1 Raloxifene for the Reduction in the Risk of Invasive Breast Cancer July 24, 2007 Eli Lilly and Company Oncologic Drugs Advisory Committee Presentation

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

3 Expert Participants 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 Additional External Consultants Joseph Costantino, DrPH Director, NSABP Biostatistical Center National Surgical Adjuvant Breast and Bowel Project (NSABP) Norman Wolmark, MD Chairman, NSABP National Surgical Adjuvant Breast and Bowel Project (NSABP)

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 a Selective 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 History Breast Cancer ( ) IND for treatment of Breast Cancer opened with the Oncology Division 1992IND for osteoporosis opened with Endocrine Division 1994MORE study initiated (breast cancer – secondary endpoint) 1998IND for invasive breast cancer risk reduction opened IND for STAR opened by NSABP RUTH study initiated (CV risk reduction)

7 Raloxifene Development History Breast Cancer (1999 – present) 1999CORE study initiated (follow-up to MORE; invasive breast cancer – primary endpoint) 2000RUTH protocol amended to add invasive breast cancer as a second primary endpoint 2005 Pre-NDA meetings with the Oncology Division 2006Invasive breast cancer risk reduction NDA submitted

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

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

10 Studied in More Than 37,000 Postmenopausal Women 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 Multiple Outcomes of Raloxifene Evaluation MORE Continuing Outcomes Relevant to Evista CORE Raloxifene Use for The Heart Trial RUTH Steven R. Cummings, MD Director, San Francisco Coordinating Center Professor of Medicine and Epidemiology (emeritus) CPMC Research Institute and UC San Francisco

12 Study Design MORE 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

13 Secondary Objectives MORE 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 Baseline Characteristics MORE N=5133* Mean age66.9 years Caucasian95.9% Family history of breast cancer12.5% Hysterectomy23.1% Previous hormone therapy29.3% * Placebo and raloxifene 60 mg/day only

16 Raloxifene Is Approved for the Prevention and Treatment of Osteoporosis MORE Clinical vertebral fractures per 1000 woman-yrs 5.2 fewer fractures per 1000/yr HR = 0.57 (95% CI, ) 43% decreased risk

17 Invasive Breast Cancer MORE 3.1 fewer cases per 1000/yr

18 Invasive Breast Cancer MORE

19 Invasive and Non-Invasive Breast Cancers MORE

20 Invasive Breast Cancer by ER Status MORE

21 Study Design CORE 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

Year Placebo Raloxifene 60 mg/day Raloxifene 120 mg/day Study Design MORE Followed by CORE: 8 Years MORE (N=7705) CORE (N=4011)

Year Placebo Raloxifene 60 mg/day Raloxifene 120 mg/day Placebo Raloxifene 60 mg/day Study Design MORE Followed by CORE (N = 1286) MORE (N=7705) CORE (N=4011) Gap CORE Screening 5678

Year Placebo Raloxifene 60 mg/day Raloxifene 120 mg/day Placebo Raloxifene 60 mg/day Study Design MORE Followed by CORE (N = 1286) (N = 2725) MORE (N=7705) CORE (N=4011) Gap CORE Screening 5678

Year Placebo Raloxifene 60 mg/day Raloxifene 120 mg/day Placebo Raloxifene 60 mg/day Study Design MORE Followed by CORE: 8 Years (N = 1286) (N = 2725) MORE (N=7705) CORE (N=4011) Gap CORE Screening more years

26 Breast Cancer Assessments CORE 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

27 5-Year Predicted Risk of Breast Cancer by Gail Model CORE Placebo N=1286 Raloxifene N=2725 Average 5-year predicted risk1.94% Percent with 5-year predicted risk ≥1.66% 53%54%

28 Invasive Breast Cancer Risk Reduction CORE HR, 0.44 (95% CI ) p = Placebo N=1274 Raloxifene N= fewer cases per 1000/yr

