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Epoetin beta in the Treatment of Anemia in
Cancer Patients
Oncologic Drugs
Advisory Committee Meeting
May 4, 2004
Presentation by Marty Huber, M.D.Vice President, Drug Safety
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Purpose of Presentation
• Review data from study MF4449* and other studies regarding epoetin beta in the treatment of cancer patients
*Henke M et al. Lancet 2003; 362: 1255–60
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Background on NeoRecormon (epoetin beta)• Recombinant human erythropoietin
• Well-established benefit risk profile
• More than 1 million patient years of experience
• Available outside U.S. since 1990
• Approved for patients with renal anemia as well as oncologic indications
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Agenda of Presentation
• Review of study MF4449– Primary study results– Additional analyses
• Review of meta-analysis of epoetin beta clinical trials
• Review of long term survival in randomized trial MF4467
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Overview of Study MF4449
Study Objective
• Investigate whether the efficacy of radiotherapy can be improved by correction of anemia with epoetin beta
Primary Endpoint
• Local Progression Free Survival (PFS)
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MF4449: Study Design
Patients with
HEAD AND NECK CANCER
Hb <13 g/dL (M) or <12 g/dL (F)
Epoetin beta 300 IU/kg sc tiw + RT
Placebo + RT
Follow-up
*Patients stratified by TNM (IV vs. III) & tumor resection status: Stratum 1: RT after clean margin tumor resection Stratum 2: RT after non-radical tumor resection Stratum 3: definitive RT alone
Radiotherapy (RT)2 wks
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MF4449: Population Characteristics• Smoking Status– 53% smokers in placebo vs. 66% in
epoetin beta group
• Relapse at baseline– 7.6% in placebo vs. 10% in epoetin beta
group
• TNM Status (Stage 4)– 72% on placebo vs. 75% on epoetin beta
group
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Study month
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 6 12 18 24 30 36 42 48 54 60 66
Probability
Epoetin betaPlacebo
MF4449 Results: PFSITT population
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MF4449 Further Analyses
• Secondary and other prospectively planned analyses show:– Lack of robustness of primary result
– Heterogeneity across important subgroups
• Outcome in contrast to known clinical experience with epoetin beta
• To understand these findings, additional analyses were performed
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Study month
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 6 12 18 24 30 36 42 48 54 60 66
Probability
Epoetin betaPlacebo
Planned Secondary Analyses
Progression free survival Probability
Study month
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 6 12 18 24 30 36 42 48 54 60 66
Study month
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 6 12 18 24 30 36 42 48 54 60 66
ITT population RCP population PP population
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Subgroup Analysis
3 4
Total
Stratum 1Stratum 2Stratum 3
Oral CavityOropharynx
HypopharynxLarynx
TNM – Stage I, II, IIITNM – Stage IIITNM – Stage IV
Age < 60 yrsAge 60 yrs
MaleFemale
SmokerNon-smoker
Baseline Hb < 11 g/dLBaseline Hb 11g/dL
Category Subgroup
0.2 0.4 0.6 1 2 56 10 20
N
Risk ratio
1.33
Better withepoetin beta
Better withplacebo
Stratum
Location
Staging
Age
Gender
Smoking Status
HGB
351
1967778
79146
8380
9383
258
208143
30348
209141
86264
1.022.74
1.97
1.02
1.242.86
0.90
0.78
0.731.48
1.690.93
1.192.75
1.07
1.59
0.841.48
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MF4449: PFS by StratumStratum 1
Progression-free survivalStratum 2
Progression-free survival
Study month
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 6 12 18 24 30 36 42 48 54 60 66
Study month
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 6 12 18 24 30 36 42 48 54 60 66
Epoetin betaPlacebo
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MF4449: PFS by Tumor Site (ITT)
Epoetin betaPlacebo
Study month
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 6 12 18 24 30 36 42 48 54 60 66
Location other than hypopharynx
Study month
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 6 12 18 24 30 36 42 48 54 60 66
Hypopharynx only
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MF4449: Treatment Stratum and Resection Margin Status of Hypopharynx Subgroup
Placebo Epoetin
n=43 n=40
Treatment Stratum
Stratum 1 (R0) 21 (49%) 18 (45%)
Stratum 2 (R1 + R2) 9 (21%) 4 (10%)
Stratum 3 (Rx only) 13 (30%) 18 (45%)
TNM
III 13 (30%) 6 (15%)
IV 30 (70%) 34 (85%)
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Summary of Non-cancer Related Adverse EventsBody system/adverse event Placebo
n = 171 No. (%) Epoetin beta
