1. 1 ESAs in Oncology and Management of Risks Vinni Juneja, MD Division of Biologic Oncology Products Oncologic Drugs Advisory Committee March 13, 2008

2. 2 Review Team Chaohong Fan Patricia Keegan Mark Rothmann Yuan Li Shen Kyung Lee Monica Hughes

3. 3OutlineBackground –Regulatory History –Benefits vs Risks –Adverse Findings in Oncology Trials Updates since 2007 ODAC –Adverse Findings in 2 Additional Trials –New FDA Analyses –FDA Actions Risk Evaluation and Mitigation Strategies (REMS)

4. 4 ESAs for Chemotherapy-Induced Anemia (CIA) Brand-name Proper name Sequence homology to human erythropoietin Year approved for chemo anemia Available in US Procrit ® Epoetin alfa 100%1993 Aranesp ® Darbepoetin alfa 97% 97%2002 Available outside US Eprex ® Epoetin alfa 100%1994 NeoRecormon ® Epoetin beta 100%1995 Aranesp ® Darbepoetin alfa 97% 97%2002 Epoetin alfa and beta have same amino acid sequence but differ in glycosylation

5. 5 1989 2007 Epoetin AZT 1991 1993 1995 19971999 20012003 2005 Epoetin Chemo induced Anemia (CIA) Epoetin Pre-surgical Darbepoetin CRF Darbepoetin Chemo induced Anemia (CIA) ODAC 2004 ODAC 2007 Epoetin CRF

6. 6OutlineBackground –Regulatory History –Benefits vs Risks –Adverse Findings in Oncology Trials Updates since 2007 ODAC –Adverse Findings in 2 Additional Trials –New FDA Analyses –FDA Actions Risk Evaluation and Mitigation Strategies (REMS)

7. 7 Benefits of ESAs Basis for Approval: Clinical benefits of ESAs demonstrated in anemic pts receiving chemo → avoid RBC transfusions & concomitant risks At best 30% of pts (1 in 3) → benefit through avoidance of transfusion All patients incur risks

8. 8 Benefits of ESAs Week 5-12 Procrit N=51 Placebo N=58 % transfused 22%43% Procrit 1993 Approval Week 5-End of Rx Aranesp N=148 Placebo N=149 % transfused 21%51% Aranesp 2002 Approval

9. 9 Unproven perceptions of ESA “benefits” Improved QOL, fatigue, and other symptoms associated with anemia NOT established in randomized, double-blind, placebo-controlled trials. Improved survival or improved tumor control NOT established

10. 10 Risks of RBC transfusion Transfusion Related Acute Lung Injury (TRALI) Clerical error Transfusion Associated Graft vs Host disease Infectious (HIV, HBV, HCV, HTLV, West Nile, Bacteria) No trial has collected data on RBC transfusion risks to assess impact of ESAs on reduction of transfusion risks in pts w/cancer

11. 11 Risks of ESAs Increased thrombovascular events (TVEs) –Increased Morbidity, Potential Increased Mortality Decreased Survival Increased Tumor Promotion –Decreased Locoregional Control –Decreased Progression-Free Survival

12. 12 Risks of ESAs 6 studies→ statistically significant evidence of ↑ tumor promotion and/or ↓ survival –BEST (Breast)* –ENHANCE (Head/Neck) –DAHANCA (Head/Neck) –161 (Lymphoid Ca)* –CAN-20 (NSCLC) –103 (Anemia of Cancer) (Many tumor types) 2 studies→ trends of ↑ tumor promotion and/or ↓ survival –PREPARE (neoadjuvant breast)* –GOG 191 (cervical cancer) † * = pts receiving chemo † †=pts receiving chemoRT

13. 13OutlineBackground –Regulatory History –Benefits vs Risks –Adverse Findings in Oncology Trials Updates since 2007 ODAC –Adverse Findings in 2 Additional Trials –New FDA Analyses –FDA Actions Risk Evaluation and Mitigation Strategies (REMS)