29 Raloxifene Reduced the Incidence of Invasive Breast Cancer in Women with High or Low Risk CORE N=674N=1475N=604N= HR 0.35 (95% CI, ) HR 0.65 (95% CI, ) <1.66%≥1.66% 5-year Predicted Invasive Breast Cancer Risk by Gail Score 1.2 fewer cases per 1000/yr 4.6 fewer cases per 1000/yr

30 Raloxifene Reduced the Incidence of Invasive Breast Cancer in Women with High or Low Risk CORE N=674N=1475N=604N= HR 0.35 (95% CI, ) HR 0.65 (95% CI, ) <1.66%≥1.66% 5-year Predicted Invasive Breast Cancer Risk by Gail Score 1.2 fewer cases per 1000/yr 4.6 fewer cases per 1000/yr Interaction p = 0.37

31 Invasive Breast Cancer Raloxifene 60 mg vs. Placebo In women assigned to raloxifene 60 mg or placebo in both MORE and CORE over 8 years: 60% decrease: HR 0.40 (95% CI = )

32 Raloxifene Use for The Heart Trial RUTH

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 Study Design RUTH 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)

35 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 Study Design RUTH

36 Characteristic Age67.5 years Caucasian84.0% BMI28.8 kg/m 2 Current smoker12.4% Previous estrogen use14.0% Previous estrogen/progestin6.1% Baseline Characteristics RUTH

37 Characteristic Total (N=10,101) Mean 5-yr estimated breast cancer risk1.73% Percent with 5-yr risk ≥1.66%41.4% Family history of breast cancer9.8% Prior breast biopsy8.8% Diagnosis of atypical hyperplasia1.7% Baseline Breast Cancer Risk RUTH

38 No Effect on Coronary Events* RUTH *First occurrence of non-fatal MI, hospitalized ACS or coronary death

39 Significant Reduction in Invasive Breast Cancer Incidence RUTH 1.2 fewer cases per 1000/yr

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

41 Raloxifene Reduces the Incidence of Invasive Breast Cancer in Women with High or Low Gail Risk RUTH HR 0.65 (95% CI, ) HR 0.49 (95% CI, ) <1.66%≥1.66% 5-year Predicted Invasive Breast Cancer Risk 1.1 fewer cases per 1000/yr 1.2 fewer cases per 1000/yr Interaction p-value = 0.50

42 71% 56% 44% Summary Reductions in Invasive Breast Cancer

43 Raloxifene Safety

44 Adverse Events MORE – 4 Years Percent (%) Placebo (n=2576) Raloxifene (n=5129) p-value Thromboembolic disease17 (0.7)64 (1.3) deep vein thrombosis8 (0.3)44 (0.9) pulmonary embolism4 (0.2)22 (0.4)0.060 Death 36 (1.4)64 (1.2)0.584

45 Adverse Events MORE – 4 Years Percent (%) Placebo (n=2576) Raloxifene (n=5129) p-value Vaginal bleeding*74 (3.7)220 (3.7)0.977 Endometrial hyperplasia*5 (0.3)11 (0.3)0.846 Endometrial cancer*5 (0.3)8 (0.2)0.707 Cataracts141 (5.5)257 (5.0)0.386 Hot Flushes151 (5.9)512 (10.0)<.001 Leg Cramps150 (5.8)443 (8.6)<.001 Peripheral edema134 (5.2)340 (6.6)0.014 *In participants with a uterus

46 Balance of Efficacy and Safety Outcomes MORE FAVORS RALOXIFENEFAVORS PLACEBO

47 Balance of Efficacy and Safety Outcomes MORE FAVORS RALOXIFENEFAVORS PLACEBO

48 Endometrial and Uterine Cancer RUTH, MORE, CORE (N=5959)(N=3146)(N=7782) Including only women with a uterus

49 Safety Summary RUTH 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.

51 RUTH Overall benefit risk profile is neutral in women at high risk of cardiovascular disease

52 An Additional Benefit for Women with Osteoporosis Raloxifene is indicated for osteoporosis Postmenopausal women considering Evista for osteoporosis should be informed about its effect on risk of breast cancer