N = 180 No. (%)
All body systems 111 (65) 123 (68) General disorders 43 (25) 54 (30) Skin & subcutaneous tissue disorders 37 (22) 43 (24) Gastrointestinal disorders 34 (20) 37 (21) Infections & infestations 36 (21) 30 (17) Disorders of blood & the lymphatic system 13 (8) 23 (13) Respiratory, thoracic & mediastinal disorders 19 (11) 11 (6) Vascular disorders 9 (5) 19 (11) Injury & poisoning 6 (4) 7 (4) Neurological disorders 4 (2) 8 (4) Psychiatric disorders 7 (4) 5 (3) Hepato-biliary disorders 6 (4) 4 (2) Musculoskeletal, connective tissue & bone disorders
5 (3) 5 (3)
Disorders of the immune system 3 (2) 7 (4) Disorders of metabolism & nutrition 3 (2) 6 (3) Cardiac disorders 4 (2) 5 (3) Investigations 4 (2) 3 (2) Disorders of the ear & labyrinth 5 (3) 2 (1) Disorders of the eye 4 (2) 3 (2) Surgical & medical procedures 2 (1) 4 (2) Renal & urinary disorders 1 (<1) 3 (2) Endocrine disorders 1 (<1) 1 (<1)
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MF4449 Thromboembolic Events Placebo
N=171
No. (%)
Epoetin beta N=180
No. (%)
Patients with thromboembolic events 6 (3.5%) 10 (5.6%)
Intestinal ischemia 1 (0.6%) 0
Pulmonary embolism 1 (0.6%) 2 (1.1%)
Venous phlebitis 0 2 (1.1%)
Venous thrombosis 0 2 (1.1%)
Brain stem infarction 0 1 (0.6%)
Cerebrovascular accident 1 (0.6%) 1 (0.6%)
Angina 1 (0.6%) 1 (0.6%)
Necrosis 2 (1.2%) 1 (0.6%)
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MF4449: Summary• Heterogeneity of treatment effect across various
subgroups
– e.g. stratum, baseline Hb, age, gender, disease location
• Imbalances in important baseline characteristics
– Smoking for overall population
– Stage and resection status for patients with tumors in hypopharyngeal location
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Analyses of Data from Other Studies: Meta-
Analysis
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Epoetin beta: Overview of Meta-analysis
Methods
• Pooled results from 9 controlled clinical trials
• 1409 patients with solid organ or hematological tumors
Evaluations Performed
• Tumor progression
• Overall survival
• Thromboembolic events
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Meta-analysis: Tumor Progression
3 4
MF4249
MF4250
MF4252
MF4253
MF4266
MF4313
MF4321
MF4421
MF4467
Solid
Hematological
Other
Category
Total
Study
Tumor class
Subgroup
0.2 0.40.6 1 2 56 10 2030
N
1409
116
144
54
109
20
146
218
259
343
613
791
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Risk ratio
0.79
1.07
0.72
1.43
0.55
0.36
0.69
0.83
0.97
0.84
Better withepoetin beta
Better withplacebo
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Meta-analysis: Survival
3 4
MF4249
MF4250
MF4252
MF4253
MF4266
MF4313
MF4321
MF4421
MF4467
Solid
Hematological
Other
Category
Total
Study
Tumor class
Subgroup
0.2 0.40.6 1 2 56 10 2030
N
1409
116
144
54
109
20
146
218
259
343
613
791
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Risk ratio
0.97
1.01
0.93
1.02
3.39
0.59
0.37
0.61
1.02
1.29
1.04
Better withepoetin beta
Better withplacebo
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Meta-analysis: Thromboembolic Events
Body System Controln = 609No. (%)
Epoetin betan = 800No. (%)
All body systems
Total patients with at least one AE 27 (4) 49 (6)
Total number of AEs 29 53
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Meta-analysis: Summary
• No evidence of increased tumor progression in patients treated with epoetin beta (HR=0.79)
• No evidence of decreased overall survival (HR=0.97)
• Small increase in the incidence of thromboembolic events (6% on epoetin beta vs. 4% on placebo)– Similar rates when normalized for patient years
of observation
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Analyses of Data from Other Studies: Long-term Survival in Study MF4467
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MF4467: Overview
• Double-blind, placebo-controlled study of epoetin beta in patients with lymphoid malignancies
• Primary endpoint transfusion-free survival with outcome of 43% risk reduction (p=0.0012)
• Overall survival update performed on previously enrolled patients– 170 patients in the epoetin beta group
– 173 patients in the placebo group
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MF4467: Overall Survival- (ITT)
Censored patients marked by
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 10 20 30 40 50 60 70 80 90 100110120130140150160170180
Su
rviv
al
Weeks from treatment start
Stu
dy
end
Placebo
Epoetin beta
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Conclusion
• MF4449 study results are inconsistent with other epoetin beta studies in oncology
• Most likely explanation for the adverse outcomes observed in MF4449 are factors independent of epoetin beta
• Large majority of existing data shows that epoetin beta does not adversely affect tumor progression or survival in cancer patients