006 published online

  19. Increasing benefit of letrozole with longer duration of treatment: conclusions • Recent guidelines recommend • ASCO 2004: a minimum of 2.5 years of extended letrozole consistent with median follow-up of MA.17 • NCCN 2006: 5 years of letrozole following 5 years of tamoxifen • St Gallen: switch to AI (letrozole) after 5 years of tamoxifen • Ingle et al. study shows that, at least to about 48 months, longer duration of letrozole is associated with greater benefit • Based on these data* extended adjuvant letrozole therapy should be for at least 4 years Winer et al. J Clin Oncol 2005;23:1609–10; Goldhirsch et al. Ann Oncol 2005;16:1569–83; National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology – v.2.2006, Breast Cancer. At: www.nccn.org/professionals/physician_gls/PDF/breast.pdf; *Ingle et al.Breast Cancer Res Treat Mar2006 published online

  20. Late extended adjuvant therapy Analysis post-unblinding Letrozole (Let) n = 2457 Letrozole n = 2593 Tamoxifen n = 5187 Placebo n = 2594 No Letrozole (Plac) n = 613 Letrozole (Plac–Let) n = 1655 5 years 0–3 mo Median F/U (months) 30 54 Unblinding Purpose: compare placebo–letrozole vs placebo to determine benefits/safety of starting letrozole after prolonged periods (1–5 years) off tamoxifen Update of Goss et al.Breast Cancer Res Treat 2005;94:S10(abstract 16)

  21. Significantly different baseline characteristics (all p < 0.01) Plac–Let 120 Plac 96 100 92 80 80 66 57 Per cent 60 49 49 40 33 20 0 Age < 70 years ECOG = 0 N– Prior CTx Update of Goss et al.Breast Cancer Res Treat 2005;94:S10(abstract 16)

  22. Plac–Let Plac Late extended adjuvant therapy analysis post-unblinding: DFS 100 80 60 Percentage disease-free DFS 40 Adjusted HR: 0.31 (0.18–0.55); p < 0.0001 20 0 0 20 40 60 80 Time from randomization (months) Update of Goss et al.Breast Cancer Res Treat 2005;94:S10(abstract 16)

  23. Late extended adjuvant therapy analysis post-unblinding Summary of efficacy Hazard ratio(placebo–letrozole vs placebo) 0.6 0.53 0.5 p = 0.05 0.4 0.31 0.28 0.3 p < 0.0001 0.23 p = 0.002 p = 0.012 0.2 0.1 0 DFS Distant DFS OS CBC Update of Goss et al.Breast Cancer Res Treat 2005;94:S10(abstract 16)

  24. p = 0.007 4.5 p = 0.60 4.0 p = 0.84 3.5 3.0 2.5 Incidence (%) 2.0 1.5 1.0 0.5 0.0 Fracture New osteoporosis CV disease Late extended adjuvant therapy analysis post-unblinding Adverse events Plac–Let Plac Update of Goss et al.Breast Cancer Res Treat 2005;94:S10(abstract 16)

  25. MA.17: updated analysis safety conclusions • Letrozole associated with low-grade estrogen depletion symptoms • Overall QoL unaffected (in ~3600 women) • No changes in CV events or lipid profiles • Mild decreases in bone density, but no significant increase in fracture risk • Bone density changes can be easily monitored and corrected • AEs with letrozole after unblinding similar to those in the main trial for osteoporosis, fractures, and CV disease

  26. MA.17: updated analysis efficacy conclusions • Letrozole significantly increased DFS and distant DFS (all patients) and OS (patients with N+ disease) • Benefit with letrozole increased with treatment duration • Late extended adjuvant letrozole (after prolonged treatment-free interval) significantly improved all outcomes • Women with long tamoxifen-free periods should be considered for letrozole therapy • International guidelines*: based on MA.17 findings postmenopausal women with HR+ EBC finishing 5 years of tamoxifen should consider treatment with letrozole • Updated analysis suggests extended adjuvant letrozole therapy should be for at least 4 years *Winer et al. J Clin Oncol 2005;23:1609–10; Goldhirsch et al. Ann Oncol 2005;16:1569–83; National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology – v.2.2006, Breast Cancer. At: www.nccn.org/professionals/physician_gls/PDF/breast.pdf

  27. MA.17R re-randomization study n= 800 MA.17 Placebo n = 900 Tamoxifen Letrozole* Non-study patients n = 900 MA.17 + Non-study patients MA.17R 0 5 10 15 Years post-surgery *Women remaining disease-free Goss et al.Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentation

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