53 Study of Tamoxifen and Raloxifene STAR Larry Wickerham, MD NSABP STAR Project Officer

54 # Events Placebo93 Tamoxifen # Events Placebo250 Tamoxifen Cumulative Rate/1000 Invasive Breast Cancer Noninvasive Breast Cancer Time to Breast Cancer (Years) P < P= NSABP P1 Study

55 STRATIFICATION Age Gail Model Risk Race History of LCIS Hysterectomy Tamoxifen 20 mg/day x 5 years Study Design STAR Raloxifene 60 mg/day x 5 years Risk-Eligible Postmenopausal Women

56 Inclusion and Exclusion Criteria STAR Inclusion –At least 35 years of age –Postmenopausal –Risk eligible Lobular carcinoma in situ or 5-year Gail risk of breast cancer >1.66% Exclusion History of: –Invasive breast cancer –Ductal carcinoma in situ –DVT, PE –CVA, TIA –Uncontrolled diabetes, hypertension or atrial fibrillation

57 Primary Aims STAR The primary aim of the study was to determine which of the following three statements is true: –Compared to tamoxifen, raloxifene significantly reduces the incidence rate of IBC –Compared to raloxifene, tamoxifen significantly reduces the incidence rate of IBC –The statistical superiority of one of the treatments cannot be demonstrated and the choice of therapy should be based on benefit/risk considerations

58 Primary Objective STAR Evaluate the effect of raloxifene versus tamoxifen in reducing the incidence of invasive breast cancer in postmenopausal women who are at increased risk.

59 Secondary Objectives STAR Non-invasive breast cancer Endometrial cancer Ischemic heart disease Fractures of the hip, spine or wrist Toxicity and side effects

60 Screening, Accrual and Follow-up STAR Screened184,460 Eligible96,368 Randomized19,747 Woman-years of follow-up79,173 Average follow-up (years) 4.06

61 Baseline Characteristics STAR Age (mean)58.5 Caucasian93% Hysterectomy51% First degree relative(s) with breast cancer71% History of Lobular carcinoma in situ9% Atypical hyperplasia23% 5-year predicted Gail risk of invasive breast cancer (mean)4.03%

62 Effects on Invasive Breast Cancer STAR RR (95% CI) = 1.02 (0.82, 1.27)

63 Invasive Breast Cancer STAR

64 Invasive Breast Cancer by 5-year Predicted Risk STAR

65 Invasive Breast Cancer Tumor Characteristics STAR Tamoxifen n=168 Raloxifene n=173 Estrogen Receptor Status +72%69% -28%31% Tumor Size <129%39% %54% >3.110%8% Nodal Status -74%80% +26%20%

Invasive Breast Cancer in Women with a History of LCIS or Atypical Hyperplasia STAR

67 Non-Invasive Breast Cancer STAR

68 Non-Invasive Breast Cancer STAR Tamoxifen (n) Raloxifene (n) RR (95%CI) DCIS ( ) LCIS ( ) Mixed ( )

69 Uterine Cancer STAR

70 Tamoxifen (n) Raloxifene (n) RR (95% CI) Hysterectomy during study (0.28, 0.47) Hyperplasia (0.09, 0.28) with atypia (0.01, 0.56) w/o atypia (0.09, 0.30) Uterine Hyperplasia and Hysterectomy STAR

71 Ischemic Heart Disease STAR Tamoxifen (n) Raloxifene (n) RR (95% CI) Myocardial infarction ( ) Severe angina ( ) Acute ischemic syndrome ( ) Total ( )

72 Osteoporotic Fractures STAR Tamoxifen (n) Raloxifene (n) RR (95% CI) Hip ( ) Spine ( ) Wrist ( ) Total* ( ) *Columns not additive because one patient may have had fractures at multiple sites.

