Update on the Safety of Erythropoietin Products in Patients With Cancer

1
Update on the Safety of Erythropoietin Products
in Patients With Cancer

• Peter Bowers, MD
• Senior DirectorClinical Team Leader
• Johnson JohnsonPharmaceutical Research
  Development

2
Todays Agenda

• Evaluation of Studies Dr. Peter Bowers
• Supportive Anemia Care
• Beyond Correction of Anemia
• Future Clinical Data Dr. Martine George
• Conclusions Dr. Martine George

3
Supportive Anemia Care StudiesAnalysis

• Combined analysis from all completed, randomized,
  double-blind trials of anemic patients (n
  1,976 10 trials)
• Mortality hazard ratios
• Tumor response and disease progression where data
  available (5 of 10 studies)
• Thrombotic vascular event (TVE) frequency
• Considerations for this analysis
• Variations in design and patient heterogeneity
• Studies primarily evaluated transfusion reduction
  over 12 to 24 weeks

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Supportive Anemia Care StudiesNo Survival Effect
Seen in Combined Analysis
Mortality, n/N () Mortality, n/N ()
Placebo Epoetin alfa
13/59 (22.0) 13/65 (20)
9/76 (12) 10/81 (12)
9/65 (14) 8/67 (12)
6/79 (8) 16/142 (11)
1/12 (8) 1/33 (3)
2/80 (3) 6/164 (4)
7/76 (9) 1/69 (1)
3/65 (5) 9/135 (7)
22/124 (18) 41/251 (16)
26/165 (16) 31/168 (19)

Favors Epoetin alfa
Favorsplacebo
Tumor type/study Hazardratio
Mixed (non-chemo) 0.89
Mixed (non-cisplatin) 1.08
Mixed (cisplatin) 0.86
CLL (J89-040) 1.68
CLL (P-174) 0.42
Ovarian (EPO-INT-1) 1.58
MM (EPO-INT-2) 0.15
Mixed (EPO-INT-3) 1.56
Mixed (EPO-INT-10) 0.81
Mixed (PR98-27-008) 1.17
OVERALL 0.99
(0.76, 1.28)
0.1
1
10
Test for heterogeneity, P .66
HR (95 CI) log scale
5
Supportive Anemia Care StudiesSimilar Tumor
Response/Disease Progression
ResponseDisease progression Patients, Patients,
Tumor type/study N ResponseDisease progression Placebo Epoetin alfa
Ovarian (EPO-INT-1) 246 CR/PR 72 68
Disease progression 15 16
MM (EPO-INT-2) 145 CR/PR 26 29
Disease progression 21 22
Mixed (EPO-INT-3) 201 CR/PR 54 48
Disease progression 20 20
Mixed (EPO-INT-10) 375 CR/PR 32 45
Disease progression 33 24
Mixed (PR98-27-008) 344 CR/PR 19 16
Disease progression
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Supportive Anemia Care Studies Conclusion
Favorable Benefit/Risk Profile

• Established benefits include transfusion
  reduction and reduction in debilitating symptoms
  of anemia
• No adverse survival signal or indication of
  adverse impact on tumor response ordisease
  progression

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Todays Agenda

• Evaluation of Studies Dr. Peter Bowers
• Supportive Anemia Care
• Beyond Correction of Anemia
• Preclinical Background
• EPO-INT-76
• Other Studies
• Future Clinical Data Dr. Martine George
• Conclusions

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Studies Beyond the Correction of Anemia
Preclinical Experience and Rationale
16

• Tumor cell lines (gt 25) did not proliferate in
  presence of EPO including lines EPO-R
• Systemic administration did not increase tumor
  volume in several in vivo models
• Erythropoietin products with chemotherapy or
  radiotherapy delay tumor growth in vivo
• Despite extensive investigations, inconsistent
  reports of proliferation seen with EPO
  concentrations 5- to 100-fold greater than
  achieved clinically

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Studies Beyond Correction of Anemia EPO-INT-76
(Metastatic Breast Cancer)