14. 14 BEST (Breast) N93-004 (SCLC) ENHANCE (Head/Neck) ODAC 2004 EPO-ANE-3010 (Breast) Darbepoetin 2001-0145 (SCLC) PREPARE (Breast) ARA-03 (Breast) DAHANCA (H/N) GELA (NHL) Epoetin GBR-7 (H/N) RTOG 9903 (H/N) GER-22 (NSCLC) CAN-20 (NSCLC) CAN-17 (Breast) AGO (Cervical) Other Amgen Studies Anemia of Cancer (103) Lymphoid Ca (161) GOG-191 (Cervical) ODAC 2007

15. 15 BEST (Breast) ENHANCE (Head/Neck) ODAC 2004 Darbepoetin PREPARE (Breast) DAHANCA (H/N) Epoetin CAN-20 (NSCLC) Other Amgen Studies Anemia of Cancer (103) Lymphoid Ca (161) GOG-191 (Cervical) ODAC 2007 Studies with ↓ Survival and/or ↑ Tumor Promotion Studies with ↓ Survival and/or ↑ Tumor Promotion

16. 16 Study N1° Endpoint ESA Adverse Outcome Chemo BEST (breast)93912 mo OS↓ 12 mo OS 161 (Lymphoid)344∆ Hgb↓ OS PREPARE (breast)733RFS, OS↓ RFS*, ↓ OS* GOG 191 (cervical)114PFS↓ OS* RT ENHANCE (H/N)351LR PFS↓ LR PFS, ↓ OS DAHANCA (H/N)522LRC↓ LRC, ↓ OS* No Chemo or RT CAN-20 (NSCLC)70QOL↓ OS 103 (Heterogenous)989Transfusion↓ OS *=trend

17. 17OutlineBackground –Regulatory History –Benefits vs Risks –Adverse Findings in Oncology Trials Updates since 2007 ODAC –Adverse Findings in 2 Additional Trials –New FDA Analyses –FDA Actions Risk Evaluation and Mitigation Strategies (REMS)

18. 18 Hazard Ratios 1.0 0.9 0.80.7 1.1 1.2 1.3 Favors ControlFavors ESA

19. 19 May Feb Jun Jul Aug SepOct NovDec Jan ODAC 2007 PREPARE/ GOG-191 Results CSR/Data Submitted Labeling Updates initiated 2007-2008

20. 20 ODAC 2004 Darbepoetin PREPARE (Breast) Epoetin Other Amgen Studies ODAC 2007 PREPARE Neoadjuvant Breast

21. 21 PREPARE Neoadjuvant Breast Post Marketing Commitment study as of March 2006 March 2006 FDA letter→Sponsor –“To obtain and submit a final study report, including the primary data and analyses, of the... PREPARE [study]... the final study report will be submitted to FDA by 11/30/07.”

22. 22 PREPARE Neoadjuvant Breast Trial identified at ODAC 2004 Accrual June 2002-March 2005 E=epirubicin, C=cyclophosphamide, T=paclitaxel, M=MTX, F=5FU Breast Cancer ≥2 cm N=733 EC→T q 21 Dose Dense + Intense E→T→CMF Aranesp Transfusion Support SURGERYSURGERY 1° Objectives RFS, OS [Q21 vs Q14] 2° Objectives RFS, OS [control vs ESA] pCR, LN status, in breast recurrence, remission rate, QOL, # transfusions Target Hgb 12.5-13

23. 23 PREPARE Neoadjuvant Breast Results (N=733) Median f/u 3 yrs 3 yr RFS 3 yr Survival Endpoint 0.99, 1.79 1.3378%72% 1.42HR86%ESA 0.93, 2.18 90% 95% CI Control HR = ESA : Control

24. 24 PREPARE: RFS Control ESA

25. 25 PREPARE: OS Control ESA

26. 26 ODAC 2004 Darbepoetin Epoetin Other Amgen Studies GOG-191 (Cervical) ODAC 2007 GOG-191 Cervical

27. 27 GOG-191 Cervical Cervical CA (Stage IIB-IVA) N=114 Platinum+RT Epoetin Alfa Platinum+RT Transfusion Support 1° Endpoint: PFS Accrual August 2001-September 2003 Terminated early due to ↑ TVE (19% vs 9%) in ESA arm (Target accrual=460) Survival results not available in 2004 Target Hgb: 12-14 2° Endpoint: OS, LC LC: Local Control

28. 28 GOG-191 Cervical Results (N=114) 0.68, 2.42 0.58, 1.91 95% CI 1.2871%61% Survival (3 yr) Local+Distant Recurrence PFS (3 yr) Endpoint 27% 33% 1.06 HR 59% ESA 62% Control HR = ESA : Control

