1
r
Pharmaceuticals
Epoetin beta in the
Treatment of Anemia in
Cancer Patients
Oncologic Drugs
Advisory Committee Meeting
...
r
Pharmaceuticals
2
Purpose of Presentation
• Review data from study MF4449* and
other studies regarding epoetin beta in
t...
r
Pharmaceuticals
3
Background on NeoRecormon
(epoetin beta)
• Recombinant human erythropoietin
• Well-established benefit...
r
Pharmaceuticals
4
Agenda of Presentation
• Review of study MF4449
– Primary study results
– Additional analyses
• Review...
r
Pharmaceuticals
5
Overview of Study MF4449
Study Objective
• Investigate whether the efficacy of radiotherapy
can be imp...
r
Pharmaceuticals
6
MF4449: Study Design
Patients with
HEAD AND NECK CANCER
Hb <13 g/dL (M)
or <12 g/dL (F)
Epoetin beta
3...
r
Pharmaceuticals
7
MF4449: Population
Characteristics• Smoking Status
– 53% smokers in placebo vs. 66% in
epoetin beta gr...
r
Pharmaceuticals
8
Study month
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
Probability
Ep...
r
Pharmaceuticals
9
MF4449 Further Analyses
• Secondary and other prospectively planned
analyses show:
– Lack of robustnes...
r
Pharmaceuticals
10
Study month
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
Probability
E...
r
Pharmaceuticals
11
Subgroup Analysis
3 4
Total
Stratum 1
Stratum 2
Stratum 3
Oral Cavity
Oropharynx
Hypopharynx
Larynx
T...
r
Pharmaceuticals
12
MF4449: PFS by Stratum
Stratum 1
Progression-free survival
Stratum 2
Progression-free survival
Study ...
r
Pharmaceuticals
13
MF4449: PFS by Tumor Site
(ITT)
Epoetin beta
Placebo
Study month
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
...
r
Pharmaceuticals
14
MF4449: Treatment Stratum and
Resection Margin Status of
Hypopharynx Subgroup
Placebo Epoetin
n=43 n=...
r
Pharmaceuticals
15
Summary of Non-cancer
Related Adverse Events
Body system/adverse event Placebo
n = 171 No. (%)
Epoeti...
r
Pharmaceuticals
16
MF4449 Thromboembolic
Events
Placebo
N=171
No. (%)
Epoetin beta
N=180
No. (%)
Patients with thromboem...
r
Pharmaceuticals
17
MF4449: Summary
• Heterogeneity of treatment effect across various
subgroups
– e.g. stratum, baseline...
18
r
Pharmaceuticals
Analyses of Data from
Other Studies: Meta-
Analysis
r
Pharmaceuticals
19
Epoetin beta: Overview of
Meta-analysis
Methods
• Pooled results from 9 controlled clinical trials
• ...
r
Pharmaceuticals
20
Meta-analysis: Tumor
Progression
3 4
MF4249
MF4250
MF4252
MF4253
MF4266
MF4313
MF4321
MF4421
MF4467
S...
r
Pharmaceuticals
21
Meta-analysis: Survival
3 4
MF4249
MF4250
MF4252
MF4253
MF4266
MF4313
MF4321
MF4421
MF4467
Solid
Hema...
r
Pharmaceuticals
22
Meta-analysis:
Thromboembolic Events
Body System Control
n = 609
No. (%)
Epoetin beta
n = 800
No. (%)...
r
Pharmaceuticals
23
Meta-analysis: Summary
• No evidence of increased tumor progression
in patients treated with epoetin ...
24
r
Pharmaceuticals
Analyses of Data from Other
Studies: Long-term Survival
in Study MF4467
r
Pharmaceuticals
25
MF4467: Overview
• Double-blind, placebo-controlled study of
epoetin beta in patients with lymphoid
m...
r
Pharmaceuticals
26
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...
r
Pharmaceuticals
27
Conclusion
• MF4449 study results are inconsistent with
other epoetin beta studies in oncology
• Most...
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PPT - ENHANCE Investigators Meeting

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PPT - ENHANCE Investigators Meeting

  1. 1. 1 r Pharmaceuticals 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. 2. r Pharmaceuticals 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: 1255–60
  3. 3. r Pharmaceuticals 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. 4. r Pharmaceuticals 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. 5. r Pharmaceuticals 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. 6. r Pharmaceuticals 6 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
  7. 7. r Pharmaceuticals 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. 8. r Pharmaceuticals 8 Study month 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 Probability Epoetin beta Placebo MF4449 Results: PFS ITT population
  9. 9. r Pharmaceuticals 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. 10. r Pharmaceuticals 10 Study month 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 Probability Epoetin beta Placebo 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 0 0 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 0 0 6 12 18 24 30 36 42 48 54 60 66 ITT population RCP population PP population
  11. 11. r Pharmaceuticals 11 Subgroup Analysis 3 4 Total Stratum 1 Stratum 2 Stratum 3 Oral Cavity Oropharynx Hypopharynx Larynx TNM – Stage I, II, III TNM – Stage III TNM – Stage IV Age < 60 yrs Age ≥ 60 yrs Male Female Smoker Non-smoker Baseline Hb < 11 g/dL Baseline Hb ≥ 11g/dL Category Subgroup 0.2 0.4 0.6 1 2 56 10 20 N Risk ratio 1.33 Better with epoetin beta Better with placebo Stratum Location Staging Age Gender Smoking Status HGB 351 196 77 78 79 146 83 80 93 83 258 208 143 303 48 209 141 86 264 1.02 2.74 1.97 1.02 1.24 2.86 0.90 0.78 0.73 1.48 1.69 0.93 1.19 2.75 1.07 1.59 0.84 1.48
  12. 12. r Pharmaceuticals 12 MF4449: PFS by Stratum Stratum 1 Progression-free survival Stratum 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 0 0 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 0 0 6 12 18 24 30 36 42 48 54 60 66 Epoetin beta Placebo
  13. 13. r Pharmaceuticals 13 MF4449: PFS by Tumor Site (ITT) Epoetin beta Placebo Study month 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 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 0 0 6 12 18 24 30 36 42 48 54 60 66 Hypopharynx only
  14. 14. r Pharmaceuticals 14 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%)
  15. 15. r Pharmaceuticals 15 Summary of Non-cancer Related Adverse Events Body 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)
  16. 16. r Pharmaceuticals 16 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%)
  17. 17. r Pharmaceuticals 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. 18. 18 r Pharmaceuticals Analyses of Data from Other Studies: Meta- Analysis
  19. 19. r Pharmaceuticals 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
  20. 20. r Pharmaceuticals 20 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 5 Risk ratio 0.79 1.07 0.72 1.43 0.55 0.36 0.69 0.83 0.97 0.84 Better with epoetin beta Better with placebo
  21. 21. r Pharmaceuticals 21 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 5 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 with epoetin beta Better with placebo
  22. 22. r Pharmaceuticals 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. 23. r Pharmaceuticals 23 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
  24. 24. 24 r Pharmaceuticals Analyses of Data from Other Studies: Long-term Survival in Study MF4467
  25. 25. r Pharmaceuticals 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 (p=0.0012) • Overall survival update performed on previously enrolled patients – 170 patients in the epoetin beta group – 173 patients in the placebo group
  26. 26. r Pharmaceuticals 26 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 0.0 0 10 20 30 40 50 60 70 80 90 100110120130140150160170180 Survival Weeks from treatment start Studyend Placebo Epoetin beta
  27. 27. r Pharmaceuticals 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

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