Epoetin beta in the Treatment of Anemia in Cancer Patients

1
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

2
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 125560

3
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

4
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

5
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)

6
MF4449 Study Design
Epoetin beta 300 IU/kg sc tiw RT
Patients with HEAD AND NECK CANCER Hb lt13 g/dL
(M) or lt12 g/dL (F)
Follow-up
Placebo RT
Radiotherapy (RT)
2 wks
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
7
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

8
MF4449 Results PFSITT population
9
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

10
Planned Secondary Analyses
ITT population
RCP population
PP population
Probability
Progression free survival
Probability
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Epoetin beta Placebo
0 6 12 18 24 30 36 42 48 54 60 66
0 6 12 18 24 30 36 42 48 54 60 66
0 6 12 18 24 30 36 42 48 54 60 66
Study month
Study month
Study month
11
Subgroup Analysis
12
MF4449 PFS by Stratum
Stratum 1
Stratum 2
Progression-free survival
Progression-free survival
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
0 6 12 18 24 30 36 42 48 54 60 66
0 6 12 18 24 30 36 42 48 54 60 66
Study month
Study month
13
MF4449 PFS by Tumor Site (ITT)
14
MF4449 Treatment Stratum and Resection Margin
Status of Hypopharynx Subgroup
Placebo Epoetin
n43 n40
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)
15
Summary of Non-cancer Related Adverse Events
16
MF4449 Thromboembolic Events
17
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

18
Analyses of Data from Other Studies Meta-Analysis
19
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
21
Meta-analysis Survival
Better withepoetin beta
Better withplacebo
N 1409
Category Total
Subgroup
0.97
Study
1.01
MF4249 MF4250 MF4252 MF4253 MF4266 MF4313 MF4321 M
F4421 MF4467
116 144 54 109 20 146 218 259 343
1.02
3.39
0.59
0.37
0.61
1.02
1.29
0.93
Solid Hematological Other
Tumor class
613 791 5
1.04
3
4
0.2
0.4
0.6
1
2
5
6
10
20
30
Risk ratio
22
Meta-analysis Thromboembolic Events
Body System Control n 609 No. () Epoetin beta n 800 No. ()
All body systems
Total patients with at least one AE 27 (4) 49 (6)
Total number of AEs 29 53
23
Meta-analysis Summary

• No evidence of increased tumor progression in
  patients treated with epoetin beta (HR0.79)
• No evidence of decreased overall survival
  (HR0.97)
• 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

24
Analyses of Data from Other Studies Long-term
Survival in Study MF4467
25
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 (p0.0012)
• 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)
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Survival
Placebo
Study end
Epoetin beta
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140
150 160 170 180
Weeks from treatment start
Censored patients marked by
27
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