Raloxifene for the Reduction in the Risk of Invasive Breast Cancer

1. July 24, 2007Eli Lilly and CompanyOncologic Drugs Advisory CommitteePresentation Raloxifene for the Reduction in the Risk of Invasive Breast Cancer

2. Lilly’s Presentation • Introduction Gwen Krivi, PhD Eli Lilly and Company • Benefits and Risks of Evista • MORE/CORE/RUTH Steven R. Cummings, MD Director, San Francisco Coordinating Center Professor of Medicine and Epidemiology (emeritus) CPMC Research Institute and UC San Francisco • STAR Larry Wickerham, MD NSABP STAR Project Officer National Surgical Adjuvant Breast and Bowel Project (NSABP) • Conclusions George Sledge, MD Ballve Lantero Professor of Oncology Indiana University School of Medicine

3. Expert Participants Additional External Consultants Joseph Costantino, DrPHDirector, NSABP Biostatistical CenterNational Surgical Adjuvant Breast and Bowel Project (NSABP) Norman Wolmark, MDChairman, NSABPNational Surgical Adjuvant Breast and Bowel Project (NSABP) • Eli Lilly and Company • Bruce Mitlak, MD (moderator) • John Mershon, MD • Dan Masica, MD • Michelle McNabb, MS • Jingli Song, PhD • Matt Rotelli, PhD • Dan Brady, PhD

4. Why Is Breast Cancer Risk Reduction Important? • 2nd most common cause of cancer death in women • 178,000 cases diagnosed annually • 40,000 deaths annually • Disease prevention remains an unmet need in breast cancer • Identification of women at risk continues to improve • Postmenopausal women need additional options to reduce risk of breast cancer

5. Raloxifene is aSelective Estrogen Receptor Modulator • Non-steroidal ligand of the estrogen receptor • Has estrogen-like effects in some tissues • Blocks estrogen effects in other tissues Evista® (raloxifene HCl 60 mg/day) is approved for the prevention and treatment of osteoporosis

6. Raloxifene Development HistoryBreast Cancer (1982-1998) • 1982-1990 IND for treatment of Breast Cancer opened with the Oncology Division • IND for osteoporosis opened with Endocrine Division • MORE study initiated (breast cancer – secondary endpoint) • IND for invasive breast cancer risk reduction opened • IND for STAR opened by NSABP • RUTH study initiated (CV risk reduction)

7. Raloxifene Development HistoryBreast Cancer (1999 – present) • CORE study initiated (follow-up to MORE; invasive breast cancer – primary endpoint) • RUTH protocol amended to add invasive breast cancer as a second primary endpoint • 2005 Pre-NDA meetings with the Oncology Division • 2006 Invasive breast cancer risk reduction NDA submitted

8. Evista®: Current Indication The prevention and treatment of osteoporosis. • Proposed Additional Indication • The reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis.

9. Evista®: Current Indication The prevention and treatment of osteoporosis. • Proposed Additional Indication • The reduction in risk of invasive breast cancer in postmenopausal women at high risk for breast cancer.

10. Studied in More Than 37,000 PostmenopausalWomen Across a Spectrum of Breast Cancer Risk • Randomized active comparator trial Study of Tamoxifen and Raloxifene (STAR) • Randomized placebo-controlled trials Raloxifene Use for The Heart Trial (RUTH) Multiple Outcomes of Raloxifene Evaluation (MORE) • Placebo-controlled follow-up study of MORE participants Continuing Outcomes Relevant to Evista (CORE) 76,000 patient years of exposure to raloxifene

11. Steven R. Cummings, MD Director, San Francisco Coordinating Center Professor of Medicine and Epidemiology (emeritus) CPMC Research Institute and UC San Francisco Source: Silvana Martino Oral Presentation at ASCO 2004 Review: Multiple Outcomes of Raloxifene EvaluationMORE Continuing Outcomes Relevant to EvistaCORE Raloxifene Use for The Heart Trial RUTH Reviewer Memo: Slide Modified: Memo:

12. International multicenter, double-blind, placebo-controlled 7705 postmenopausal women with osteoporosis; excluded women with a history of breast cancer Raloxifene 60 mg, 120 mg, or placebo daily 3 years with 1 year extension Primary objectives: radiographic vertebral fracture, bone mineral density Source: Study DesignMORE Review: Reviewer Memo: Slide Modified: Memo:

13. Secondary ObjectivesMORE • All fractures • Cardiovascular health • Breast cancer • Endometrial cancer • Cognitive function and dementia • Health outcomes

