# Presentation: 665618

## 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**

## 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**

## 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**

## 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**

## 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)**

## 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**

## 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**

## MF4449 Results: PFSITT population

**MF4449 Results: PFS****ITT population**

## 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**

## Planned Secondary Analyses

**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**

## Subgroup Analysis

## 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**

## MF4449: PFS by Tumor Site (ITT)

## 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%) |

## Summary of Non-cancer Related Adverse Events

## MF4449 Thromboembolic Events

## 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**

## Analyses of Data from Other Studies: Meta-Analysis

## 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**

## Meta-analysis: Tumor Progression

## 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**

**0.4**

**0.6**

**1**

**2**

**5**

**6**

**10**

**20**

**30**

**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**

## 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 |

## 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**

## Analyses of Data from Other Studies: Long-term Survival in Study MF4467

## 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**

## 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****	****100****	****110****	****120****	****130****	****140****	****150****	****160****	****170****	****180**

**Survival**

**Weeks from treatment start**

**Study end**

**Placebo**

**Epoetin beta**

## 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  **