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Continuing Reassessment of the Risks of Erythropoiesis-Stimulating Agents (ESAs) in Patients with Cancer

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. Credits. Chaohong Fan Patricia Keegan Mark Rothmann Yuan Li Shen

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Continuing Reassessment of the Risks of Erythropoiesis-Stimulating Agents (ESAs) in Patients with Cancer

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

  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. 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. ESAs for Chemotherapy-associated Anemia Epoetin alfa and beta have same amino acid sequence but differ in glycosylation

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

  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. 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. 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. 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. 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. Approval of Aranesp: 2002Study 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. 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. 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. 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. 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. Benefits of ESAs Procrit 1993 Approval Aranesp 2002 Approval

  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. Transfusion Medicine • RBC transfusion rarely given when Hgb >10 • Body can compensate for chronic anemia by: • ↑ DPG • shift of O2 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. RBC Transfusions Risks Procrit Approval Blajchman et al 2006

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

  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. 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. 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. 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. GBR-7 (H/N) RTOG 9903 (H/N) GER-22 (NSCLC) CAN-20 (NSCLC) CAN-17 (Breast) AGO (Cervical) BEST (Breast) Epoetin alfa Studies ODAC 2004 N93-004 (SCLC) EPO-ANE-3010 (Breast) Other Amgen Studies 2001-0145 (SCLC) PREPARE (Breast) ARA-03 (Breast) DAHANCA (H/N) GELA (NHL) ENHANCE (Head/Neck) Aranesp Studies Anemia of Cancer (103) Lymphoid Ca (161) Non-Myeloid (232)

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

  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. Studies w/Primary Data Submitted to FDA Epoetin alfa Studies BEST (Breast) ODAC 2004 N93-004 (SCLC) Other Studies Aranesp Studies

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

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

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

  35. Study N93-004 (SCLC) • 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. BEST(Breast) Epoetin alfa Studies BEST (Breast) ODAC 2004 Other Studies Aranesp Studies

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

  38. BEST (Breast) • 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. ENHANCE (Head/Neck)Henke et al Epoetin alfa Studies ODAC 2004 Other Studies ENHANCE(Head/Neck) Aranesp Studies

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

  41. ENHANCE (Head/Neck) Henke et al N=351, Intent to treat population Epoetin beta demonstrated a detrimental effect on all 3 endpoints LR PFS: Locoregional Progression Free Survival LRC: Locoregional control

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

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

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

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

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