1. 1 Continuing Reassessment of the Risks of Erythropoiesis- Stimulating Agents (ESAs) in Patients with Cancer Vinni Juneja, MD Division of Biologic Oncology Products Oncologic Drugs Advisory Committee May 10, 2007

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

3. 3 Outline Introduction Regulatory History Benefits vs Risks of ESAs Safety signals leading to ODAC May 2004 ODAC 2004 Data from Recent Trials since ODAC 2004 “Meta Analyses” considerations

4. 4 Continuing assessment of ESA risks vs benefits Risks of ESAs in Cancer Patients Decreased Survival Tumor Promotion –Decreased locoregional control –Decreased progression free survival? Increased thrombovascular events (TVEs)

5. 5 ESAs for Chemotherapy-associated Anemia 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

6. 6 Class Effect of ESAs FDA considers all ESAs as members of the same product class Risks of ESAs apply to all products

7. 7 Outline Introduction Regulatory History Benefits vs Risks of ESAs Safety signals leading to ODAC May 2004 ODAC 2004 Data from Recent Trials since ODAC 2004 “Meta Analyses” considerations

8. 8 Procrit/Epogen (epoetin alfa) Epoetin alfa products licensed in the U.S. are manufactured by Amgen –EPOGEN distributed by Amgen → Dialysis pts –PROCRIT distributed by Ortho Biotech (subsidiary of J&J) → all other indications EPOGEN and PROCRIT labeling is identical

9. 9 Procrit/Epogen (epoetin alfa) Non-cancer Approvals –1988-anemia of Chronic Renal Failure –1991-AZT related anemia in AIDS –1995-reduction of perioperative transfusion Cancer Approvals –1993-Anemia associated with chemo –June 2004-Weekly dosing in Anemia with chemo Revisions to Label –May 2004-Effects on RR, TTP, and OS in solid tumors

10. 10 Approval of Procrit/Epogen: 1993 Approved for cancer patients on chemotherapy based on reduction in % pts transfused Infectious risks of blood transfusion in 1993 higher than in 2007 Pooled data from 6 randomized, double blind, placebo controlled trials in a total of 131 patients, with different malignancies was basis for approval. Theoretical potential for tumor promotion based on EPO receptor expression in tumors/vasculature unresolved Post Marketing Commitment to address impact of Procrit on tumor response and survival

11. 11 Aranesp (darbepoetin alfa) First approval in 2001 for anemia of CRF –Subsequent approvals in cancer patients: July 2002- Anemia associated with cancer chemotherapy, weekly dosing March 2006- Every 3 week dosing for anemia associated with cancer chemotherapy

12. 12 Approval of Aranesp: 2002 Study 980297 Approved for cancer patients on chemotherapy based on reduction in % pts transfused Approval based on data from Study 980297, a randomized, double blind, placebo controlled trial (N=314) Patient Population: Lung CA (NSCLC + SCLC) No difference in PFS or OS –Limitation: Study not sized to detect small but clinically meaningful differences in PFS and OS.

13. 13 Current Label The dose of ESAs should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion and not to exceed 12 g/dL

14. 14 Current Label ESAs are indicated for treatment of anemia in pts w/non-myeloid malignancies where anemia is due to effect of concomitantly administered chemo ESAs are indicated to decrease need for transfusions in patients who will be receiving concomitant chemo for a minimum of 2 months ESAs are not indicated for the treatment of anemia in cancer patients due to other factors such as iron/folate deficiencies, hemolysis, or GI bleeding, which should be managed appropriately

15. 15 Outline Introduction Regulatory History Benefits vs Risks of ESAs Safety signals leading to ODAC May 2004 ODAC 2004 Data from Recent Trials since ODAC 2004 “Meta Analyses” considerations

16. 16 Benefits of ESAs Clinical benefits of ESAs were demonstrated in anemic pts receiving chemo who were able to avoid RBC transfusions & their concomitant risks Use of ESAs reduced proportion of pts receiving RBC transfusions & their concomitant risks

17. 17 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

18. 18 Current Practices for ESAs vs RBC Transfusion ESAs –Initiated when pt anemic –Reimbursement for ESAs begin when Hgb<12.0 RBC Transfusion –Recommended when Hgb 7-8, or as clinically necessary Because benefit of ESA is avoidance of transfusion, should ESAs be initiated at or titrated to achieve a lower Hgb?