14. Ascertainment and Validation of Invasive Breast Cancer • Mammograms or ultrasound required at baseline • Mammograms were performed at years 2, 3, & 4 • All investigator-reported breast cancers were reviewed and adjudicated by a board of breast cancer specialists • blinded to treatment assignment • not employed by Lilly

15. Source: Baseline CharacteristicsMORE Review: Reviewer Memo: * Placebo and raloxifene 60 mg/day only Slide Modified: Memo:

16. Raloxifene Is Approved for the Preventionand Treatment of OsteoporosisMORE HR = 0.57 (95% CI, 0.42-0.78) 43% decreased risk 5.2 fewer fractures per 1000/yr Clinical vertebral fracturesper 1000 woman-yrs

17. Source: Source: Invasive Breast CancerMORE Review: Review: Reviewer Memo: Reviewer Memo: 3.1 fewer cases per 1000/yr Slide Modified: Slide Modified: Memo: Memo:

18. Source: Source: Invasive Breast CancerMORE Review: Review: Reviewer Memo: Reviewer Memo: Slide Modified: Slide Modified: Memo: Memo:

19. Invasive and Non-Invasive Breast CancersMORE

20. Source: Invasive Breast Cancer by ER StatusMORE Review: Reviewer Memo: Slide Modified: Memo:

21. Double-blind, placebo-controlled continuation of MORE Does raloxifene continue to reduce the risk of breast cancer after 4 years? 1° endpoint: invasive breast cancer 4011 women from MORE continued in CORE Source: Study DesignCORE Review: Reviewer Memo: Slide Modified: Memo:

22. MORE (N=7705) CORE (N=4011) Source: Study Design MORE Followed by CORE: 8 Years Review: Placebo Reviewer Memo: Raloxifene 60 mg/day Raloxifene 120 mg/day Year 0 1 2 3 4 Slide Modified: Memo:

23. Gap CORE Screening MORE (N=7705) CORE (N=4011) Source: Study Design MORE Followed by CORE Review: (N = 1286) Placebo Placebo Reviewer Memo: Raloxifene 60 mg/day Raloxifene 60 mg/day Raloxifene 120 mg/day Year 0 1 2 3 4 5 6 7 8 Slide Modified: Memo:

24. Gap CORE Screening MORE (N=7705) CORE (N=4011) Source: Study Design MORE Followed by CORE Review: (N = 1286) Placebo Placebo Reviewer Memo: Raloxifene 60 mg/day Raloxifene 60 mg/day (N = 2725) Raloxifene 120 mg/day Year 0 1 2 3 4 5 6 7 8 Slide Modified: Memo:

25. Gap CORE Screening MORE (N=7705) CORE (N=4011) Source: Study Design MORE Followed by CORE: 8 Years Review: (N = 1286) Placebo Placebo Reviewer Memo: Raloxifene 60 mg/day Raloxifene 60 mg/day (N = 2725) Raloxifene 120 mg/day Year 0 1 2 3 4 5 6 7 8 4 more years Slide Modified: Memo:

26. Source: Breast Cancer AssessmentsCORE Review: • Baseline: 5-year risk of breast cancer by Gail Model • Annual clinical breast exams • Mammograms required at baseline and years 2 and 4 • Reports of breast cancer adjudicated by 3 breast cancer specialists • who were blinded to patient treatment assignment • who were not employed by Lilly Reviewer Memo: Slide Modified: Memo:

27. Source: 5-Year Predicted Risk of Breast Cancer by Gail ModelCORE Review: Reviewer Memo: Slide Modified: Memo:

28. Invasive Breast Cancer Risk ReductionCORE HR, 0.44 (95% CI 0.24-0.83) p = 0.009 20 3.0 fewer cases per 1000/yr 19 Raloxifene N=2716 Placebo N=1274

29. Raloxifene Reduced the Incidence of InvasiveBreast Cancer in Women with High or Low RiskCORE HR 0.35(95% CI, 0.16-0.78) 14 4.6 fewer cases per 1000/yr HR 0.65(95% CI, 0.23-1.87) 1.2 fewer cases per 1000/yr 6 11 8 <1.66% ≥1.66% N=674 N=1475 N=604 N=1243 5-year Predicted Invasive Breast Cancer Risk by Gail Score

