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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

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 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

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Weeks from treatment start

Stu

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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