19. 19 Transfusion Medicine RBC transfusion rarely given when Hgb >10 Body can compensate for chronic anemia by: –↑ DPG shift of O 2 dissociation curve→ ↑ release of O2 to body tissues –↑ peripheral vasodilation –↑ cardiac output Usually does not increase until Hgb < 7 Symptoms due to chronic anemia may not appear until Hgb < 7-8

20. 20 RBC Transfusions Risks Blajchman et al 2006 Procrit Approval

21. 21 Current RBC Transfusion Risks (per RBC unit) 1 in 10 1 in 1 HIV HCV 1 in 100 1 in 1000 1 in 10,000 1 in 100,000 1 in 1,000,000 1 in 10 million 1 in 100 million Bacterial Infection Fatal Bacteremia HBV Mistransfusion TRALI TA-GVHD

22. 22 Effects of ESAs Improved QOL, fatigue, and other symptoms associated with anemia NOT established in properly conducted, randomized, double-blind, placebo- controlled trials. Improved survival or improved tumor control NOT established

23. 23 Risks of ESAs Increased thrombovascular events (TVEs) –Increased Morbidity, Potential Increased Mortality Decreased Survival Increased Tumor Promotion –Decreased Locoregional Control –Decreased Progression-Free Survival?

24. 24 Risks of ESAs 5 studies w/evidence of ↑ tumor promotion or ↓ survival with excessive target Hgb –BEST (Breast)* –ENHANCE (Head/Neck) –DAHANCA (Head/Neck) –161 (Lymphoid Ca)* –CAN-20 (NSCLC) 1 study w/evidence of ↓ survival with target Hgb consistent w/prior label (<13 g/dL) –103 (Anemia of Cancer) (Many tumor types) * = pts receiving chemo

25. 25 Outline Introduction Regulatory History Benefits vs Risks of ESAs Safety signals leading to ODAC May 2004 ODAC 2004 Data from Recent Trials since ODAC 2004 “Meta Analyses” considerations

26. 26 BEST (Breast) N93-004 (SCLC) ENHANCE (Head/Neck) ODAC 2004 Epoetin alfa Studies EPO-ANE-3010 (Breast) Aranesp Studies 2001-0145 (SCLC) PREPARE (Breast) ARA-03 (Breast) DAHANCA (H/N) GELA (NHL) 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) Non-Myeloid (232)

27. 27 Trial Design Considerations Superiority trial purpose: show improved outcome (i.e. improved OS, PFS, or RR) for ESA –Hypothesis: ↑ Hgb=improved outcome –Failure to show superior survival with ESAs does NOT exclude the possibility of ↓ survival. Non Inferiority trial purpose: exclude ↑ risk –2 trials w/ESAs in cancer pts were specifically designed to detect unacceptable risk –Non-inferiority design preferable to exclude ↑ risk

28. 28 N93-004 (SCLC) ODAC 2004 Epoetin alfa Studies EPO-ANE-3010 (Breast) Aranesp Studies ESA Non Inferiority Studies ESA Non Inferiority Studies Other Studies

29. 29 Primary Data vs Summary Result Primary Data: database from clinical trial with efficacy data (i.e. OS, RR), safety data (i.e. TVE), & all data captured on CRFs submitted to FDA –FDA independently analyzes database/verifies result Summary Result: descriptive data analyzed by investigators submitted to FDA –Examples: journal abstract/ publication/ report –FDA cannot perform independent analysis & cannot verify results –FDA cannot detect flaws in data