30. Raloxifene Reduced the Incidence of InvasiveBreast Cancer in Women with High or Low RiskCORE HR 0.35(95% CI, 0.16-0.78) 14 Interactionp = 0.37 4.6 fewer cases per 1000/yr HR 0.65(95% CI, 0.23-1.87) 1.2 fewer cases per 1000/yr 6 11 8 <1.66% ≥1.66% N=674 N=1475 N=604 N=1243 5-year Predicted Invasive Breast Cancer Risk by Gail Score

31. Source: Invasive Breast CancerRaloxifene 60 mg vs. Placebo Review: • In women assigned to raloxifene 60 mg or placebo in both MORE and CORE over 8 years: • 60% decrease: HR 0.40 (95% CI = 0.21-0.77) Reviewer Memo: Slide Modified: Memo:

32. Source: Raloxifene Use for The Heart Trial RUTH Review: Reviewer Memo: Slide Modified: Memo:

33. Background RUTH • RUTH began enrollment in June, 1998 • It was believed that estrogen may reduce risk of CHD by improving lipoproteins and vascular function • Raloxifene improved lipoproteins and fibrinogen • Hypothesis: Treatment with raloxifene would reduce the risk of CHD events.

34. Source: Study DesignRUTH • Randomized, double-blind, placebo-controlled • Raloxifene 60 mg or placebo daily • 10,101 postmenopausal women at high risk for coronary heart disease • Primary Outcome • Coronary heart disease events (CHD death, nonfatal MI, hospitalized acute coronary syndrome besides MI) Review: Reviewer Memo: Slide Modified: Memo:

35. Source: Study DesignRUTH • Randomized, double-blind, placebo-controlled • Raloxifene 60 mg or placebo daily • 10,101 postmenopausal women at high risk for coronary heart disease • Primary Outcome • Coronary heart disease events (CHD death, nonfatal MI, hospitalized acute coronary syndrome besides MI) • Invasive breast cancer Review: Reviewer Memo: Slide Modified: Memo:

36. Baseline CharacteristicsRUTH

37. Baseline Breast Cancer RiskRUTH

38. Source: No Effect on Coronary Events*RUTH Review: Reviewer Memo: *First occurrence of non-fatal MI, hospitalized ACS or coronary death Slide Modified: Memo:

39. Source: Significant Reduction inInvasive Breast Cancer IncidenceRUTH Review: Reviewer Memo: 1.2 fewer cases per 1000/yr Slide Modified: Memo:

40. Raloxifene Reduces the Incidence of Invasive Breast Cancer in Women with High or Low Gail Risk RUTH HR 0.65(95% CI, 0.38-1.09) HR 0.49(95% CI, 0.28-0.88) 1.2 fewer cases per 1000/yr 35 1.1 fewer cases per 1000/yr 34 23 17 <1.66% ≥1.66% 5-year Predicted Invasive Breast Cancer Risk

41. Raloxifene Reduces the Incidence of Invasive Breast Cancer in Women with High or Low Gail Risk RUTH Interactionp-value = 0.50 HR 0.65(95% CI, 0.38-1.09) HR 0.49(95% CI, 0.28-0.88) 1.2 fewer cases per 1000/yr 35 1.1 fewer cases per 1000/yr 34 23 17 <1.66% ≥1.66% 5-year Predicted Invasive Breast Cancer Risk

42. SummaryReductions in Invasive Breast Cancer 56% 71% 44%

43. Raloxifene Safety

44. Adverse EventsMORE – 4 Years

45. Adverse EventsMORE – 4 Years *In participants with a uterus

46. Balance of Efficacy and Safety OutcomesMORE FAVORS RALOXIFENE FAVORS PLACEBO

47. Balance of Efficacy and Safety OutcomesMORE FAVORS RALOXIFENE FAVORS PLACEBO

48. 21 3 17 5 4 8 (N=7782) (N=5959) (N=3146) Endometrial and Uterine CancerRUTH, MORE, CORE Including only women with a uterus

49. Safety SummaryRUTH • Compared to placebo, raloxifene was associated with: • Increased risk of VTEs • No effect on all-cause mortality • No effect on all strokes • Increased risk of death due to stroke • Reduced risk of clinical vertebral fractures

50. Safety Information in Evista Label • Based on the osteoporosis prevention and treatment trials, MORE and CORE, the safety profile in the label includes: • VTEs • Hot flushes, leg cramps, peripheral edema • Based on the RUTH trial, the label also states: • Evista should not be used for the primary or secondary prevention of cardiovascular disease. • Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events. No increased risk of stroke was seen. Consider risk-benefit balance in women at risk for stroke.