29. 29 Summary of Post ODAC 2007 Trials: ↓ Survival and/or ↑ Tumor Promotion PREPARE (neoadjuvant Breast Ca; N=733) –Trend to ↓ survival w/ESA (HR 1.42 [95% CI 0.93, 2.18]) –Trend to ↓ RFS w/ESA (HR 1.33 [95% CI 0.99, 1.79]) GOG 191 (Cervical Ca; N=114) –Trend to ↓ survival w/ESA (HR 1.28 [95% CI 0.68, 2.42])

30. 30OutlineBackground –Regulatory History –Benefits vs Risks –Adverse Findings in Oncology Trials Updates since 2007 ODAC –Adverse Findings in 2 Additional Trials –New FDA Analyses –FDA Actions Risk Evaluation and Mitigation Strategies (REMS)

31. 31 New FDA Analyses Achieved vs Targeted hemoglobin Current evidence by tumor histology

32. 32 Achieved vs Target Hgb Achieved Hgb ≠ Target Hgb

33. 33 Study Hgb Target Achieved Hgb Median (Q1, Q3) Chemo BEST (breast)12-1412.9 (12.2, 13.3) 161 (Lymphoid)13-15 ♂, 13-14 ♀11.0 (9.8, 12.1) PREPARE (breast)12.5-1313.1 (12.5, 13.7) GOG 191 (cervical)12-1412.7 (12.1, 13.3) RT ENHANCE (H/N)≥15 ♂, ≥14 ♀ 14.0 (13.0, 14.9) DAHANCA (H/N)14-15.5Not Available No Chemo or RT CAN-20 (NSCLC)12-14Insufficient Data 103 (Heterogeneous)12-1310.6 (9.4, 11.8)

34. 34 Study 103 “Anemia of Cancer”-Achieved vs Target Hgb Target Hgb Achieved Hgb, Aranesp

35. 35 ♂ Target Hgb ♂ ♀ Target Hgb ♀ Achieved Hgb, Aranesp Study 161 “Lymphoid Ca”-Achieved vs Target Hgb

36. 36 Achieved vs Target Hgb Both 161 & 103 trials –median achieved Hgb <12 g/dL –statistically significant ↓ OS Is the upper range for target Hgb of 12 g/dL safe? Boxed Warning The risks of ↓ OS and tumor progression have not been excluded when ESAs are dosed to target Hgb < 12 g/dL. To minimize these risks, as well as the risk of serious CV events/TVEs, use the lowest dose needed to avoid RBC transfusions.

37. 37 New FDA Analyses Achieved vs Targeted hemoglobin Current evidence by tumor histology

38. 38 Survival results in SCLC trials TumorStudy NSurvival HR (95% CI) SCLCN93-004224 1.17 (0.89, 1.55) 2001-0145596 0.94 (0.78, 1.12) 980297* 92 0.68 (0.41, 1.11) *=SCLC subset HR = ESA : Control

39. 39 Tumor Types: Tumor Types: Survival and Tumor Promotion TumorStudy N Adverse Effects NSCLCCAN-20 70↓ OS 980297*222OS HR 0.86 (0.62, 1.18) PFS OS 0.92 (0.68, 1.23) BreastBEST939↓ OS BRAVE463OS HR 1.09 (0.88, 1.35) PFS HR 1.09 (0.90, 1.31) PREPARE733↓ OS † ↓ RFS † Head/NeckENHANCE351↓ OS ↓ LR PFS DAHANCA522↓ OS † ↓ LRC Lymphoid161344↓ OS CervicalGOG-191114↓ OS † Mixed103989↓ OS *=NSCLC subset † =trend

40. 40 Other Tumor Types ESA Adverse Effects not determined Tumor Types –GI –GU –Ovarian –Uterine –Germ Cell –Leukemia –CNS –Renal Cell –Melanoma –Sarcoma

41. 41OutlineBackground –Regulatory History –Benefits vs Risks –Adverse Findings in Oncology Trials Updates since 2007 ODAC –Adverse Findings in 2 Additional Trials –New FDA Analyses –Post ODAC 2007 Actions Risk Evaluation and Mitigation Strategies (REMS)