30. 30 BEST (Breast) N93-004 (SCLC) ODAC 2004 Epoetin alfa Studies Aranesp Studies Studies w/Primary Data Submitted to FDA Studies w/Primary Data Submitted to FDA Other Studies Anemia of Cancer (103) Lymphoid Ca (161) Non-Myeloid Ca (232) 2001-0145 (SCLC)

31. 31 BEST (Breast) N93-004 (SCLC) ODAC 2004 Epoetin alfa Studies Aranesp Studies Data Leading to ODAC 2004 Other Studies ENHANCE (Head/Neck)

32. 32 ODAC May 2004 ODAC convened after FDA received 1° data from N93- 004, and ↑ mortality in BEST + ENHANCE NSCLC trial (CAN-20) terminated early due to ↑ TVEs in other trials & ↑ mortality in BEST + ENHANCE –Unplanned analysis suggested ↑ mortality in ESA arm Head & Neck cancer trial (RTOG 9903) terminated early due to publication of ENHANCE trial in 2003 –Unplanned analysis demonstrated non-significant trend to ↓ loco- regional control & ↑ mortality in ESA arm 4 other randomized controlled trials terminated early due to ↑ TVEs

33. 33 N93-004 (SCLC) ODAC 2004 Epoetin alfa Studies Aranesp Studies N93-004 (SCLC) Other Studies

34. 34 Study N93-004 (SCLC) PMC for 1993 approval of Procrit Non-inferiority study on ORR Intended to enroll 400 patients Study terminated for poor accrual at 224 patients Limited/Extensive Stage SCLC N=224 Cisplatin/Etoposide/RT Procrit Cisplatin/Etoposide/RT Placebo 1° Endpoint: ORR 2° Endpoint: OS ORR=CR+PR Target Hgb 14-16

35. 35 Study N93-004 (SCLC) EndpointProcritPlacebo Primary ORR (CR+PR) 72.5%67% Secondary Median Survival 10.5 mo 10.4 mo ORR was determined w/o central review of images 17% of patients had missing tumor response data Confirming ORR by repeat imaging was not required ORR not a sensitive detection method for tumor promotion

36. 36 BEST (Breast) ODAC 2004 Epoetin alfa Studies Aranesp Studies BEST (Breast) Other Studies

37. 37 BEST (Breast) Superiority Trial on 12 month OS Stratified by site of metastases Stage 4 Breast Cancer N=939 Chemo Eprex Chemo Placebo 1° Endpoint: 12 mo OS 2° Endpoint: ORR, TTP TTP: Time to Progression ORR=CR+PR Target Hgb 12-14

38. 38 BEST (Breast) EndpointEprexPlacebo p value Primary 12 mo OS 70%76%0.0117 Secondary ORR (CR+PR) 45%46% Increased Mortality & Shorter TTP evident in 1st 4 months Inadequate tumor assessments at baseline  26% of placebo subjects; 29% of Eprex subjects Incomplete tumor assessments throughout study  28% of all patients No reported set schedule for objective tumor assessment Incomplete assessment of all known metastatic lesions

39. 39 ODAC 2004 Epoetin alfa Studies Aranesp Studies ENHANCE (Head/Neck) Henke et al Other Studies ENHANCE (Head/Neck)

40. 40 ENHANCE (Head/Neck) Henke et al Head/Neck Cancer (T3, T4, or node +) N=351 Adjuvant or Definitive RT Epoetin Beta Adjuvant or Definitive RT Placebo 1° Endpoint: LR PFS 2° Endpoint: OS, LRC Superiority Trial on LR PFS Stratified by resection status LR PFS: Locoregional Progression Free Survival LRC: Locoregional control Target Hgb 14-15