• Key design elementslarge trial, simple design
• EPREX QW or placebo continued for 12 mo
  regardless of chemotherapy changes or disease
  progression
• Initiate at 13 g/dL, target hemoglobin 12 to 14
  g/dL
• Primary endpoint 12-mo survival
• Design limitations
• Objective measures of tumor response and disease
  progression not specified (timing/method)
• Study drug treatment discontinued at
  recommendation of DSMB, 88 completed or withdrawn

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Summary of Survival Over TimeEPO-INT-76
25
12-mo mortality N n () Censored P
value Placebo 470 115 (24) 92 .012 Epoetin
alfa 469 148 (30) 81
12-mohazard ratio (95 CI) 1.37 (1.07, 1.74)
Time, mo
At-risk pts
Placebo
Epoetin
470 453 419 348 168 79 33 7 0 0
469 426 390 320 154 74 39 11 3 0
Vertical line represents end of double-blind
phase at 12 mo. Based on Kaplan-Meier estimate.
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Studies Beyond Correction of Anemia Factors
Considered in Analyses EPO-INT-76

• Extensive analysis to understand differences
• Additional data collection from source documents
• Retrospective blinded chart review
• Some imbalances noted but did not explain
  difference
• Analyses provide hypotheses that might explain
  survival difference

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Studies Beyond Correction of Anemia
Investigator-attributed Causes of
DeathsEPO-INT-76
Table 6 BD
Patients, n Patients, n Patients, n
Placebon 470 Epoetin alfan 469 DifferenceEPO-placebo
Died within 4 mo, n () 16 (3) 41 (9) 25
Investigator attributed
Disease progression 13 28 15
Thrombotic vascular event 1 5 4
Chemotherapy toxicity 1 3 2
Missing/other 1 5 4
Retrospective chart review
Disease progression 10 21 11
Thrombotic vascular event 2 11 9
Chemotherapy toxicity 1 2 1
Missing/other 3 7 4
Intent-to-treat population.
13
25
Studies Beyond Correction of Anemia Time to
Disease Progression EPO-INT-76
P .71
N CR/PR, Hazard ratio (95 CI) Placebo
454 46 0.97 (.82, 1.14) Epoetin alfa 445 45
Time, mo
At-risk pts
Placebo
Epoetin
454 445 425 400 368 338 314 297 284 274 261 247 194
445 437 411 386 361 332 311 288 269 248 239 227 188
Intent-to-treat population
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Studies Beyond Correction of Anemia
ConclusionsEPO-INT-76

• Survival disadvantage observed in treatment
  group
• Reasons for outcome not well understood, despite
  extensive investigation and analysis of data
• Investigators attributed a greater number of
  deaths to disease progression in the epoetin
  alfa arm, yet, reported TTP and CR/PR are
  similar
• Other possible explanations for outcome merit
  consideration
• Excess mortality due to TVEs

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Todays Agenda

• Evaluation of Studies Dr. Peter Bowers
• Supportive Anemia Care
• Beyond Correction of Anemia
• Preclinical Background
• EPO-INT-76
• Other Studies
• Future Clinical Data Dr. Martine George
• Conclusions Dr. Martine George