42. 42 May Feb FDA- Sponsor Meetings Jun Jul Aug SepOct NovDec Jan ODAC 2007 Labeling Revision Request MedGuide submitted 145 study (SCLC) CSR/Data submitted Revised Label DHCP GOG-191 PREPARE Results, CSR/Data Submitted Labeling Updates initiated Additional Study CSR/Data submitted CMS NCD proposed GOG 191 PREPARE FDA Press Release 2007-2008

43. 43 CMS NCD ESA use is indicated when … –Hgb is < 10 g/dL prior to initiation/maintenance of ESA treatment –Hgb 1 g/dL Must submit most recent Hgb levels at least as often as prior to each ESA claim for reimbursement Stop ESA 8 wks post chemo NCD Dose adjustment guidelines

44. 44 Boxed Warning ESAs ↓ OS and/or time-to-tumor progression in clinical studies in breast, NSCLC, head & neck, lymphoid, & cervical Ca when dosed to target Hgb ≥ 12 g/dL. Risks of ↓ OS & tumor progression not excluded when ESAs are dosed to target Hgb < 12 g/dL. To minimize these risks, and the risk of serious CV events/TVEs, use the lowest dose needed to avoid RBC transfusions. Use only for treatment of anemia due to concomitant myelosuppressive chemo. Discontinue following the completion of a chemo course.

45. 45 Risks of ESAs 6 studies→ statistically significant evidence of ↑ tumor promotion and/or ↓ survival –BEST (Breast)* –ENHANCE (Head/Neck) –DAHANCA (Head/Neck) –161 (Lymphoid Ca)* –CAN-20 (NSCLC) –103 (Anemia of Cancer) (Many tumor types) 2 studies→ trends of ↑ tumor promotion and/or ↓ survival –PREPARE (neoadjuvant breast)* –GOG 191 (cervical cancer) † * = pts receiving chemo † †=pts receiving chemoRT

46. 46 Analyses presented by … Treatment Type –chemo-induced anemia vs RT vs no anticancer Rx Tumor Type Achieved or target Hgb Examples of ↑ Risk present across these factors Is there an oncology setting where ESAs do not have ↑ risk?

47. 47 Summary Treatment Type ↑ Risk present in –chemo-induced anemia (4 studies) –RT (2 studies) –No anticancer Rx (2 studies)

48. 48 Summary Tumor types SCLC –3 trials without survival difference Results in SCLC unlikely to be applicable to other tumor types No data in numerous tumor types

49. 49 Tumor Type # studies with ↓ OS and/or ↑ tumor promotion Head/Neck2 Breast 1 (Stg IV) 1 (Stg IV) 1* (neoadj) 1* (neoadj) NSCLC1 Lymphoid1 Cervical 1* 1* Heterogeneous1 Summary Tumor types *=trend

50. 50 Summary Achieved vs Target Hgb No adequately designed studies have been completed with target Hgb < 12 2 studies (161 and 103) where the achieved median Hgb < 12 showed ↓ OS Safety of target Hgb < 12 is not established

51. 51Conclusions ESAs=supportive care agents→establishing safety is necessary Efficacy of ESAs: ↓ RBC transfusions 8 post-approval studies: ↓ OS, ↓ locoregional control/RFS Numerous studies: ↑ TVE risk ESAs do NOT ↑ survival, and may ↑ tumor growth Reconsideration of risk:benefit ratio of ESAs Results from adequately designed ongoing or proposed studies will not be available for several years

52. 52OutlineBackground –Regulatory History –Benefits vs Risks –Adverse findings in oncology trials Updates since 2007 ODAC –Adverse findings in 2 additional trials –New FDA Analyses –FDA Actions Risk Evaluation and Mitigation Strategies (REMS)

53. 53 Risk Evaluation and Mitigation Strategies (REMS) Risk Evaluation → strategies to further characterize risks –Meta-analysis of completed trials –Assessment of individual studies Risk Mitigation → strategies that apply to current use

54. 54 Risk Evaluation Meta-Analysis Meta-analysis is problematic to definitively rule out risks of ESAs No studies have demonstrated superior OS or PFS for an ESA-containing arm