41. 41 ENHANCE (Head/Neck) Henke et al Endpoint Hazard Ratio (ESA v Control) 95% CI P value Primary LR PFS 1.62 1.22 to 2.14 0.0008 SecondaryLRC1.69 1.16 to 2.47 0.007 OS1.39 1.05 to 1.84 0.02 Epoetin beta demonstrated a detrimental effect on all 3 endpoints N=351, Intent to treat population LR PFS: Locoregional Progression Free Survival LRC: Locoregional control

42. 42 Summary of Pre ODAC 2004 Trials N93-004 (SCLC): met its non-inferiority endpoint, ORR BEST (Stg IV Breast Ca): ↓ survival for pts on ESA arm ENHANCE (Head/Neck Ca): ↓ survival & ↓ locoregional control for pts on ESA arm

43. 43 Outline Introduction Regulatory History Benefits vs Risks of ESAs Safety signals leading to ODAC May 2004 ODAC 2004 Data from Recent Trials since ODAC 2004 “Meta Analyses” considerations

44. 44 BEST (Breast) N93-004 (SCLC) ODAC 2004 Epoetin alfa Studies Aranesp Studies ODAC 2004 Recommendations Other Studies ENHANCE (Head/Neck)

45. 45 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 Tumor biopsies to assess for EPO receptors was optional Studies conducted outside of US would be generalizable to the US cancer population Assessment of TVEs should be prospectively defined endpoint. –Case report forms should be designed to capture clinically symptomatic TVEs. –TVEs should be assessed at prespecified intervals.

46. 46 Outline Introduction Regulatory History Benefits vs Risks of ESAs Safety signals leading to ODAC May 2004 ODAC 2004 Data from Recent Trials since ODAC 2004 “Meta Analyses” considerations

47. 47 ODAC 2004 Epoetin alfa Studies EPO-ANE-3010 (Breast) Aranesp Studies 2001-0145 (SCLC) PREPARE (Breast) ARA-03 (Breast) DAHANCA (H/N) GELA (NHL) GBR-7 (H/N) RTOG 9903 (H/N) GER-22 (NSCLC) CAN-20 (NSCLC) CAN-17 (Breast) AGO (Cervical) Other Amgen Studies ODAC 2004: Trials to Assess Risk

48. 48 ODAC 2004: Trials to Assess Risk Have any ongoing or proposed trials presented at ODAC 2004 or since ODAC 2004 fully met ODAC’s recommendations? NO 2 trials have come close –Amgen SCLC (2001-0145) –J&J Breast Ca (EPO-ANE-3010) Other trial designs have not met several of ODAC recommendations

49. 49 ODAC 2004 Epoetin alfa Studies EPO-ANE-3010 (Breast) Aranesp Studies “Adequately” Designed Trials Other Studies 2001-0145 (SCLC)

50. 50 Amgen SCLC (2001-0145) Extensive Stage SCLC N=596 Platinum/Etoposide Aranesp Platinum/Etoposide Placebo 1° Endpoints: Survival ∆Hgb Target Hgb 13-14 Superiority Trial on co-primary endpoints, OS & ∆Hgb Pts on 1 st line chemo Trial design presented at ODAC 2004 Accrual from December 2002 to July 2006

51. 51 Amgen SCLC (2001-0145) Results (summary result April 2007) –Failed to demonstrate superior OS –OS- HR 0.93, 95% CI 0.78, 1.11 –↑ TVE for Aranesp arm (12.3% vs 7.4%) Limitation –SCLC results unlikely to be generalizable to other tumor types

52. 52 J&J Breast Cancer (EPO-ANE-3010) Stage IV Breast Ca N=108 of 1000 Chemotherapy Eprex Chemotherapy Transfusion Support 1° Endpoint: PFS Target Hgb 12 Non-inferiority trial on PFS Stage IV Breast Ca receiving a variety of 1 st line metastatic chemo regimens Design presented at ODAC May 2004 Final protocol submitted to FDA in December 2004 Accrual began March 2006, and is currently ongoing 2° Endpoint: ORR, TTP, OS, TVEs, Response Duration