73 Mortality STAR Tamoxifen (n) Raloxifene (n) Cancer52 Breast cancer52 Circulatory/vascular2521 Other3231 Any cause RR (95% CI) 0.95 ( )

74 Venous Thromboembolic Events STAR

75 Cataracts and Cataract Surgery During Follow-up STAR RR = 0.78 (95% CI = 0.68–0.91) RR = 0.81 (95% CI = 0.68–0.96)

76 Summary STAR Compared with tamoxifen, raloxifene was: similar in decreasing the risk of invasive breast cancer not as effective at decreasing the risk of non-invasive breast cancer associated with fewer: –adverse events related to uterus –VTEs –cataracts and cataract surgery

77 Risk Benefit and Conclusions George Sledge, MD Indiana University School of Medicine

78 Do We Need a New Chemoprevention Agent? Breast cancer continues to represent a major cause of morbidity and mortality Few women actually receive tamoxifen as chemoprevention for breast cancer –Real toxicities (VTE, uterine cancer) limit its use –Perception that it is a “cancer drug” with poor risk/benefit ratio

79 Raloxifene Demonstrates Efficacy in Postmenopausal Women Across a Spectrum of Breast Cancer Risk 71% 56% 44% RR 1.02

80 Confirmation of Raloxifene’s Effectiveness Relative to Tamoxifen in STAR STAR Non-inferiority Analysis Proportion retention of tamoxifen’s effect* (95% CI) = 97% (65%, 128%) STAR Primary Analysis RR (95% CI) = 1.02 (0.82, 1.27) * Tamoxifen’s effect based on women 50 years or older in P-1

81 Raloxifene as an Alternative to Tamoxifen: Benefit Similar efficacy with regard to prevention of invasive breast cancer –Less effect on noninvasive cancers

82 Non-Invasive Breast Cancer in Placebo-Controlled Studies MORE, CORE, RUTH 11/50445/50572/12745/2716 (N=5133)(N=3990)(N=10,101) 5/25763/2557 SEER SEER annual US incidence rate per 1,000 in white women ≥50 (2000 data)

83 Efficacy and Important Safety Outcomes STAR FAVORS RALOXIFENE FAVORS TAMOXIFEN Difference in Number of Events (95% CI) per 1000 Women/Yr P=0.055 P=0.057 * * * * *P < 0.05 vs. tamoxifen

84 Difference in # of events per 1000 treated per 5 years (RALOXIFENE VS. TAMOXIFEN) Non-invasive breast cancer3 more DCIS only2 more Hysterectomy40 fewer † Hyperplasia20 fewer † Uterine cancer4 fewer Venous thromboembolism6 fewer † Deep vein thrombosis3 fewer Pulmonary embolism3 fewer Cataracts10 fewer † Cataract surgery9 fewer † Outcome †P < 0.05 Differences in Outcomes for Raloxifene versus Tamoxifen STAR

85 1 Sever PS et al., Lancet Apr 5;361(9364): MRC Working Party Br Med J 1992;304: Berger JS et al. JAMA 2006;295: Fisher B et al., J Natl Cancer Inst Sep 16;90(18): Invasive Breast Cancer Risk Reduction Compares Favorably with Other Prevention Therapies TherapyEventNNT* Atorvastatin 1 MI/CHD death294 Antihypertensives 2 Strokes370 Coronary event417 Aspirin 3 MI753 Tamoxifen 4 Invasive BrCa303 Raloxifene (MORE)Invasive BrCa323 Raloxifene (CORE)Invasive BrCa335 Raloxifene (RUTH)Invasive BrCa862 *NNT = number of patients needed to treat for 1 year to prevent 1 outcome

86 Postmenopausal women at high risk for breast cancer should now have a choice

87 Well established, FDA approved agent for prevention and treatment of osteoporosis Reduced risk of invasive breast cancer observed in MORE has been confirmed in RUTH and STAR Clinically important benefit for these women Raloxifene and Postmenopausal Women with Osteoporosis

88 Invasive Breast Cancer and Vertebral Fracture MORE and P-1 Clinical Vertebral Fracture (No. per 1000/yr) Invasive Breast Cancer (No. per 1000/yr) MORE Placebo P-1 (age≥50) Placebo