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Studies Beyond Correction of Anemia Summary of
Design Features
Cancertherapy Hemoglobin, g/dL Hemoglobin, g/dL
Tumor type (study) Cancertherapy Initiate Target
Completed or in follow-up
MBC (EPO-INT-76) CT 13 12 - 14
SCLC (N93-004) CT 14.5 14 - 16
HN (EPO-GBR-7) RT 15 12.5 - 15
Cervical (AGO/NOGGO) CTRT 14 12.5 - 13.5
Discontinued
SCLC (EPO-CAN-15) CTRT 14 14 - 16
NSCLC (EPO-CAN-20) CT 12 12 - 14
HN (RTOG-99-03) RT (CT) 13.5 12 - 16
Cervical (GOG-0191) CTRT 12 13
Gastric, rectal (PR00-03-006) CTRT 15 14 - 15
Pre-amendment.
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Studies Beyond Correction of AnemiaAnalysis of
Mortality Outcomes
Mortality, n/N () Mortality, n/N ()
Tumor type (study) Control Epoetin alfa
Completed or in follow-up
MBC (EPO-INT-76) 115/470 (24) 148/469 (30)
SCLC (N93-004) 101/115 (88) 100/109 (92)
HN (EPO-GBR-7) 50/149 (34) 52/151 (34)
Cervical (AGO/NOGGO) 23/116 (20) 16/113 (14)
Discontinued
SCLC (EPO-CAN-15) 10/53 (19) 21/53 (40)
NSCLC (EPO-CAN-20) 20/31 (65) 25/31 (81)
HN (RTOG-99-03) 12/68 (18) 17/67 (25)
Cervical (GOG-0191) 9/55 (16) 8/58 (14)
Gastric, rectal (PR00-03-006) 1/31 (3) 0/28 (0)
Based on Kaplan-Meier estimates.
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Studies Beyond Correction of Anemia No Evidence
of Tumor Proliferation/Response
Tumor type (study) N Endpoint Control vs EPO
Completed or in follow-up
MBC (EPO-INT-76) 939 CRPR, 46 vs 45
SCLC (N93-004) 224 CRPR, 67 vs 72
HN (EPO-GBR-7) 109 2-yr local DFS, 85 vs 93
Cervical (AGO/NOGGO) 229 DFS (126 wk), 73 vs 83
Discontinued
SCLC (EPO-CAN-15) 106 Median TTP (days) 419 vs 467
NSCLC (EPO-CAN-20) 62
HN (RTOG-99-03) 117 1-yr local PFS, 65 vs 60
Cervical (GOG-0191) 113 Progression free, 82 vs 83
Gastric, rectal (PR00-03-006) 60
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Studies Beyond the Correction of
AnemiaClinically Relevant TVEs
Patients with TVEs, n/N () Patients with TVEs, n/N () Difference, EPO-control
Tumor type (study) Control Epoetin alfa Difference, EPO-control
SCLC (EPO-CAN-15) 2/52 (4) 16/52 (31) 27
Gastric, rectal (PR00-03-006) 2/31 (6) 6/28 (21) 15
Cervical (GOG-0191) 5/55 (9) 10/58 (17) 8
SCLC (N93-004) 11/115 (10) 12/109 (11) 1
MBC (EPO-INT-76) 25/456 (5) 36/448 (8) 3
HN (EPO-GBR-7) 2/149 (1) 4/133 (3) 2
NSCLC (EPO-CAN-20) 2/31 (6) 1/31 (3) 3
Cervical (AGO/NOGGO) 3/122 (2) 2/119 (2) 0
HN (RTOG-99-03) 0/68 (0) 1/67 (1) 1
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Supportive Anemia Care - Clinically Relevant TVEs
Consistent With Known Risks
Patients with TVEs, n/N () Patients with TVEs, n/N () Difference, EPO-placebo
Tumor type (study) Placebo Epoetin alfa Difference, EPO-placebo
Mixed (cisplatin) 8/65 (12) 6/67 (9) 3
MM (EPO-INT-2) 1/76 (1) 5/69 (7) 6
CLL (J89-040) 2/79 (3) 9/142 (6) 3
Mixed (EPO-INT-3) 1/65 (2) 8/135 (6) 4
Mixed (EPO-INT-10) 5/124 (4) 14/251 (6) 2
Mixed (PR98-27-008) 6/165 (4) 9/168 (5) 1
Mixed (non-cisplatin) 3/76 (4) 2/81 (2) 2
Ovarian (EPO-INT-1) 1/80 (1) 3/164 (2) 1
Mixed (non-chemo) 0/59 (0) 1/65 (2) 2
CLL (P-174) 0/12 (0) 0/33 (0) 0

• Overall odds ratio (95 CI) 1.55 (0.96, 2.50)

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Evaluation of Safety Conclusions

• In supportive anemia care, data and extensive
  clinical experience support favorable
  benefit/risk profile
• No signal of tumor proliferation
• In investigational studies beyond correction of
  anemia, adverse outcomes have been seen
• Signal in overall survival in some studies
• Lack of clear signal regarding tumor
  proliferation
• Increased incidence of TVEs in studies of
  epoetin alfa beyond correction of anemia
• Additional data being collected, new trial under
  discussion