53. 53 J&J Breast Cancer (EPO-ANE-3010) Limitations –Target accrual 2000 pts (ODAC 04)→1000 pts now 2000 pts: 80% power to exclude a 15% reduction in PFS 1000 pts: 90% power to exclude a 25% reduction in PFS –Heterogeneity of chemotherapy –Open Label Accrual has been slow –Final protocol submitted December 2004 –Enrollment began March 2006, and 108 pts of target 1000 accrued as of March 2007

54. 54 BEST (Breast) ODAC 2004 Epoetin alfa Studies Aranesp Studies Studies with ↓ Survival or ↑ Tumor Promotion Studies with ↓ Survival or ↑ Tumor Promotion Other Studies ENHANCE (Head/Neck) CAN-20 (NSCLC) DAHANCA (H/N) Anemia of Cancer (103) Lymphoid Ca (161)

55. 55 Anemia of Cancer (2001-0103) Non Myeloid Ca (not on chemo or myelosuppressive RT) N=989 Aranesp Placebo 1° Endpoint: % transfusion 2° Endpoint: OS Pts could not receive myelosuppressive Rx Stratified by tumor/Rx (CLL/indolent NHL, hormonal/antibody Rx, vs all other pts) Accrual April 2004 – May 2006 Summary of results December 2006 Primary Data submitted to FDA March 2007 Target Hgb: 12-13

56. 56 Anemia of Cancer (2001-0103) Results (FDA review of primary data) –Shorter OS (HR 1.30; [95% CI: 1.07, 1.57], p=0.008) in Aranesp arm –No statistically significant reduction in % patients receiving RBC transfusions in Aranesp arm –Increased TVEs, 3.1% vs 1.3%, in Aranesp arm Indication in Rx of “Anemia of Cancer” (i.e. for cancer pts not on chemo) existed only outside US Following results of Anemia of Cancer study, J&J removed the “Anemia of Cancer” indication

57. 57 Lymphoid Ca (2000-0161) Lymphoid Ca (MM, NHL, WM, HD, CLL) N=344 Chemo Aranesp Chemo Placebo 1° Endpoint: Hgb response Stratified by Tumor Type and Prior chemo Accrual November 2000 – November 2001 Results presented by Amgen ODAC 2004 Updated Primary Data submitted April 2007 Target Hgb: 13- 15 M, 13-14 F

58. 58 Lymphoid Ca (2000-0161) Results (FDA review of updated primary data) –Shorter OS (HR 1.37 [95% CI 1.02, 1.83], p=0.037) in Aranesp arm –Increased TVE Grade 3-5 (3.4% vs 0.6%) in Aranesp arm

59. 59 DAHANCA Head/Neck Head/Neck Cancer (T1-T4) N=522 Definitive RT Aranesp Definitive RT Transfusion Support 1° Endpoint: LRC 2° Endpoint: OS, LC, DSS Superiority trial for LRC Trial presented at ODAC 2004 Accrual July 2002 - October 2006 Terminated early based on interim analysis LRC: Locoregional control LC: Local Control DSS: Disease Specific Survival Target Hgb 14.0-15.5 Study SE 2002-9001

60. 60 DAHANCA Head/Neck Result summary provided by DAHANCA –Locoregional Control: worse in Aranesp arm (p=0.01) –OS: shorter survival in Aranesp arm (p=0.08) Study SE 2002-9001

61. 61 EPO-CAN-20 NSCLC NSCLC, palliative care (Stage IIIA/IIIB/IV or recurrent) N=70 Eprex Transfusion Support 1° Endpoint: QOL Superiority trial on QOL Trial presented at ODAC 2004 Accrual February 2001-November 2003 Terminated early; Unplanned analysis = ↑ mortality in ESA arm (Target accrual=300) Target Hgb: 12-14