55. 55 Risk Evaluation Meta-Analysis Can obscure safety signals from individual studies Results depend on the studies included –Earlier meta-analyses suggested statistical significance on OS favoring ESAs –Later meta-analyses suggest statistical significance on OS favoring controls Issues on appropriate allocation of alpha Heterogeneous trials w/ variable quality, variable lengths of follow up, variable target Hgb, and heterogeneous tumor types

56. 56 Risk Evaluation Individual Studies ODAC 2004 Recommendations on optimal trial design Studies satisfying these recommendations

57. 57 ODAC 2004 Recommendations Double Blind, Placebo-Controlled Trials Preferred Primary Endpoint: Survival Adequately powered trials to detect survival differences Routine Assessment of Tumor Progression Homogeneous Tumor Type Assessment of TVEs → prospectively defined endpoint

58. 58 Risk Evaluation Individual Studies Studies, meeting ODAC 2004 recs, designed to detect & exclude an upper limit of risk –EPO-ANE-3010 (Stg 4 breast cancer) Poor accrual: 236/1000 pts accrued since March 2006 –N93-004 (SCLC) Prematurely terminated 7/01 for slow accrual w/224 pts –2007-0782 (advanced breast, lung, colorectal cancer) Proposed since ODAC 2007, not initiated Studies, meeting ODAC 2004 recs, designed to detect a superior outcome w/ ESAs –2001-0145 (SCLC) Finished accrual 7/06 w/596 pts

59. 59 Data submitted to FDA by Sponsors 12/20/07-3/5/08 Clinical Study Reports received on 18 studies –35,642 pages total Datasets received on 30 studies None of these 30 studies are specifically designed to detect and exclude increased risks of death

60. 60 Data submitted to FDA by Sponsors 12/20/07-3/5/08 FDA is aware that some of these studies do not report statistically significant ↑ risk of tumor promotion and/or ↓ survival Absence of evidence of ↑ risk is not evidence of absence

61. 61 Risk Mitigation proposals Risk Evaluation → strategies to further characterize risks –Meta-analysis of completed trials –Assessment of individual studies Risk Mitigation → strategies that apply to current use

62. 62 Amgen Risk Mitigation Plan Physician Education –Literature dissemination –DHCP letters –FAQ handout on ESAs, NCD, ODAC –Support for CME Pt advocacy group communication Medication Guide* Assessment of risk communication to pts/ providers Labeling changes *=active negotiations occurring b/t FDA & Sponsor

63. 63 FDA Risk Mitigation Labeling changes Removal of the indication for chemotherapy-induced anemia?

64. 64 FDA Risk Mitigation Strategies Possible Labeling changes If indication for chemotherapy induced anemia remains … –Limit to CIA in pts w/SCLC? “ESA is indicated for treatment of CIA in pts w/SCLC receiving myelosuppressive chemotherapy”

65. 65 FDA Risk Mitigation Strategies Possible Labeling changes If indication for chemotherapy induced anemia remains … –Limit to CIA in pts w/locally advanced or metastatic cancer? “ESA is indicated for treatment of CIA in pts w/locally advanced or metastatic cancer receiving myelosuppressive chemotherapy”

66. 66 FDA Risk Mitigation Strategies Possible Labeling changes If indication for chemotherapy induced anemia remains … –State not indicated for neoadjuvant and/or adjuvant? “ ESA is indicated for treatment of CIA in pts w/locally advanced or metastatic cancer receiving myelosuppressive chemotherapy. ESA is not indicated for use in pts receiving neoadjuvant and/or adjuvant chemo”

67. 67 FDA Risk Mitigation Strategies Possible Labeling changes If indication for chemotherapy induced anemia remains … –State not indicated for breast and/or head/neck? 2 studies with adverse findings in Breast Ca 2 studies with adverse findings in Head/Neck Ca “ ESA is indicated for treatment of CIA in certain pts with cancer receiving myelosuppressive chemotherapy. ESA is not indicated for use in pts with breast or head/neck cancer.”

68. 68 FDA Risk Mitigation Strategies Possible Labeling changes If indication for chemotherapy induced anemia remains … –Based on currently available data, should labeling specify the hemoglobin at which ESA should be initiated?

69. 69 FDA Risk Mitigation Required Informed Consent Restricted Distribution system –Thalidomide (STEPS) –Lenalidomide (RevAssist) –Isotretinoin (iPLEDGE)

70. 70