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ESAs in Oncology and Management of Risks

ESAs in Oncology and Management of Risks. Vinni Juneja, MD Division of Biologic Oncology Products. Oncologic Drugs Advisory Committee March 13, 2008. Review Team. Chaohong Fan Patricia Keegan Mark Rothmann Yuan Li Shen Kyung Lee Monica Hughes. Outline. Background Regulatory History

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ESAs in Oncology and Management of Risks

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

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

  3. Outline • Background • 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. ESAs for Chemotherapy-Induced Anemia (CIA) Epoetin alfa and beta have same amino acid sequence but differ in glycosylation

  5. Epoetin AZT Epoetin CRF Darbepoetin CRF Epoetin Pre-surgical 1997 1999 1993 1995 2005 1989 1991 2001 2003 2007 Epoetin Chemo induced Anemia (CIA) Darbepoetin Chemo induced Anemia (CIA) ODAC 2004 ODAC 2007

  6. Outline • Background • 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. 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. Benefits of ESAs Procrit 1993 Approval Aranesp 2002 Approval

  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. 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. 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. 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 chemoRT * = pts receiving chemo

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

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

  16. StudyN1° EndpointESA AdverseOutcome Chemo BEST (breast) 939 12 mo OS ↓ 12 mo OS 161 (Lymphoid) 344 ∆ Hgb ↓ OS PREPARE (breast) 733 RFS, OS ↓ RFS*, ↓ OS* GOG 191 (cervical) 114 PFS ↓ OS* RT ENHANCE (H/N) 351 LR PFS ↓ LR PFS, ↓ OS DAHANCA (H/N) 522 LRC ↓ LRC, ↓ OS* No Chemo or RT CAN-20 (NSCLC) 70 QOL ↓ OS 103 (Heterogenous) 989 Transfusion ↓ OS *=trend

  17. Outline • Background • 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. Hazard Ratios Favors ESA Favors Control 1.3 1.2 1.1 0.7 0.8 1.0 0.9

  19. 2007-2008 Sep Oct Jul Aug Jan May Jun Nov Dec Feb PREPARE/ GOG-191 Results CSR/Data Submitted Labeling Updates initiated ODAC 2007

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

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

  23. Endpoint ESA Control HR 95% CI 3 yr Survival 86% 90% 1.42 0.93, 2.18 3 yr RFS 72% 78% 1.33 0.99, 1.79 PREPARE Neoadjuvant Breast • Results (N=733) • Median f/u 3 yrs HR = ESA : Control

  24. PREPARE: RFS Control ESA

  25. PREPARE: OS Control ESA

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

  27. GOG-191 Cervical Platinum+RT Epoetin Alfa 1° Endpoint: PFS Cervical CA (Stage IIB-IVA) N=114 2° Endpoint: OS, LC Platinum+RT Transfusion Support Target Hgb: 12-14 • 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 LC: Local Control

  28. Endpoint ESA Control HR 95% CI PFS (3 yr) 59% 62% 1.06 0.58, 1.91 Survival (3 yr) 61% 71% 1.28 0.68, 2.42 Local+Distant Recurrence 27% 33% GOG-191 Cervical Results (N=114) HR = ESA : Control

  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. Outline • Background • 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. New FDA Analyses • Achieved vs Targeted hemoglobin • Current evidence by tumor histology

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

  33. StudyHgb TargetAchieved HgbMedian (Q1, Q3) Chemo BEST (breast) 12-14 12.9 (12.2, 13.3) 161 (Lymphoid) 13-15 ♂, 13-14 ♀11.0 (9.8, 12.1) PREPARE (breast) 12.5-13 13.1 (12.5, 13.7) GOG 191 (cervical) 12-14 12.7 (12.1, 13.3) RT ENHANCE (H/N) ≥15 ♂, ≥14 ♀ 14.0 (13.0, 14.9) DAHANCA (H/N) 14-15.5 Not Available No Chemo or RT CAN-20 (NSCLC) 12-14 Insufficient Data 103 (Heterogeneous) 12-13 10.6 (9.4, 11.8)

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

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

  36. 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. Achieved vs Target Hgb

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

  38. Survival results in SCLC trials Tumor Study N Survival HR (95% CI) SCLC N93-004 224 1.17 (0.89, 1.55) 2001-0145 596 0.94 (0.78, 1.12) 980297* 92 0.68 (0.41, 1.11) *=SCLC subset HR = ESA : Control

  39. Tumor Types: Survival and Tumor Promotion Tumor Study N Adverse Effects NSCLC CAN-20 70 ↓ OS 980297* 222 OS HR 0.86 (0.62, 1.18) PFS OS 0.92 (0.68, 1.23) Breast BEST 939 ↓ OS BRAVE 463 OS HR 1.09 (0.88, 1.35) PFS HR 1.09 (0.90, 1.31) PREPARE 733 ↓ OS† ↓ RFS† Head/Neck ENHANCE 351 ↓ OS ↓ LR PFS DAHANCA 522 ↓ OS† ↓ LRC Lymphoid 161 344 ↓ OS Cervical GOG-191 114 ↓ OS† Mixed 103 989 ↓ OS *=NSCLC subset †=trend

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

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

  43. CMS NCD • ESA use is indicated when … • Hgb is < 10 g/dL prior to initiation/maintenance of ESA treatment • Hgb <10 g/dL four weeks after initiation of ESA AND rise in Hgb is > 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. 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. 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 chemoRT * = pts receiving chemo

  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. SummaryTreatment Type • ↑ Risk present in • chemo-induced anemia (4 studies) • RT (2 studies) • No anticancer Rx (2 studies)

  48. SummaryTumor 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. SummaryTumor types *=trend

  50. SummaryAchieved 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

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