62. 62 EPO-CAN-20 NSCLC Results (JCO March 2007) –Shorter survival in Eprex arm (HR 1.84; [95% CI, 1.01, 3.35], p= 0.04) –TVE incidence not reported

63. 63 Summary of Post ODAC 2004 Trials with ↓ Survival or ↑ Tumor Promotion Anemia of Cancer (variety of tumors) –↓ OS with ESA (HR 1.30; [95% CI: 1.07, 1.57]) Lymphoid Ca (variety of Lymphoid Ca) –↓ OS with ESA (HR 1.37 [95% CI 1.02, 1.83]) DAHANCA (Head/Neck Ca) –↓ Locoregional control with ESA (p=0.01)* –Trend to ↓ OS with ESA (p=0.08)* EPO-CAN-20 (NSCLC) –↓ OS with ESA (HR 1.84; [95% CI, 1.01, 3.35]) *=nominal p value

64. 64 Studies without Reported Safety Signal 9 completed/ongoing studies: no safety signals but have significant design limitations 1/9 studies: Primary data submitted to FDA 1/9 studies: Primary data submitted but data not analyzable 7/9 studies: Summary results only

65. 65 ODAC 2004 Epoetin alfa Studies Aranesp Studies Other Studies GBR-7 (H/N) RTOG 9903 (H/N) GER-22 (NSCLC) CAN-17 (Breast) AGO (Cervical) PREPARE (Breast) ARA-03 (Breast) GELA (NHL) 232 (Non-Myeloid Ca) Studies without a Reported Safety Signal that have Significant Limitations

66. 66Limitations Limitations to detect safety signals –Inadequate frequency/modality of radiological assessments to evaluate tumor recurrence –Inadequate radiological assessments to rule out distant metastases at baseline/during surveillance –No systematic TVE assessment –Open Label –Target Hgb not consistent w/current recommendations –Off Label ESA dosage & dose adjustments Primary data not submitted to FDA on trials that have finished enrollment (except 232)

67. 67 Specific Limitations Heterogeneous tumor type –232 Survival data limited to 5 months follow up –232 Use of ESA in control group –GELA DLBCL

68. 68 Ongoing Studies 3 of 12 studies ongoing/proposed at ODAC 2004 as capable of addressing safety concerns of ESAs continue to accrue pts Only 1 of these studies, EPO-ANE-3010 is “adequately” designed, but has significant difficulties accruing pts

69. 69 ODAC 2004 Epoetin alfa Studies EPO-ANE-3010 (Breast) Aranesp Studies Studies with ongoing pt accrual Other Studies ARA-03 (Breast) GELA (NHL)

70. 70 Outline Introduction Regulatory History Benefits vs Risks of ESAs Safety signals leading to ODAC May 2004 ODAC 2004 Data from Recent Trials since ODAC 2004 “Meta Analyses” considerations

71. 71 Reasons against performing 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 Cumulative meta-analyses and retrospective meta-analyses have issues on appropriate allocation of alpha Heterogeneous trials w/ variable quality, variable lengths of follow up, variable target Hgb, and heterogeneous tumor types

72. 72 Collective Evidence 6 studies have demonstrated inferior OS, LR PFS, or locoregional control for the ESA-containing arm No studies that FDA has knowledge of have demonstrated superior OS or PFS for an ESA-containing arm

73. 73 FDA Forest Plot vs Amgen/J&J “Meta Analysis” FDA Forest Plot Amgen/J&J “Meta Analysis” All Studies had Adequate follow up for OS Some studies had adequate follow up for OS Included all ESAs Included either epoetin or Aranesp Only Phase 3 trials Phase 1-3 trials Hazard Ratio Odds Ratio (Amgen) Hazard Ratio (J&J)

74. 74 Summary of Hazards Ratios for Overall Survival 1.00 Worse for Control Worse for ESA