89 Invasive Breast Cancer and Vertebral Fracture MORE and P-1 Clinical Vertebral Fracture (No. per 1000/yr) Invasive Breast Cancer (No. per 1000/yr) P-1 (age≥50) Placebo Tamoxifen 3.6 fewer MORE Placebo Raloxifene 3.1 fewer

90 Clinical Vertebral Fracture (No. per 1000/yr) Invasive Breast Cancer (No. per 1000/yr) MORE Placebo P-1 (age≥50) Placebo Raloxifene 3.1 fewer 3.6 fewer Tamoxifen 0.5 fewer 5.2 fewer Invasive Breast Cancer and Vertebral Fracture MORE and P-1

91 Postmenopausal women considering raloxifene for treatment of osteoporosis should be informed about the potential additional benefit on their risk of invasive breast cancer Slide Modified:Memo:

92 Conclusion Since 1998 an estimated 22 million postmenopausal women worldwide have received raloxifene to prevent or treat osteoporosis. Clinical trials involving more than 37,000 postmenopausal women now provide information on the benefits and risks of the use of raloxifene to reduce the risk of invasive breast cancer. The benefit-risk is favorable in postmenopausal women at high risk for breast cancer and in postmenopausal women taking raloxifene for osteoporosis.

94 PlaceboRLX N=5057N=5044Hazard Ratio Stroken (%) n (%) (95% CI)p-Value a 1 year 35 (0.7)40 (0.8)1.14 (0.73, 1.80) year 73 (1.4)82 (1.6)1.12 (0.82, 1.54) year 118 (2.3)124 (2.5)1.04 (0.81, 1.34) year 148 (2.9)167 (3.3)1.12 (0.90, 1.39) year 187 (3.7)216 (4.3)1.14 (0.94, 1.39) year 221 (4.4)242 (4.8)1.08 (0.90, 1.30) year 224 (4.4)249 (4.9)1.10 (0.92, 1.32).3034 a p-value obtained from log-rank test Time to Event Analysis of Stroke by Year All Randomized Patients RUTH

95 Stroke Across Studies Incidence per 1000 woman-yrs (N=10,101)(N=7705)(N=19,487)(N=8018) P=0.19 P=0.30 P=0.82 P=0.04 Tamoxifen

96 Evista Label Update: Precautions and Warnings Death Due to Stroke Section 5.3 Death Due to Stroke In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with EVISTA. During an average follow- up of 5.6 years, 59 (1.2%) EVISTA -treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 versus 15 per 10,000 women-years; hazard ratio 1.49; 95% confidence interval, ; p=0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (249 in EVISTA [4.9%] versus 224 placebo [4.4%]). EVISTA had no significant effect on all-cause mortality. The risk-benefit balance should be considered in women at risk for stroke, such as prior stroke or transient ischemic attack (TIA), atrial fibrillation, hypertension, or cigarette smoking [see Clinical Studies (14.4)].

97 Proportion of Tamoxifen Efficacy Retained by Raloxifene (Invasive Breast Cancer) Rothmann Analysis Source for Historical Effect Data P-1 (>50) P-1 Cuzick meta-analysis (>50) Cuzick meta-analysis

98 TrialStudy Population and Duration Primary EndpointEnrollment CriteriaUse of ET (%) During the Study Royal Marsden N= European Trial Occurrence of breast cancer High risk and family history of breast cancer Yes, 26% ItalianN= European Trial Occurrence of breast cancer and deaths from breast cancer Normal risk and hysterectomy Yes, not reported P-1N=13, North American Trial Occurrence of invasive breast cancer 5 year risk of invasive breast cancer ≥1.66% or had a history of LCIS or atypical hyperplasia No IBIS-IN= European Trial Occurrence of breast cancer including DCIS Had risk factors for breast cancer with at least 2-fold relative risk Yes, 40% Four Tamoxifen Breast Cancer Prevention Trials Study Design