75. 75 ↑ Risks in patients without cancer CHOIR –1432 anemic CRF pts not on dialysis assigned to ESA targeting Hgb 13.5 vs 11.3 –Increased CV events (Death, MI, CVA, CHF hospitalization) for Hgb 13.5 group (HR 1.3, 95% CI:1.0, 1.7, p=0.03). Normal Hematocrit Study –1265 hemodialysis pts w/clinically evident CV history (Ischemic heart dz or CHF) randomized to ESA targeting Hct 42 ± 3% vs 30 ± 3% –Increased mortality for Hct 42 group (35% v 29%)

76. 76 ↑ TVE in pts without cancer SPINE –681 patients undergoing major elective spinal surgery randomized to peri- operative ESA vs transfusion support –Primary endpoint: incidence of DVT –↑ DVTs in patients receiving ESA (4.7% vs. 2.1%)

77. 77 Recent ESA-specific Triggers for FDA Actions November 2006 – CHOIR December 2006 – DAHANCA (Head/Neck) January 2007 - Anemia of Cancer February 2007 - EPO CAN-20 (NSCLC), SPINE April 2007 - Lymphoid Ca

78. 78 FDA Actions FDA communication activities include: –Black Box Warning –Revised prescribing information –Public Health Advisories –Press Releases –Healthcare professional sheets –Medwatch Safety Alerts –E-mailed burst communications to healthcare professional societies

79. 79 Black Box Warning Use lowest dose of ESAs that will gradually increase Hgb concentration to lowest level sufficient to avoid RBC transfusion ESAs ↑ risk for death & for serious CV events when administered to target Hgb > 12 In pts w/cancer: use of ESAs –↓ TTP w/advanced H&N Ca on RT when target Hgb>12, ↓ OS –↑ deaths attributed to dz progression @ 4 months w/ Stg 4 Breast Ca on chemo when target Hgb>12 –↑ risk of death when target Hgb> 12 w/ active malignant disease receiving neither chemo nor RT Surgery pts: ↑ incidence of DVT documented in pts on ESAs who were not receiving anticoagulation. Antithrombotic prophylaxis should be strongly considered when ESAs are used to ↓ allogeneic RBC transfusions

80. 80Summary 5 studies w/evidence of ↑ tumor promotion or ↓ survival with excessive target Hgb –BEST (Breast)* –ENHANCE (Head/Neck) –DAHANCA (Head/Neck) –161 (Lymphoid Ca)* –CAN-20 (NSCLC) 1 study w/evidence of ↓ survival with target Hgb consistent w/prior label (<13 g/dL) –103 (Anemia of Cancer) (Many tumor types) * = pts receiving chemo

81. 81 Summary A difference in OS was not observed in 2 trials in SCLC –Results in SCLC unlikely to be applicable to other tumor types –Both trials used ESAs to target Hgb > current or previous recommendations

82. 82Summary EPO-ANE-3010 (Breast Ca) –Close to ideal in design –Uses US-labeled epoetin dose –Proposed at ODAC 2004 as capable of addressing tumor promotion risks –The only trial that adequately addresses TVE risk –Trial not accruing 3 studies continue to accrue pts –Only EPO-ANE-3010 designed close to ideal

83. 83Summary 12 studies presented at ODAC 2004 by J&J and Amgen as capable of addressing ESA tumor promotion risks. –10 of these 12 studies are not adequately designed with respect to ODAC 04’s recommendations Primary data from 5 completed epoetin studies with no reported safety signals not submitted to FDA. –These studies finished accrual as long as 6 years ago

84. 84Conclusions Efficacy of ESAs: ↓ RBC transfusions Post-approval studies: ↓ OS, ↓ locoregional control, ↑ TVE risk ESAs do NOT ↑ survival, and may ↑ tumor growth Since 1993: ↓ RBC transfusion infectious risk vs ↑ ESA risk Reconsideration of risk:benefit ratio of ESAs No completed or ongoing trial has addressed safety issues of ESAs in cancer pts w/chemo associated anemia using currently approved dosing regimens in a generalizable tumor type